Historical overview

Systemic lupus erythematosus (SLE) is a complicated disease that frustrates many clinicians with its wide variety of presentations, signs, and symptoms. SLE is defined as a chronic disease characterized by inflammation of various organs, primarily the skin and joints. The disease does not have a clear etiologic picture. Immunologic abnormalities, highlighted by the production of various antinuclear antibodies, are a prominent feature. Patients with SLE suffer a variety of symptoms, most commonly related to the skin, musculoskeletal, hematologic, and serologic organs. In the recent past, a diagnosis of SLE implied a decreased lifespan resulting from internal organ system involvement or the toxic effects of therapy; however, recent improvements in research and clinical trials have provided clinical data that have dramatically enhanced survival in SLE patients. Nonetheless, SLE mortality rates remain a major concern. 
 
Many clinicians in the field of rheumatology have substantial knowledge and practice gaps related to the diagnosis and care of patients with lupus. Even SLE experts disagree on points of SLE management. To address some of the issues, this supplement will present insights from internationally known experts in the field of lupus research and patient care. 
 
The four abstracts in this supplement summarize live presentations at an educational symposium titled "Treatment of SLE: Bridging the Gap from Clinical Trials to Practice". Conceptually intertwined with the pathogenesis of SLE, the newly evolving topic of targeted therapy is the focus of this educational activity. A review of the current scientific implications for the biologic basis of SLE pathogenesis and the therapeutic management of the disease will increase rheumatologists' medical understanding of the molecular and cellular basis of SLE pathogenesis that is crucial to improving outcomes in these patient populations. 
 
An adapted version of each of the full presentations given at the symposium is attached to each abstract. These adaptations bridge knowledge gaps on the latest SLE clinical research, biologic agents, and targeted therapies, as expert faculty compile and critically appraise new evidence and interpret its implications for improving the clinical management of patients with SLE. 
 
The presentations are designed to address issues for clinical immunologists and rheumatologists who provide care for patients with SLE but who do not necessarily practice in the field of lupus. To that end, the expert faculty members provide analyses of the grueling and complex matrix of basic science and clinical science and then offer insight into how to translate those advances from the bench to the bedside. 
 
The presentations start, appropriately, with a historical overview of SLE from its first reference during the 1100s, through the neoclassic period of the 1800s when it began to be defined, and into the modern era that began with the laboratory discovery of SLE cells. Weaved into this overview are descriptions of the most important contributions from the leading practitioners and researchers. 
 
The faculty are among the most respected in the field. Bevra Hahn, MD, Professor Emerita of Medicine at the David Geffen School of Medicine at UCLA, has been in the field for a long time. She is a prolific author who has many contributions to medicine, including being the lead author on the American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Dr Hahn's presentation 'Unmet Needs: Therapeutic Standards of Care' focuses on the evidence-based best practices for SLE and how to fit the American College of Rheumatology guidelines into clinical care. 
 
Michelle Petri, MD, MPH, Professor of Medicine at the Johns Hopkins University School of Medicine, Baltimore, MD, has organized several outstanding educational initiatives in lupus. She is lead author of the most recent classification criteria for lupus. In her presentation 'Measuring Disease Activity and Severity in Clinical Trials and the Clinic: Same or Different?' Dr Petri discusses the revised clinical and immunologic criteria for the classification of SLE, necessitated by substantial advances in knowledge of immunologic interplay of SLE. The question of when to monitor patients with stable disease has perplexed many clinicians, and Dr Petri describes evidence showing when specific variables usually can be detected and offers clinical guidance based on the evidence. She also presents a convincing argument for limiting the use of high-dose prednisone therapy, which has shown significant evidence of increased morbidity and mortality. To help those relying on prednisone, she describes some options found to be effective in head-to-head trials. 
 
Daniel Wallace, MD, is a clinical leader and a highly respected clinical trial investigator. His presentation 'Clinical Impact of Biologic Therapy in the Treatment of SLE' is a thoroughly researched and referenced review of clinical trial data on biologic therapies in SLE, providing insights into the subtleties of the responder indexes, their impact on potential new therapies, and their potential use in clinical practice. He finishes with an in-depth review of belimumab, the clinical trial evidence base (including American College of Rheumatology and European League Against Rheumatology annual meetings and peer-reviewed literature), and his summary of its clinical implications for practice. 
 
The goal of these presentations is to provide readers with a review the current evidence regarding SLE and translate it into implications for clinical practice. By providing the current best practices and addressing the identified knowledge and practice gaps, the supplement has the potential to substantially improve outcomes in this patient population.

on regression analyses of SLE and control patients [1]. The SLICC used a large set of clinical scenarios and stringent methodology in their revisions and then subjected the criteria to validation.
The revised criteria provide two options for classifying SLE: • Patient has at least four criteria: one has to be a clinical criterion and one an immunologic criterion. or: • Patient has lupus nephritis diagnosed by kidney biopsy demonstrating immune complex-mediated glomerulonephritis compatible with lupus neph ritis in the setting of antinuclear antibodies or anti-DNA. The revisions kept the rule of needing to meet at least four criteria, but the SLICC now requires that at least one be a clinical criterion and one be an immunologic criterion. The SLICC also revised the list of 17 clinical and immunologic criteria. Rationales for changes are described below.

Clinical criteria
The revised clinical criteria classification lists 11 criteria ( Table 1). The first criterion -acute and subacute cutaneous lupus -is new. Subacute lupus was omitted in the previous ACR criteria. The second criterionchronic cutaneous lupus -replaces discoid rash. This term includes discoid lupus as well as all the other kinds of chronic cutaneous lupus disease such as tumid lupus and verrucous lupus.
The third criterion -oral and/or nasal ulcers -is the same. The fourth criterion -nonscarring alopecia -has been resurrected from the American Rheumatism Association criteria for SLE. It is typical of lupus because of the two hair findings of lupus: fragile (breaks off with minor trauma) and thinner than normal (scalp shows through). If the patient has scarring alopecia, that counts under chronic cutaneous lupus.
The fifth and sixth criteria -arthritis and serositisare the same. The renal criterion (seventh criterion) is for patients who have not had a kidney biopsy; a spot urine protein:creatinine ratio of 500 mg/24 hours or more can be used.
The neurologic criterion (eighth criterion) is im proved. Previously, it was limited to psychosis and seizures. The new definition (for example, seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, cerebritis) is more representative of neurologic lupus. In fact, seizures and psychosis are rarer now in SLE than when the ACR criteria were devised.
Hematologic anemia manifestations have been separated into three criteria: hemolytic anemia (criterion nine), leukopenia or lymphoma (criterion 10), and thrombocytopenia (criterion 11). In the previous classification, they were all lumped together. Table 2 presents the revised immunologic criteria. The first criterion -antinuclear antibody test results -stayed the same. The second criterion -anti-DNA antibody level -has been revised to address frustrations with the ELISA testing results. Low titers from ELISA testing had mistakenly identified SLE in many patients who did not have SLE. The criterion now requires a stricter cutoff for ELISA anti-DNA antibody levels -it has to be twice the upper limit of normal to meet this criterion.

Immunologic criteria
Presence of anti-Sm antibodies is now a separate criterion (third criterion). The antiphospholipid antibodies are in the fourth criterion. This has been expanded to allow IgG, IgM, or IgA isotypes for anti-β 2 GPI and anticardiolipin antibodies, which reflects new insights into the role of IgA isotypes in SLE. Low complement is the fifth criterion, reflecting its importance in SLE pathogenesis.
Criterion number six is the direct Coombs test. The regression analysis showed that the direct Coombs test detects a specific antibody for SLE, and the great majority of patients with positive results will never develop autoimmune hemolytic anemia. Nevertheless, this test is not counted if the patient has hemolytic anemia.

Additional notes on the revisions
One should note that these criteria were developed for classification of SLE; however, in clinical practice, they also can help with the diagnosis. Some items were left out of the criteria that are going to become more important. One is the role of anti-C1q in lupus. This is important in terms of prognosis because it predicts patients who will develop lupus nephritis, as does anti-DNA and low complement. The greater role of anti-C1q is going to be following patients with lupus nephritis, because it is the only serologic test that correlates with disease activity in individual patients over time. There may be US Food and Drug Administration-approved quality anti-C1q assays that can be used in clinical practice.

PREDNISONE RISKS
As a therapy for patients with SLE, prednisone presents a clinical challenge because of its severe toxicities. It is especially toxic in high doses, which have been shown to significantly increase morbidity. In clinical practice, high doses should be defined as 6 mg/ day rather than 0.5 mg/kg. Toxicity claims are based on a considerable body of evidence from prospective studies. In the Hopkins Lupus Cohort [2], a cohort analysis of 525 patients with SLE, results showed that doses of 6 mg/day and above increased the risk of permanent organ damage by 50% (Table 3). However, some lupus nephritis regimens use doses >18 mg/day. At that dose, the odds for permanent organ damage are 2.5-fold increased.
This cohort also showed that prednisone increases cardiovascular (CV) events. At doses ≥10 mg/day, the CV event risk increased by 2.5-fold (P = 0.0002) [3]. At 20 mg/day, the risk increased to fivefold. This analysis was particularly rigorous because it adjusted for both the disease activity for which the prednisone was prescribed and for traditional CV risk factors. Because CV disease remains the major cause of late death in lupus patients, it is appropriate to conclude that these prednisone doses can contribute to mortality.
These increased risks are not restricted to patients with SLE; it has been proven in other diseases, such as chronic obstructive pulmonary disease. These all point to the conclusion that prednisone can increase mortality.

Alternatives to prednisone
Not all patients with SLE have to be given chronic prednisone therapy, as there are well-documented thera peutic options. The Flares in Lupus: Outcome Assess ment Trial showed that intramuscular triamcinolone, another corticosteroid, is an effective option [4]. This randomized clinical trial recruited patients with SLE who presented with mild to moderate flares. These were patients whose disease was not life-threatening.
Instead of increasing the prednisone dose and having patients return in 1 to 3 months, subjects were randomized to a short burst of two treatment options: oral prednisone with a rapid tapering (medrol dose pack for a week); or a single intramuscular dose of triamcinolone (100 mg). This trial used patient-reported outcomes, a rational choice because patients know when their symptoms improve (for example, rash, arthritis, fever). Table 4 shows that at day 1 most patients receiving triamcinolone already felt better (approximately 70% reported partial improvement). At 4 weeks, their health status was very good.
From my viewpoint, not a single patient in this trial required additional therapy. If any patients had flared again at 1 month, this would have been a sign that they needed additional immunosuppressive therapy.

NSAID use and cardiovascular damage
In addition to eliminating prednisone use, practitioners also need to reduce use of NSAIDs, based on evidence linking chronic exposure to several toxicities. Data presented at the 2012 ACR meeting show that NSAID use significantly increases the risk of CV events in patients with mild to moderate SLE (hazard ratio, 1.66; P <0.03) [5]. This should not be a big surprise because the US Food and Drug Administration requires NSAID labeling to warn of the increased risk of CV disease. Additionally, there are known issues of nephrotoxicity associated with NSAID use in patients with lupus nephritis.

Treatment: hydroxychloroquine
Practitioners do have an option for safe, long-term background therapy in patients with SLE -hydroxy-  showed that HCQ prevented renal damage, but there were also data on prevention of central nervous system damage [7]. • Reduced CV risks. In addition to data showing reduced low-density lipoprotein cholesterol with HCQ therapy [8,9], it has also been shown to reduce thrombosis risks [10,11]. In addition, data were presented at the 2012 ACR meeting showing that HCQ reduces both arterial and venous thrombosis, particularly in antiphospholipid-positive patients with SLE. • Improved survival. Several studies have documented improvements in mortality rates associated with HCQ therapy [12]. • Improved response rates to mycophenolate mofetil therapy. Data from the Hopkins Lupus Cohort found adding HCQ to mycophenolate mofetil tripled complete renal remissions rates in patients with lupus nephritis [13].

Timing of follow-up
How often to schedule follow-up visits in a patient with stable SLE is an important clinical practice question. Data in Table 5 show that during a 2-year period one in four patients will have a silent symptom that can only be detected by laboratory tests [14]. This indicates that 3 months is the ideal time interval for routine follow-up clinical and laboratory tests.

Managing chronic fatigue
Chronic fatigue is the most common symptom in patients with SLE, affecting between 50 and 80% of patients [15]. In most patients, however, chronic fatigue is not caused by active lupus. Instead, their chronic fatigue is highly correlated with fibromyalgia, pain, depression, sleep abnormalities, and poor quality of life [16,17]. Fibromyalgia, for example, is seen in approximately 30% of patients with lupus [18]. Thus, prescribing medications for lupus will not address this complaint, and practitioners should focus efforts on treating the associated diseases that may be causing the fatigue. One option for treating fatigue in these patients is use of tai-chi exercises. Their efficacy was shown in a small but well-controlled trial that found clinically significant, durable improvement in fatigue scores after 12 weeks. These scores increased out to 24 weeks [19]. This supports recommending tai chi to all lupus patients with fibromyalgia.
Furthermore, exercise in general has been shown to be beneficial in lupus patients [20]. At 12 weeks, patients who exercised had significantly better fatigue scores than the controls (48% vs. 16%; P = 0.02). These improvements were maintained to 3 months in patients who continued to exercise. These findings support recommending aerobic exercises to all eligible patients with SLE to manage fatigue.

MEASURING DISEASE ACTIVITY
Although there is no confirmed technical standard for measuring SLE disease activity, several instruments are available. Their clinical usefulness depends on several factors related to user friendliness and complexity of the test as well as their clinical accuracy.

Physicians Global Assessment
The Physicians Global Assessment tool uses a visual analog scale to measure disease activity both globally and in individual organ systems. The tool is relatively simple and quick to complete. Research has found it to be clinically relevant [21,22] and to correlate well with other disease indices [23]. Having the tool preprinted on an encounter form makes it easy for practitioners to use. Having visual scales makes it easy for practitioners to quickly assess which organs have been active. In general, having rheumatologists complete the Physicians Global Assessment tool at every office visit provides a degree of reliability for evaluating disease activity. However, the tool does have limitations, leading to some disagreement among lupus practitioners regarding its clinical importance.

SELENA-SLEDAI
The SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment -SLE Disease Activity Index) instrument is a validated disease activity index that lists 24 lupus manifestations. It meets the requirement of being easy and quick to complete -one simply checks the box for parameters that are present at the time of visit or have occurred in the previous 10 days. The checks also make it easy for practitioners to assess the results. For practitioners, the SELENA-SLEDAI tool offers several positive features: • The index only scores parameters that are present and attributable to SLE; partial changes in disease activity are not scored. • Items are weighted with scores ranging from 1 to 8; more serious effects involving organs such as renal or the central nervous system have higher weights. • The index sets a high threshold for responses; it is not easily triggered by minimal variations in disease activity. • Score reduction requires complete elimination of disease signs and symptoms, or resolution of laboratory abnormalities. This SELENA-SLEDAI instrument has limitations in clinical practice: • The index does not track partial changes in disease activity (on the SLEDAI, it is either present or absent); thus, practitioners cannot determine whether symptoms have improved or worsened. • The composite score cannot distinguish patients with multiple mild manifestations from those with fewer but more severe features.
• Improvement in one organ may be offset by new involvement in another organ. Clinically, SELENA-SLEDAI is useful for identifying a patient's global score, but not for tracking partial improvement.

SLE Responder Index response criteria Clinical trials
Do outcome measures used in clinical trials of patients with SLE have relevance for clinical practice? Realis tically, the SLE Responder Index (SRI) -used to measure outcomes in SLE clinical trials -does not provide a practical option for clinical practice because it is not simple to use. For example, the SRI used in phase III trials of belimumab required responders to meet criteria from three tools: SELENA-SLEDAI, British Isles Lupus Assessment Group index, and Physicians Global Assess ment (see Table 6).
The most important requirement was the four-point reduction on the SELENA-SLEDAI. This can have clinical importance for measuring disease activity because point reductions on the SLEDAI only occur if the organ manifestation resolves.
It is possible, mathematically, for a patient to have both improvements and exacerbations in disease activity and still meet the criteria for a responder on SELENA-SLEDAI. For example, thrombocytopenia only counts as 1 point on SELENA-SLEDAI regardless of its severity. If a patient's platelet count dropped from 99,000 to 2,000 but some other measurements improved, then that patient would be considered a responder. To compensate, the SRI built in the flare criteria on the British Isles Lupus Assessment Group instrument and the physician global assessment to gain a more accurate assessment of a patient's disease activity.

Clinical practice
What does it really mean in clinical practice to be a responder on the SRI? Simply put, it means an improvement in disease activity. It also means the patient has had a substantial reduction in severe lupus Frequency of new isolated variables of interest in 515 patients, ≥18 months of follow-up. Adapted from [15].

Pronunciation note
In clinical practice situations, SLEDAI should be pronounced 'slee-day' rather than 'slee-die.' Patients who hear 'slee-die' may misconstrue it as an instrument that predicts mortality. Thus, it is better to pronounce it 'slee-day.' flares, which can potentially improve a patient's outcomes in terms of attending work or school, and it is likely that the prednisone dose can be reduced or, at least, not increased. Furthermore, improvements in serology matter. Patients who have high anti-DNA or low complement are twice as likely to flare during the next year, although they are not necessarily going to flare during the next week or month. Also, improvements in quality of life are important. These criteria matter to patients.
These parameters also matter to clinical researchers. Although the requirements for SRI response in clinical trials are more stringent, the goal is the same -to accurately measure clinical parameters that provide data to gauge clinically important improvements in the patient's SLE disease activity.