However, their absence does not rule out the diagnosis. In addition, ANA can be seen in other systemic diseases. Antinuclear antibodies include anti-native double-stranded DNA (anti-ds DNA) that is very specific for SLE, anti-single-stranded DNA (anti-ss DNA) that is commonly found but nonspecific, and the anti-ribonucleoproteins (RNP), the anti-Ro/SSA, and the anti-La/SSB antibodies. Ro/SSA and La/SSB are antigens detectable in the nuclei and cytoplasm of cells. Antibodies against these RNP are highly associated with certain subsets of lupus including ANAnegative lupus, subacute cutaneous lupus erythematosus (SCLE), neonatal lupus, and lupus associated with inherited disorders of complement [8, 9]. These heterogeneous autoantibodies are known to affect the clinical features of SLE. A concept that has been developed in recent years considers the kinetics of the disease, with lupus autoantibodies present in serum of lupus patients up to 5 years prior to the development of clinical manifestations of disease. It is notable that autoimmunity, when considered in a population of lupus patients, develops in a stereotypical manner, with anti-Ro and anti-La antibodies, common to several systemic autoimmune diseases, developing early in the preclinical stage of disease, while anti-Sm and anti-RNP antibodies, those that are more specific for SLE, developing very close to the time that disease becomes clinically apparent [7].

Autoantibodies to cytoplasmic antigens include a group reactive against phospholipids. These antibodies, including the “lupus anticoagulant” (LA) and anticardiolipin (ACA), are a heterogeneous group of immunoglobulins and appear to have major clinical significance. These autoantibodies are thrombogenic in the coagulation cascade and can also react directly with phospholipid antigens present on the surfaces of platelets and endothelial cells. Lupus anticoagulant and ACA have been associated with recurrent arterial and venous thromboses, recurrent abortions, thrombocytopenia, and most of the neurological complications of lupus [10, 11]. The antiphospholipid antibodies cross-react with the cardiolipin used in standard screening tests for syphilis leading to the “biologic false-positive” test for syphilis that has long been associated with lupus and related disorders.

Damage to Target Organs

Antibodies, immune complexes, cytokines, and product generated by Fc receptor ligation and complement activation likely represent important mediators of tissue damage in SLE including placental inflammation and fetal loss, atherosclerosis, and central nervous system manifestations, particularly cognitive dysfunction. The strong association of a polymorphism in the ITGAM genes raises the possibility that leukocytes expressing the lupus-associated ITGAM variant might demonstrate a propensity to adhere more avidly to the local renal vasculature. In addition to augmented inflammatory mechanisms, target organ damage, particularly in the kidney, might be amplified by impaired protective mechanism [7].

In addition, sex hormones are known to affect the disease. Estrogen enhances SLE and testosterone suppresses it. Drugs such as chlorpromazine, hydralazine, methyldopa, isoniazid, and procainamide can produce a systemic inflammatory disorder that usually fulfills all of the diagnostic criteria for SLE. The pathophysiological mechanism by which this induction occurs remains unknown, and the associated systemic complications are typically mild.

General Clinical Findings

Constitutional symptoms include fever, malaise, arthralgias, myalgias, headache, loss of appetite and weight, and fatigue. Systemic lupus erythematosus may be triggered by sunlight, infection, and other stresses. Recurrences are common and tend to occur during active phases of disease. The most common systemic manifestations of SLE involve the skin and musculoskeletal systems [12, 13]. Mucocutaneous complications include the classic butterfly malar rash (Fig. 18.2), photosensitivity eruptions, mucosal ulcers, and discoid skin lesions. The term “discoid” refers to a specific type of skin lesion, not to a subtype of lupus. Musculoskeletal changes may be due to the disease process itself or may be secondary to the drugs that are used to treat it. Inflammatory arthralgias and arthritis are frequent. Aseptic bone necrosis may result from either lupus or corticosteroids. Lupus myopathy may result from steroids or antimalarial drugs.

Fig. 18.2 Classic butterfly malar rash (Courtesy of Rafael Muci-Mendoza, M.D.)

Lupus serositis includes pleurisy, pericarditis, and peritonitis. Renal disease accounts for a significant portion of the mortality from lupus. Circulating immune complexes localize in the kidney, resulting in lupus nephritis, the nephrotic syndrome, and renal failure [13]. Central nervous system manifestations include organic brain syndrome, generalized seizures, and psychosis. Focal seizures, strokes, movement disorders, and cranial and peripheral neuropathies are also seen. Headaches, including classic migraines with scotomas, occur frequently. These neurological complications result from small vessel occlusive disease as well as direct autoantibody damage to neuronal tissue [14]. Lupus vasculitis, Raynaud’s phenomenon, myocarditis, endocarditis (LibmanSacks), pneumonitis, and diffuse interstitial fibrosis are other major complications of SLE.

Ocular Symptoms

In general terms, pain (often accompanied by visible inflammation or redness) usually indicates significant external/anterior segment disease, whereas problems with vision (blurring, distortion, double vision) usually indicates posterior segment/neuro-ophthalmic disease. Visual impairment is usually secondary to ischemic retinopathy, and higher incidences are reported in association with antiphospholipid syndrome (APS) [15, 16]. Mild retinopathy may be asymptomatic, but more severe disease may cause permanent or transitory

loss of vision, field defects, distortion, or floaters. Sometimes a SLE patient could present with ocular symptoms without any identifiable ocular manifestations, and the etiology of the problem could not be elucidated unless the doctor activates a systemic workup. In that sense, transient visual symptoms are usually not properly evaluated until they turn into a more serious condition.According to Giorgi et al. [16], unilateral vision loss is the most common transient visual symptom (TVS) with a frequency of 53%, followed by blurring of vision in 20.6%, with the least common being bilateral visual loss at a frequency of 5.9%. The pathophysiology of TVS in that review has been attributed to ischemia secondary to thromboembolism induced by cardiac valve abnormalities, hence the recommendation for anticoagulation

along with immunosuppressive therapy. Binocular acute onset reversible visual loss in

association with APS is well known; however, more recently, a visual phenomenon has been described in association with a rare and recently described neurologic condition called posterior reversible encephalopathy syndrome (PRES). PRES is associated with renal insufficiency, hypertension, and rheumatologic diseases. Patients present with headache, seizures (usually generalized), loss of vision (ranging from blurred vision and hemianopia to cortical blindness) and altered mental function. The diagnosis is supported by predominantly transient hyperintensities on T2-weighted MRI images of the parieto-occipital white matter. Diffusion-weighted imaging (DWI) scans show increased diffusion in PRES, consistent with vasogenic edema. The etiology of PRES is believed to be dysregulation of brain perfusion by sympathetic innervations in the setting of severe hypertension. The causes may be diverse, but the most common precipitants are acute elevations in blood pressure, renal decompensation, and treatment with immunomodulatory drugs. It is usually treated with immunosuppression (methylprednisolone and cyclophosphamide), rapid control of seizures, and management of hypertension [15].

In SLE, acute or chronic permanent or reversible loss of vision can also be secondary to corneal, scleral, uveal, retinal, choroidal, and neuro-ophthalmological involvement.