Chapter 3 Disease Development and Outcome
Systemic lupus erythematosus (SLE) has been recognized as a disease of exacerbations and remission with variable course and prognosis. Prior to the early 1970s there were no criteria to classify SLE, and until the 1980s, there was no common method to evaluate disease activity and define flares and remission in a standard way. Physicians would describe a patient as flaring when there was evidence of new onset or increase in certain manifestations such as more arthritis, more extensive rash, increased serum creatinine, or increased proteinuria. Likewise, it was difficult to define remission. A patient who had no complaints was considered to be doing well, and some might describe that as a remission. (See Chapter 2 for a detailed discussion of methods for measuring disease activity.) Prior to the discovery of corticosteroid therapy, patients with SLE had a very poor prognosis, with the 5-year survival rate being no more than 55%.1 Corticosteroid therapy was discovered in the same year as the lupus erythematosus cell test for SLE. These early milestones facilitated the diagnosis of SLE, allowing for earlier diagnosis and therefore treatment of these patients.
Although the diagnosis of SLE was facilitated by the discovery of the lupus erythematosus (LE) phenomenon,2 it was not until the introduction of the fluorescent antinuclear antibody (ANA) test approximately 10 years later that laboratory diagnostic emphasis focused on the determination of ANAs.3 Initially, a positive ANA test was considered to be virtually synonymous with the diagnosis of active disease.4 However, the later detection of anti-DNA antibodies and depressed serum complement levels in patients allowed for more precise and earlier detection of both onset and subsequent exacerbations of disease.5 The subsequent description of the classification criteria for SLE further enhanced the ability to diagnose patients with SLE, and recent criteria have included more autoantibody systems.6
However, as far back as the early 1970s it was noted that there are patients with clinical features of SLE who do not demonstrate antinuclear antibodies.7–9 Despite the lack of ANA detection, these patients ran a similar course to ANA-positive patients. Most series of ANA-negative lupus consisted of patients with a high frequency of a photosensitive skin rash and perhaps a milder form of renal disease and central nervous system (CNS) involvement. Nevertheless, individual patients may be otherwise typical of classical SLE. These patients may have other autoantibodies in their sera, such as antibodies to cytoplasmic components.10 Thus, a negative ANA should not deter the clinician from considering a diagnosis of lupus.
A large proportion of patients with “ANA-negative” lupus did have other autoantibodies detected in their sera, including anti-DNA antibodies, and antibodies to extractable nuclear antigens, especially anti-Ro and anti-La8,9 (Box 3.1). Provost and Reichlin11 pointed out that among ANA-negative patients, anti-Ro and anti-La were much more common than among ANA-positive patients, and that these patients often present with the clinical picture of a photosensitive facial dermatitis, positive latex fixation, and Sjögren’s syndrome. Interstitial pneumonitis has been reported in two ANA-negative patients with SLE.11 Serologically negative disease has also been recognized among patients with complement deficiencies.12
BOX 3-1 ANA-Negative SLE
Another group of patients labeled as having “latent” or “incomplete” lupus has been described. These patients present with a constellation of features suggestive of SLE, but do not qualify by “classification criteria” or by a rheumatologist’s intuition as having classic SLE.13–15 These patients usually present with either one or two of the American College of Rheumatology (ACR) classification criteria for SLE, plus a number of additional and much less specific clinical features suggestive of lupus such as lymphadenopathy, fever, headache, nodules, Sjögren’s syndrome, fatigue, neuropathy, and oligoarthritis. These patients may, in addition, display some laboratory abnormalities including an increase in partial prothrombin time, hypergammaglobulinemia, an increased erythrocyte sedimentation rate, depressed complement components, positive rheumatoid factor, or aspirin-induced hepatotoxicity. Many of these patients will persist with their constellation of signs and symptoms over many years, without ever developing classic lupus. Although a small number do eventually develop classic lupus, none of the presenting clinical or laboratory features are sufficiently predictive to identify such patients in advance. Patients with latent lupus tend to have a milder form of disease and do not present with CNS involvement or renal disease. See Chapter 43 for further discussion of latent or incomplete lupus.
Two subsets of patients who do satisfy classification criteria for SLE have been described that underscore the importance of recognizing whether patients are concordant or discordant in their clinical serologic profile. Patients with serologically active clinically quiescent disease (SACQ) were first described by Gladman and colleagues in 1979 and constituted 12% of the cohort.16 These patients remained well despite elevated anti-DNA antibodies and reduced complement levels for a mean of 2.5 years. Over a longer follow-up period, half of these patients eventually did flare.17 Thus, there is a group of patients who remain serologically active but clinically quiescent, and who do not develop a disease flare even after a prolonged period of observation. These patients may not need any corticosteroids or immunosuppressive therapy.
Similarly, there is a group of patients with clinical SLE who do not demonstrate any serologic abnormalities. These patients, who also constitute about 12% of patients with SLE, have been labeled as clinically active serologically quiescent (CASQ).18 Despite the lack of serologic markers, these patients have severe lupus manifestations, and may have severe disease requiring therapy with high doses of corticosteroids and immunosuppressive medications. Patients with discordant and serologic activity challenge the role of these antibody systems in the direct pathogenesis of SLE, and also complicate the attempt to identify predictors of flares in patients with SLE.
SLE disease activity is the prototypic inflammatory autoimmune disease with multiorgan involvement, a wide variety of manifestations, and an unpredictable clinical course. The dynamic nature of the disease, with variable and intermittent signs and symptoms, makes the diagnosis particularly challenging. There are also many other diseases with multisystem organ involvement that may mimic SLE. Prolonged observation is often necessary prior to an unequivocal diagnosis. Clinical presentation along with medical and family history, medication review, and laboratory testing are essential elements used to confirm a diagnosis of SLE.
Constitutional complaints such as malaise, overwhelming fatigue, fever, and weight loss are common presenting features of SLE. The presence of these features does not help the physician in the diagnosis of the disease, or in the identification of a flare, because they are just as likely to represent other medical problems including the development of infection or of fibromyalgia. (See Chapter 29 for further discussion of constitutional factors.)
Although some organ system manifestations such as skin disease or arthritis are common in SLE, any system may be involved and may present in variable combinations with other organ systems. Thus, SLE may have such diverse clinical presentations as rash, arthritis, pleurisy, proteinuria, Raynaud’s phenomenon, seizures, or pyrexia of unknown origin. It is only with a high index of suspicion, a careful history and physical examination, and by obtaining appropriate laboratory confirmation, that the diagnosis will be recognized.
CNS dysfunction and renal disease are two of the most critical manifestations. Potential CNS abnormalities include seizure, psychosis, cognitive impairment, mood disorders, headache, strokes, movement disorders, and aseptic meningitis. There is great variability in the expression, histopathology, and clinical course of renal disease, with virtually all patients with SLE displaying some degree of glomerular abnormality by renal biopsy. However, only 50% have clinically apparent disease. Early detection of renal involvement is critical as early intervention may prevent or delay progression to end-stage renal disease.
Assessment of Disease Activity
The assessment of disease activity in SLE has become easier with the development and validation of a number of instruments over the past several years (Box 3.2). The most commonly used instruments include: the SLEDAI,19 the SLAM,20 the British Isles Lupus Assessment Group (BILAG),21 the Lupus Activity Index (LAI),22 and the European Consensus Lupus Activity Measurement (ECLAM).23 These indices have been shown to be comparable.24,25 Thus, overall disease activity now can be evaluated as a prognostic factor in SLE. (See Chapter 2 on disease activity.)
BOX 3-2 Approach to Patient with SLE
The health status of patients with SLE is related not only to disease activity, but to the damage that results from recurrent episodes of disease flare and treatment complications (Box 3.3). The Systemic Lupus International Collaborating Clinics (SLICC) group, in conjunction with ACR, developed a damage index for SLE. The SLICC/ACR Damage Index describes the accumulation of damage in patients with SLE since disease onset without attribution, and includes items that may have resulted from the inflammatory process, disease treatment, or intercurrent events.26 The SLICC/ACR Damage Index has been validated and used in a number of studies and has been found to predict mortality.27–29 The Damage Index thus provides an important outcome measure in SLE, both for studies of prognosis, and in the assessment of long-term effects of treatment. Factors contributing to the development of damage include ethnicity,30,31 disease activity at presentation and over time,31–34 older age at onset, and disease duration.30,35 Socioeconomic features have also been suggested to contribute to disease damage. Investigators in a multiethnic U.S. cohort of SLE (LUMINA–lupus in minorities, nature versus nurture) patients found poverty to be an important variable associated with disease damage and mortality.36
BOX 3-3 Spectrum of Disease Damage in SLE
The course of SLE and common complications of the illness are best understood by reviewing the individual major areas of potential disease involvement. The spectrum of disease damage includes cardiovascular disease, renal complications, musculoskeletal complications, CNS dysfunction, infections, and malignancy.