NOTE: *Part of the diagnostic classification.

Subacute Cutaneous Lupus Erythematosus

Subacute cutaneous lupus erythematosus (SCLE) can be seen as an isolated disorder or in conjunction with SLE. Patients with SCLE develop a rash that occurs in sun-exposed areas—mainly arms, trunk, and the neck, although the face and lower extremities can be involved to a lesser degree. There are two types of rashes found: annular, ring-like lesions and papulosquamous, psoriasiform lesions. Severe rashes can become superinfected and scalp involvement can lead to hair loss.

    Biopsy of the skin lesions of SCLE reveal hyperkeratosis and a mononuclear cell infiltrate in the dermal-epidermal junction. The majority of patients with SCLE have anti-Ro (SSA) and anti-La (SSB) antibodies. While up to 50% of these patients will also have systemic symptoms, it is rare that patients will have significant organ involvement such as renal or CNS disease.

    Treatment for the skin manifestations is focused on sun-avoidance behavior and medication. Limiting sun exposure to nonpeak hours, wearing sun-protective clothing, and using high-SPF sunscreen are crucial. Discontinuation of cigarette smoking, which increases the risk of skin flares, is important as well, and patients should be counseled accordingly. Medicines such as antimalarials and topical steroids can be used to treat the rash. In severe cases that are refractory to these therapies, systemic immunosuppression with steroids, azathioprine, or mycophenolate mofetil can be used. Rarely, thalidomide is employed for refractory cases. Currently, biologic agents are being evaluated for their utility in treating SCLE.

Chronic Cutaneous Lupus Erythematosus

Chronic cutaneous lupus erythematosus includes discoid lupus, lupus profundus, and other skin manifestations. Discoid lesions are the most common and occur in up to 15–20% of patients with SLE. Like SCLE, these lesions occur in sun-exposed areas; however, discoid lesions more commonly occur on the scalp, face, upper arms, and ears. These lesions can cause scarring that can be disfiguring. Biopsy of discoid lesions shows follicular plugging with central atrophy. Treatment is similar to the treatment for SCLE and includes sun avoidance and sun protection, antimalarial agents, glucocorticoids, and immunosuppressive agents.

    Lupus profundus is a rare skin finding that occurs in the absence of systemic symptoms. Lesions can destroy deep dermal layers and subcutaneous fat. As a result scarring, sunken lesions that are often disfiguring can occur. Treatment includes antimalarials, steroids, and dapsone. In some cases, plastic surgery may be necessary to repair the lesions.

Acute Cutaneous Lupus Erythematosus

The most common skin lesion found in acute cutaneous lupus is the malar rash. Classically, it appears as a reddish raised rash over the bridge of the nose and cheeks that spares the nasolabial folds. The rash can have a burning sensation or be pruritic. It is thought to be secondary to immune deposition at the dermal epidermal junction. Often the rash appears after ultraviolet light or sunlight exposure. A malar rash can be difficult to distinguish from acne rosacea, the latter tending to have an oily texture and slight scaling. Acne rosacea is more common in Caucasian women during their fourth and fifth decade of life. Photosensitivity reaction is a skin rash that occurs after sun exposure in sun-exposed areas. This reddish rash mainly occurs over the face and the neck and other sun-exposed areas. Blistering and superinfection can occur, and often patients will feel ill in conjunction with the skin rash.

OTHER

Aphthous ulcers can be seen on the soft or hard palate of the mouth, in the nose, or in the vaginal area. Bullous lesions, although rare, can occur in SLE. Other skin findings include small-vessel vasculitis (palpable purpura, petechiae, splinter hemorrhages) and panniculitis. Alopecia is also seen in SLE. In particular, lesions occur around the temporal region. Alternatively, patients may have patches of hair loss leading to “bald spots.” Urticarial lesions and urticarial vasculitis are also seen in SLE patients. Raynaud’s phenomenon is found in over half of lupus patients.

PULMONARY MANIFESTATIONS

The lungs are commonly involved in SLE. Pleural involvement, as manifested by pleuritis, is seen in up to 30–60% of patients with SLE. The most common symptom is inspiratory chest pain and associated shortness of breath. On physical examination a rub can be heard but this finding is not always present, and likewise radiographic evaluation is often negative. Thus, the diagnosis of pleuritis is often a clinical one. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) and/or glucocorticoids is generally effective.

    SLE patients can develop an inflammatory interstitial lung disease manifested by dyspnea and a dry nonproductive cough. On examination, dry crackles are heard and a reduced single-breath diffusing capacity of the lung can be demonstrated on pulmonary function testing. The best test for diagnosing this finding is a high-resolution computed tomography (CT). Poorly controlled chronic interstitial lung disease can progress to fibrosis, causing permanent lung damage.

    Pulmonary hemorrhage is a rare but devastating finding in SLE patients. Mortality from this disorder approaches 50%. Patients present with hemoptysis and dyspnea. A high percentage of these patients have associated antiphospholipid antibodies.

    Shrinking lung syndrome is another rare manifestation of SLE. On radiographs, elevated diaphragms are found and patients are dyspneic. Pathology is thought to be secondary to muscle weakness of the diaphragm and intercostal muscles as well as interstitial lung disease.

CARDIAC INVOLVEMENT

Pericarditis is the most common cardiac manifestation of SLE. Patients present with chest pain and shortness of breath. Hemodynamic compromise in the setting of pericardial tamponade is rare but can occur. Diagnosis is suggested with flattened T-waves on electrocardiogram but is confirmed by echocardiogram. Treatment with NSAIDs and steroids is generally effective, although occasionally pericardial drainage needs to occur.

    Coronary artery vasculitis and myositis are extremely rare manifestations of SLE but should be considered in patients who present with symptoms suggestive of these disorders. Leibman-Sacks endocarditis is the finding of microthrombi on the valves and subsequent impairment of valvular function. The vast majority of patients who have this disorder also have antiphospholipid antibodies.

    Persons with SLE have higher incidences of coronary artery disease. Whether this is the result of the disease or the treatment is unclear but it appears to be a combination of both risk factors. Some rheumatologists believe that lupus should be considered a cardiac risk factor along the lines of diabetes mellitus and hypertension. Certainly, patients who have lupus should be counseled regarding modification of other cardiovascular disease risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia. Early intervention with statins is being explored as potentially lowering the risk of accelerated atherosclerosis. Careful attention to lifestyle changes and maintaining a healthy weight, exercising, and smoking cessation are important measures as well.

JOINT SYMPTOMS

Over 90% of SLE patients will have joint symptoms at some time during the course of their disease. Arthralgias and arthritis are the most common. Some patients experience joint achiness without synovitis. Others will develop an arthritis that is indistinguishable from an inflammatory arthritis such as rheumatoid arthritis. This subgroup may have the presence of a positive rheumatoid factor or anticyclic citrullinated peptide antibodies. Finally, roughly 10% of lupus patients will develop a tendinopathy that causes a particular type of deforming arthropathy called Jaccoud arthropathy. In this condition, tendinopathy rather than erosions cause the observed deformities.

    Osteonecrosis can occur in particular in individuals who are on steroids at doses greater that the equivalent of twenty milligrams of prednisone a day. SLE patients who have had prior joint damage and/or are immunosuppressed are at higher risk for the development of septic arthritis.

    Myositis, with a presentation similar to dermatomyositis/polymyositis, is reported in SLE patients. Patients will complain of proximal muscle weakness (difficulty combing one’s hair, lifting one’s arms, getting out of a chair, or walking up stairs) and occasionally pain. Like the inflammatory myopathies, the muscle biopsy will demonstrate muscle inflammation. This inflammatory condition must be differentiated from drug-induced myopathies such as steroid myopathy, which likewise presents with proximal muscle weakness, and more diffuse myopathies that can be seen in those patients on statins and rarely antimalarials.

HEMATOLOGIC DISORDERS

Leukopenia and lymphopenia are common findings in SLE. An absolute white blood cell (WBC) count of <4000 cells/mm³ and an absolute lymphocyte count of 1500 cells/mm³ are part of the diagnostic criteria for classification of this disorder; thus, leukopenia and lymphopenia are frequently found in lupus patients. Thrombocytopenia (platelet count <100,000/μL), often immune mediated, is also found in systemic lupus. Anemia of chronic disease as well as a Coombs positive hemolytic anemia are the other hematologic disorders seen in SLE.

RENAL DISEASE

Over half of persons with SLE will develop renal involvement during the course of their disease. Clinically, patients will present with hypertension and edema, although sometimes patients are asymptomatic and the diagnosis is suggested by the finding of proteinuria or hematuria on urinalysis. The latter should prompt an evaluation by a nephrologist and consideration for a renal biopsy. Renal disease is classified by using the World Health Organization (WHO) biopsy categories (box 25.1). In addition to these categories, pathology specimens are given an activity—chronicity rating that reflects the degree of inflammation occurring in the kidney. Most of the morbidity and mortality from the renal disease occurs in those who have either focal or diffuse glomerulonephritis (Classes III and IV). In addition, a high degree of chronicity in the renal biopsy portends a poor prognosis, as these lesions tend to be refractory to therapy. In the past, mortality from renal disease was quite high; however, due to newer treatments this rate has dramatically diminished.

Box 25.1 WHO CLASSIFICATION OF RENAL DISEASE–REVISED

NEUROLOGIC DISEASE

Nineteen neurological syndromes have been reported to be part of neuropsychiatric lupus, although only two are listed among the classification criteria (table 25.2). Some of these disorders, such as transverse myelitis, focal seizures, and cognitive events, are thought to be due to focal lesions, often associated with antiphospholipid antibody–induced clotting events. Nonetheless, these findings can also occur in the absence of antiphospholipid antibodies. Global organic findings such as generalized seizures and psychosis are challenging neurologic syndromes in SLE that can be difficult to medically manage. Some neurologic findings such as depression, migraines, and certain types of cognitive difficulties are found in many disorders and can be difficult to attribute to SLE disease activity. For example, although headaches are frequently described in individuals with SLE, the actual frequency of headaches in SLE patients is not significantly higher than what is found in the general population. For strict classification purposes, seizures and psychosis are the only neurological symptoms included among the criteria for SLE.

DRUG-INDUCED SLE

Drug-induced SLE can occur in the setting of many medications. Isoniazid and procainamide are the most common offending agents, but many more medications can cause this entity. In most affected individuals, symptoms are limited to skin rashes, serositis, arthralgias, and fatigue. It is rare to have renal or CNS involvement. Over 95% of these individuals will have the presence of an antihistone antibody. In most scenarios, the symptoms will resolve once the medication is removed; but occasionally treatment with NSAIDs and low doses of steroids is needed. It is rare that more potent immunosuppressive agents are required for the management of this disorder.

AUTOANTIBODIES

Autoantibody production is an important driver of SLE development and disease manifestations (table 25.3). The most common, the antinuclear antibody (ANA), is found in 93–95% of individuals with SLE. Antinuclear antibodies and precipitins have been found in individuals several years prior to the diagnosis of SLE. However, it is important to remember that low titers of these antibodies can be seen in up to 5–10% of the general population, in particular in those who are elderly, on certain types of medications, and/or who have other autoimmune conditions. Therefore, the presence of ANA alone cannot be used to make the diagnosis of SLE. Nonetheless, the higher the titer of this antibody the more likely it is to be a true positive and not a false positive. Other more disease-specific antibodies such as the anti-dsDNA antibody are found in 75% of individuals with SLE, and the anti-Sm antibody is found in 25% of SLE patients. Both anti-dsDNA and anti-Sm antibodies are associated with renal disease. Anti-Ro (SSA) and anti-La (SSB) antibodies are seen in individuals with SCLE as well as SLE and are the pathologic agents in neonatal lupus and congenital complete heart block. Anti-RNP antibodies are found with higher frequency in those who have mixed connective tissue disease. Antihistone antibodies are associated with drug-induced SLE, although 60% of those with SLE also have these antibodies.

DIAGNOSIS

Making the diagnosis of SLE can be challenging. Given the myriad of combinations of clinical manifestations that individuals can present with, it is no wonder that SLE is considered one of the great disease imitators. While individuals may present to clinicians with symptoms suggestive of SLE, it is important to be rigorous in the diagnosis of this disorder. The diagnostic classification criteria were originally developed as a research tool; however, they are a useful guideline for evaluating patients with potential SLE. Technically, individuals require four out of eleven classification criteria to be diagnosed with SLE (table 24.4). However, in individuals with a clinical presentation highly suggestive of SLE, the clinician should use his or her judgment in making the diagnosis. Given that 93–95% of individuals will have the presence of an ANA, and the majority of SLE patients who do not have an ANA will have the presence of another autoantibody, antibody-negative SLE is exceedingly rare.

    Recently there has been a push to modify the existing classification system. The recommendations are to expand the criteria in the hope of ensuring that the diagnosis of SLE is not missed. New broader clinical criteria have the advantage of including neurologic symptoms and some immunologic abnormalities, they run the risk of resulting in “overdiagnosis” of SLE. Currently the older diagnostic criteria are still considered the gold standard.

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