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Disease development and outcome


Historical perspective

Systemic lupus erythematosus (SLE) is a disease of exacerbations and remissions with variable course and prognosis. There were no criteria to classify SLE before the early 1970s, and no standardized method to evaluate disease activity, flares, or remissions existed until the 1980s. SLE patients had a poor prognosis with a 5-year survival rate of only 55% in 1955. Corticosteroid treatment was introduced in 1948, the same year the lupus erythematosus (LE) cell test for SLE was discovered. In the following decades, antimetabolite and cytotoxic therapy for lupus nephritis became available. These early milestones facilitated the earlier diagnosis and treatment of SLE.

Approximately 10 years after the discovery of the LE cell test, the introduction of fluorescent antinuclear antibody (ANA) testing led to a new emphasis on laboratory diagnosis of SLE through ANA determination. A positive ANA test was initially thought to be synonymous with active disease. It was later recognized that a positive ANA, especially at low titers, has high sensitivity but low specificity for SLE. An estimated 32 million persons in the United States have a positive ANA , and one-third of persons with autoimmune thyroid disease are ANA positive. The description of antiDNA antibodies and lowered serum complement levels allowed more precise and earlier detection of SLE disease onset and flares. The American College of Rheumatology (ACR) subsequently developed SLE classification criteria that included more autoantibody systems. Recently publications updating classification criteria for SLE using new methodologies and updated definitions are alternative criteria for clinical care and research. These criteria, while not intended to replace clinical judgment in diagnosing SLE, provided a framework for considering a diagnosis of SLE.

In the 1970s, it was noted that some patients with clinical features of SLE were ANA negative. Case series of ANA-negative patients suggest a higher frequency of photosensitive rash and milder renal and central nervous system (CNS) disease than ANA-positive patients. Disease manifestations and course in patients with undetectable ANA may otherwise be typical of classical SLE. Many of these patients have measurable autoantibodies to extractable nuclear antigens, especially antiSSA/Ro and antiSSB/La. ANA negative disease among persons with complement deficiency is also well described. The spectrum of ANAs is changing to include both nuclear staining as well as cytoplasmic and mitotic cell patterns (CMPs) and accordingly a change is occurring in terminology to anticellular antibodies. In newly diagnosed systemic LE, 6.2% of patients were anticellular antibody negative, and 1.5% had isolated CMPs. The prevalence of anticellular antibody-negative systemic LE will likely decrease as emerging nomenclature guidelines recommend that nonnuclear patterns should also be reported as a positive ANA.

Another group of patients with “latent” or “incomplete” lupus has been identified. These patients present with suggestive symptoms but lack key clinical features of classic SLE. For example, incomplete lupus patients will exhibit one or two of the ACR classification criteria plus other nonspecific clinical characteristics, such as fever, fatigue, headache, lymphadenopathy, or neuropathy. Laboratory abnormalities may also exist, including hypergammaglobulinemia, increased erythrocyte sedimentation rate, or depressed complement. Approximately 20% will develop classic SLE, and the presence of antiDNA, oral ulcers, and proteinuria or cellular casts are independent predictors of developing definite lupus. The Study of AntiMalarials in Incomplete Lupus Erythematosus is ongoing and will test the hypothesis that early treatment with hydroxychloroquine can prevent the accumulation of clinical abnormalities and modify immune responses that define SLE. Although patients with incomplete lupus often have a milder disease course, this study is the first to address early treatment and prevention of disease.

Two subsets of SLE patients with discordant clinical symptoms and serologic profile have been described. First, patients may have serologically active and clinically quiescent (SACQ) disease. In the Toronto Lupus Clinic cohort, 6.1% of patients remained serologically active but without clinical activity for 3 years on average. These patients took less steroids and immunosuppressants, and accrued less damage compared to matched controls. Thus active surveillance without treatment during an SACQ period may be appropriate. In contrast, patients may have clinically active and serologically quiescent (CASQ) disease, with severe lupus manifestations requiring aggressive treatment despite a lack of serologic markers. Knowing whether a patient is concordant or discordant with clinical symptoms and serology will facilitate optimal disease monitoring and clinical care.

Clinical manifestations

SLE is characterized by multi-organ involvement, a wide spectrum of manifestations, and an unpredictable clinical course ( Box 6.1 ). The dynamic nature of the disease with intermittent signs and symptoms can make the diagnosis particularly challenging.

Box 6.1
Spectrum of disease manifestations in SLE

  • Constitutional: Fever, weight loss, lymphadenopathy, and fatigue.

  • Mucocutaneous: Photosensitivity, acute lupus rash (e.g., malar, bullous), subacute cutaneous lupus rash, chronic lupus rash (e.g., discoid, panniculitis), oral or nasal ulcers, and alopecia.

  • Musculoskeletal: Arthralgia, arthritis, tendonitis, myalgia, and myositis.

  • Cardiopulmonary: Pleurisy, pericarditis, myocarditis, endocarditis, and inflammatory lung disease.

  • Peripheral vascular: Raynaud’s phenomenon, vasculitis, and thrombophlebitis.

  • Renal: Proteinuria, hematuria, renal insufficiency, hypertension, and nephritis on renal biopsy.

  • Hematologic: Hemolytic anemia, leukopenia, lymphopenia, and thrombocytopenia.

  • Neurologic: Cognitive impairment, acute confusional state, seizure, stroke, aseptic meningitis, transverse myelitis, peripheral neuropathy, and unremitting headache (unresponsive to narcotics).

  • Gastrointestinal: Serositis, bowel ischemia, pancreatitis, and hepatitis.

  • Immunologic: Presence of ANA, antiDNA, antiSmith, anticardiolipin, lupus anticoagulant, false-positive serologic test for syphilis, positive Coombs test, and low complement.

Disease manifestations can be organ specific or nonspecific including constitutional symptom such as fever, fatigue, or pain. Skin disease and arthritis are common manifestations, but any organ system may be involved in variable combinations. SLE may have diverse clinical presentations as rash, arthritis, pleurisy, proteinuria, Raynaud’s phenomenon, or seizures. Other diseases with multisystem involvement may mimic SLE. An extended observation period is often necessary before making a definite diagnosis. The diagnosis will only be recognized with a high index of suspicion, a careful history and physical examination, and appropriate laboratory confirmation.

Neuropsychiatric dysfunction and renal disease are two critical SLE manifestations. The spectrum of neuropsychiatric abnormalities potentially related to SLE is broad and can be difficult and require exclusion of other causes before attribution to SLE can be made. Some of the more common manifestations include seizure , psychosis , stroke , mood disorders , headache , and cognitive impairment. Rare disorders also occur such as peripheral or cranial neuropathy, myelopathy, movement disorders, autonomic disorder, Guillain Barre syndrome, myasthenia gravid, and plexopathy.

Lupus renal disease also has variable expression, histopathology, and clinical course. Virtually all persons with SLE display some degree of glomerular pathology by renal biopsy, but only 50% have clinically apparent disease necessitating renal biopsy to assess type of involvement, activity, and chronicity. Repeat renal biopsy may also be indicated, as response to treatment may not be clinically apparent. Early detection of lupus nephritis is crucial, since early intervention may prevent or delay progression to end-stage renal disease.

Constitutional complaints such as fever, overwhelming fatigue, and weight loss are frequent but nonspecific manifestations of SLE. However, these symptoms are the ones most troubling to patients. A recent article posited that there are two types of lupus symptoms with type 1 being the classic signs and symptoms of inflammation whereas type 2 symptoms including the constitutional symptoms noted earlier. The presence of type 2 symptoms do not aid in diagnosing disease or recognizing classical disease flare because they may result from other medical problems, such as infection or fibromyalgia and need to be distinguished from mimickers, which would not likely respond to antiinflammatory or immunosuppressive therapies. However, in some cases both types of symptoms could be present simultaneously in persons with lupus and the authors’ recommendation is to define a research agenda that includes refining clinical and laboratory assessments and treatments specifically for type 2 symptoms in SLE.

Assessment of disease activity

A number of validated instruments have been developed to measure disease activity, which should be assessed at every visit. The clinician must distinguish whether signs and symptoms are attributable to active lupus, chronic damage, comorbidity, or drug toxicity.

Some commonly used disease activity indices are the SLE Disease Activity Index revised in 2000 (SLEDAI-2K), the Systemic Lupus Activity Measure (SLAM), the European Consensus Lupus Activity Measurement (ECLAM), and the British Isles Lupus Assessment Group (BILAG) index. The BILAG index takes into account changes in disease activity compared to the prior assessment. However, the BILAG may be cumbersome to complete in a busy practice setting. SLAM is frequently utilized in observational studies, but a disadvantage is scoring based on patient-led reporting of symptoms. SLEDAI, ECLAM, and BILAG have all been employed in clinical trials. Composite disease activity indices have also been used in clinical trials, including the SLEDAI-based SLE Responder Index and S2K-RI-50 version and the BILAG-based Combined Lupus Assessment.

Other indices are used to identify the presence of disease flare including the BILAG 2004, Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) flare index (SFI) and the revised SELENA flare index (rSFI). Three physicians assessed 986 individual lupus cases. Agreement on degree of flare was obtained in 451 (48%) and these 451 cases formed the gold standard from which an international group of investigators evaluated flare using these three instruments. The agreement with the gold standard was 67% for BILAG 2004, 72% for SFI and 70% for rSFI. Areas of disagreement including rating moderate flares as severe flares in some cases, and persistent activity as a flare. Thus the problem of capturing flare is an ongoing research question that still needs further work.

A modification of the SLEDAI-2K the S2KRI-50 provides definitions for a 50% improvement in each of the items of the SLEDAI-2K. It has face validity, is reliable, and has been used in clinical trials. Another variation of the SLEDAI-2K is the addition of a variable describing the amount of corticosteroid a patient is taking. Other strategies to assess disease activity and change over time include the Lupus Multivariate Outcome Score and SLE Disease Activity Score (SLE-DAS) both of which need further testing as outcome measures for clinical trials.

Adaption of treat-to-target (T2T) strategies has been used in rheumatoid arthritis and is being considered for SLE. In developing consensus on T2T for SLE, several recommendations were identified he control of disease activity toward remission or low disease activity and preventing flares, reduction of damage accrual, minimization of glucocorticoid therapy, the assessment and treatment of comorbidities, and maintenance of good quality of life. However, the taskforce also described the lack of validated remission and low disease activity definitions in SLE as key knowledge gaps limiting progress toward these goals. Ongoing work includes developing definitions of low-level disease activity and testing these indices in clinics and clinical trials. This is an important step in refining disease assessment with implications to improve outcomes.

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