Early Dx of Lupus

Primary Care Clinicians Play an Important Role in the Early Diagnosis of Lupus 

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Lupus is an autoimmune inflammatory disease that can lead to significant disability and organ damage. Recognizing the early signs and symptoms of this complex condition can help primary care clinicians play a key role in early diagnosis and referral while they provide ongoing and supportive care.

In 1851, doctors coined the name “systemic lupus erythematosus” (SLE) for a condition that was frequently accompanied by a facial rash that looked like the bite of a lupus, or a wolf.[1] (While there are four categories of lupus—SLE, cutaneous (discoid) lupus, drug-induced lupus, and neonatal lupus—this article uses the term “lupus” to refer to SLE.) Known as the “great masquerader” among illnesses, lupus is an autoimmune disease characterized by acute and chronic inflammation. Because the antibodies and accompanying inflammation can affect tissues and organs anywhere in the body, lupus has the potential to produce a wide range of symptoms and clinical manifestations. The causes of lupus are unknown but are believed to be linked to a combination of genetic, environmental, and hormonal factors.


Adapted from Ref 4

The course of lupus varies and is characterized by alternating periods of flares and remissions. Some people with lupus experience only mild symptoms and have few complications, while others experience frequent flares that lead to moderate or severe complications and, ultimately, organ damage. Complicating the management of lupus is its unpredictability. No two cases of lupus are exactly alike and the course of the disease is likely to take many different twists and turns even among individual patients.

According to the Lupus Foundation of America, more than 1.5 million Americans have lupus: more than AIDS, cerebral palsy, multiple sclerosis, sickle-cell anemia, or cystic fibrosis.[2] Of the more than 16,000 Americans who will develop lupus this year, more than 90% will be women of childbearing age. Of note is that the disease is two to three times more prevalent in African American and Asian women and that it is considered a polygenetic disorder[3]—a condition associated with multiple genes in combination with lifestyle and environmental factors. These disorders often cluster in families, but do not have a clear-cut pattern of inheritance.

The Importance of Early Diagnosis

Because primary care clinicians are in a position to investigate early suspicions that a patient has lupus, they play a key role in diagnosis and management—often in conjunction with a rheumatologist. Early diagnosis of lupus is critical because organ damage in patients with lupus progresses over time,[4] leading to a 5-fold increased risk of death compared with the general population.[5] One study has shown that within seven years of diagnosis, 61% of patients developed clinically detectable organ damage, with neuropsychiatric, musculoskeletal, and renal organ systems the most commonly affected.[6]

Early symptoms of lupus are typically vague, nonspecific, and easily confused with other pathological and functional disorders. Symptoms may be transient or prolonged, and individual symptoms often appear independently of the others. Common complaints may range from fatigue and a general achiness to a facial rash or alopecia. Less commonly, patients may complain of gastrointestinal, cardiac, or pulmonary symptoms.[7]

More than half the patients with lupus develop a characteristic red, flat, butterfly-shaped rash over the bridge of their nose.[8] The rash is painless and nonpruritic, and is usually precipitated or exacerbated by exposure to sunlight. This photosensitivity is often accompanied by worsening of inflammation throughout the body, which causes a flare of the symptoms.

If a female patient presents with a vague set of complaints similar to those presented in Box 1,[7] the possibility of lupus should be explored. A careful medical history that includes questions about sun exposure, use of certain drugs, viral disease, stress, or a family history of lupus or other autoimmune disease can provide a vital diagnostic clue. Unfortunately, lupus has no single diagnostic marker; instead, it is identified through a combination of clinical and laboratory criteria established by the American Academy of Rheumatology.[9] (See Practice Management at AACR for Criteria.)

The criteria state that if four of the 11 criteria develop at one time or individually during any period of observation, the patient can be classified as having lupus.[9] In real world practice, however, lupus may be present in a patient with less than four of these symptoms.

No single laboratory test can definitely prove or disprove lupus. Initial screening usually includes a complete blood count (CBC), liver and kidney screening panels, antinuclear antibodies (ANA) and an antiphospholipid antibody test, urinalysis, blood chemistries, and an erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)—both of which are nonspecific tests to detect generalized inflammation.[10] Levels are generally increased in patients with active lupus and decline when corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) are used to reduce inflammation. However, they do not directly reflect disease activity.

One of the hallmarks of lupus is the formation of high ANA titers. ANA testing has become standard in assessing for lupus because ANA titers are significantly positive in almost all patients with active lupus, usually at values 1/160 or higher. However, there are many other illnesses and conditions associated with a positive ANA, including rheumatoid arthritis, Sjögren’s syndrome, scleroderma, as well as autoimmune thyroid and liver disease.[11] Infectious diseases such as mononucleosis, subacute bacterial endocarditis, hepatitis, and malaria can cause an elevated ANA, as can medications such as procainamide, hydralazine, phenytoin, isoniazid, or quinidine. A positive ANA test can also occur in families with no history of lupus. Therefore, a positive ANA should be considered only one of several lupus indicators and should not take the place of an in-depth history and physical examination.[11] While anti-double-stranded DNA (dsDNA) antibodies and anti-Sm antibodies are both highly specific (75%-100%) for lupus, unfortunately the sensitivity is much lower at 75% and 25% respectively.[12,13]

Management

Because lupus has no cure, the overall goal of treatment is to decrease the activity of the autoimmune response. In theory, this should decrease inflammation, which in turn should prevent further damage. Unfortunately, however, the successful management of lupus is rarely this straightforward.

Although there is no way to predict how individual patients with lupus will respond to a particular management program, there is general consensus that lifestyle modifications benefit everyone. A conservative regimen of physical and emotional rest, protection from direct sunlight, a healthful diet, prompt treatment of infections, and avoidance of aggravating factors are the mainstays of lupus therapy.[14]

Medication Choices

Several different classes of medication are available to control symptoms and prevent organ damage, and a rheumatologist is likely to make the initial decision about which medication is most appropriate. Patients with mild disease or symptoms will likely be prescribed an NSAID to ease joint pain or an NSAID in combination with an antimalarial such as hydroxychloriquone (Plaquenil®). During World War II, doctors discovered that antimalarials could successfully treat the joint pain of rheumatoid arthritis; subsequent research has shown them to be effective in controlling the arthritis, skin rashes, mouth ulcers, fatigue, and fever associated with lupus.[15] Data suggest that initiating hydroxychloriquone early in treatment before any organ damage has begun may prevent the development of organ damage,[16] and that low blood concentrations of hydroxychloriquone are associated with an increased risk of flare.[17] Moreover, hydroxychloriquone is associated with improved survival. Hydroxychloriquone is less likely to be prescribed for a patient who presents with severe lupus already accompanied by organ damage.

The skin rash characteristic of lupus is usually treated with a mild cortisone cream. Patients with more severe disease may be advised to start corticosteroids, such as prednisone, which mildly suppress the immune system and reduce inflammation. However, these drugs produce a number of side effects, including infection, fractures, and osteoporosis.[18,19] In the case of a lupus flare, the goal should be to give the smallest and shortest dose of steroids required to calm the flare.

Immunosuppressants—including mycophenolate mofetil (CellCept®), azathioprine (Imuran®), the monoclonal antibody rituximab (Rituxan®), and the alkylating agent cyclophosphamide (Cytoxan®)—may all be used off label in serious, systemic cases of lupus in which major organs, especially the kidneys, are affected or in which there is severe muscle inflammation or intractable arthritis.[20] These drugs, which slow down the autoimmune response, also have a steroid-sparing effect. Therefore, they can be used to reduce the need for corticosteroids and spare the patient from undesirable side effects of corticosteroid therapy.[21] However, immunosuppressants also have serious side effects including bone marrow suppression, infertility, infection, and an increased risk of cancer. 

In 2011, the U.S. Food and Drug Administration (FDA) approved the first new drug for lupus in more than 50 years.[22] Benlysta® (belimumab) is a human monoclonal antibody that targets specific immune cells, rather than the blanket approach of other therapies which suppresses the entire immune system. In clinical trials, patients treated with Benlysta alongside standard therapies experienced less disease activity than those who received a placebo and standard of care medicines. Results suggested, but did not definitively establish, that some patients had a reduced likelihood of severe flares, and some reduced their steroid doses. Benlysta is given as an injection; the first three doses are given two weeks apart with follow-up injections given every four weeks. Live vaccines such as measles, mumps, rubella (MMR), or varicella zoster should not be given for 30 days before or concurrently with Benlysta as clinical safety has not been established. The annual treatment cost is estimated to be $35,000 per year. Benlysta is approved in the United States, Canada, and Europe and is being tested for safety and efficacy in other autoimmune diseases.

Of note is that clinical trials of Benlysta demonstrated a lack of efficacy in African Americans—who have a far higher incidence of lupus—due perhaps to a paucity of African Americans in the trials to draw a definitive conclusion. Therefore, the FDA has required the manufacturer to do another trial that will assess the safety and effectiveness of the drug in people of African descent. The drug is not recommended for patients whose disease is severely damaging their kidneys or central nervous systems because it was not tested on those patients.

Partners in Care

The diagnosis and management of lupus is a collaborative process, especially in patients with mild lupus. Because of the subtleties related to the diagnosis, you should consider referring all patients with suspected lupus to a rheumatologist, who can confirm the diagnosis and assess disease activity and severity. The rheumatologist will also establish a treatment plan and amend it as the patient’s condition changes. Rheumatologists and primary care clinicians can—and should—work together to manage patients with lupus.[23]

As the healthcare provider who sees the patient most often, you’re an important gatekeeper. Lupus is an inflammatory process than can damage many different tissues, organs, and organ systems, including blood vessels, bones, joints, and the kidney. People with lupus also take medications that may weaken the body’s response to infection or increase bone loss. Therefore, in addition to managing their lupus, you also need to provide preventive care. That may mean prescribing a baby aspirin and positive lifestyle changes to help prevent coronary artery disease, recommending interventions that increase calcium and vitamin D levels, or encouraging patients to get flu shots and to practice good sun protection. It was once thought that immunization might trigger lupus flares, but this is no longer believed to be true. Live vaccines, however, should not be administered to immunosuppressed patients. Patients should also be counseled to avoid certain medications such as the sulfonamide antibiotics and penicillin (but not the semi-synthetic penicillins).

People with lupus—like those with other chronic diseases—often experience psychological and emotional swings. These can be related to outward changes, such as skin alterations caused by the disease. Or they might be related to personal or financial concerns about the future. Young women may want to know whether it is safe to become pregnant. It is—if pregnancy is planned for times when the disease is under control and the patient is taking medications that are considered safe during pregnancy.[24] Box 2 provides some hints to help patients cope with the physical and psychological aspects of lupus.

The challenge of caring for a patient with lupus draws on all the resources, knowledge, and strengths that you have to offer. Careful listening to your patients’ concerns, a flexible plan of care, and a multidisciplinary approach will provide patients with consistent supportive care and the reassurance that their needs are being met.

Patient Education Materials

Lupus: A patient care guide for nurses and other healthcare professionals. This comprehensive monograph features 20 patient education handouts covering topics ranging from preventing lupus flares to side effects of medications.

Jill Shuman, MS, ELS
Updated July 3, 2012
Published on May 3, 2010

 

References

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  3. Grennan DM, Parfitt A, Manolios N, et al. Family and twin studies in systemic lupus erythematosus. Dis Markers. 1997;13(2):93-98.
  4. Gladman DD, Goldsmith CH, Urowitz MB, et al. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index for systemic lupus erythematosus international comparison. J Rheumatol. 2000;27(2):373-376.
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  11. Pisetsky DS, Buyon JP, Manzi S. Systemic lupus erythematosus. In: Klippel JH, Crofford LJ, Stone JH, Weyand CM. Primer on the Rheumatic Diseases. 12th ed. Arthritis Foundation, Atlanta, GA: Arthritis Foundation; 2001:329-346.
  12. Smeenk R, Brinkman K, van den Brink H, et al. Antibodies to DNA in patients with systemic lupus erythematosus. Their role in the diagnosis, the follow-up and the pathogenesis of the disease. Clin Rheumatol. 1990;9(1 Suppl 1):100-110.
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  16. Fessler BJ, Alarcón GS, McGwin G Jr, et al. Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum. 2005;52(5):1473-1480.
  17. Costedoat-Chalumeau N, Amoura Z, Hulot JS, et al. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54(10):3284-3290.
  18. Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, et al. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther. 2009;11(4):R109.
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