Systemic lupus erythematosus (SLE) is a complex autoimmune disease, predominantly affecting young women during the prime years of their life. The chronic nature of the disease, its relapsing remitting course and organ damage accrual over time frustrate both the physician and the patient. Clinical and translational research has advanced the available therapeutic options, translating into better patient outcomes. Five-year survival in patients with SLE has improved from 50% in the 1950s to over 90% currently. However, the mortality still remains high compared with the general population.

Multiple aspects of SLE remain challenging. The diverse and nonspecific presentations can lead to delay in diagnosis. Disease monitoring remains difficult due to the low sensitivity of current disease activity markers. Management of refractory disease, especially nephritis, cutaneous and neuropsychiatric manifestations, remains unsatisfactory. End-stage renal failure, scarring cutaneous lesions and neurological damage remain fearsome complications of the disease. Cardiovascular disease secondary to accelerated atherosclerosis has emerged as an important contributor to the higher morbidity and mortality in longstanding disease. Damage due to both disease and treatment, especially corticosteroid-associated damage, tends to accumulate over time. Fatigue, fibro-myalgia and depression negatively impact the quality of life (QoL). Clinical research in the field of SLE therapeutics has met with limited success in recent years. Heterogeneous patient populations, limitations of out-come measures and the lack of a uniform control group are mostly responsible for the suboptimal responses.

Although there are numerous unmet medical needs in SLE, this review will focus on some of the major out-standing issues - including early diagnosis, biomarkers in SLE, management of refractory disease, atherosclerosis in SLE, corticosteroid-associated damage, QoL in SLE, and clinical research in SLE.

SLE is a multi-system heterogeneous disease with protean manifestations. Initial nonspecific presentations can lead to diagnostic delays. The revised American College of Rheumatology (ACR) classification criteria, although not designed for diagnostic purposes, have been used by rheumatologists for almost three decades 1. The Systemic Lupus International Collaborating Clinics (SLICC) group recently developed another set of revised criteria. These new criteria include 17 variables derived by expert consensus (SLICC committee members) and statistical analysis, using real-life patient scenarios. The final set of new criteria was then validated in another group of SLE patients and controls. The control group comprised other autoimmune diseases, which may have overlapping features with SLE.

SLICC criteria require that at least one clinical criterion and one immunologic criterion be present, with a total of four criteria, to have a classification of SLE. Under this new classification, lupus nephritis by biopsy (in the presence of SLE autoantibodies) is sufficient for classification 2. Using expert consensus as the gold standard, the revised criteria demonstrated greater sensitivity (97% vs. 83%, P <0.0001) but less specificity (84% vs. 96%, P <0.0001) than the current ACR criteria in the validation group 2. These criteria are clinically more relevant and will probably identify more patients with clinically defined lupus than using the current ACR criteria. How-ever, one should stress that these criteria are primarily meant for classification of patient cohorts for research and their use for diagnostic purposes has to be carried out with caution. Some patients may initially present with insufficient features to fulfill the classification criteria, termed 'incomplete lupus' or 'lupus-like disease' by some groups.

SLE is the most diverse autoimmune disease, clinically and serologically. Genetic influences as well as epigenetic and environmental interactions probably play a role, perhaps dependent on the ethnic background of the individual. Classification criteria may help but currently, there is no single parameter that is sensitive or specific enough to correctly identify or subtype all SLE patients. Similarly, the disease course can be variable with either intermittent flares or chronic activity. Levels of auto-antibodies (anti-double-stranded (DNA) antibody) and complement components represent serologic disease activity. They are routinely used to monitor disease activity in most clinical settings, but their association with clinical activity has not been consistent in longitudinal studies 3.

There is an unmet need for more sensitive and reliable biomarkers that can predict susceptibility, activity, severity and disease subtype in SLE. Multiple candidate markers have been proposed, including the type 1 interferon signature, B-lymphocyte stimulator and many others 45678910111213. These markers are currently only a research tool and not a single biomarker has been validated for clinical use to date. As SLE is a heterogeneous disease, a single biomarker is unlikely to be sufficient. Rather, different markers may provide information about specific disease aspects, as summarized in Table 1.

There is no clear definition of refractory disease in SLE, but it generally refers to patients who fail to respond to conventional treatments. In a heterogeneous disease such as SLE, the clinical situation may vary, depending on the disease manifestations and organ involvement. Although any clinical feature may become persistent and non-responsive to therapy, the most concerning features are refractory lupus nephritis, scarring cutaneous disease and neuropsychiatric lupus (NPSLE).

SLE is associated with premature and accelerated atherosclerosis, contributing significantly to the increased mortality and morbidity associated with the disease 49. An increased frequency of conventional risk factors, such as hypertension, dyslipidemia and diabetes, has been noted in patients with SLE. Yet the excess risk cannot be fully explained by the traditional Framingham risk factors 5051.

Multiple putative mechanisms have been proposed but the exact pathogenesis of atherosclerosis in the setting of SLE is yet to be fully elucidated. High-density lipoprotein was reported to be significantly dysfunctional and pro-inflammatory in SLE patients, and correlated with measures of subclinical atherosclerosis 52. Endothelial cell dysfunction in SLE leads to abnormal vascular reactivity and repair, contributing to the accelerated atherogenesis 53. Interferon activity was independently associated with subclinical measures of atherosclerosis in a cohort study 54. Specific subtypes of peripheral blood mononuclear cells, the low-density granulocytes, and increased Toll-like receptor signaling have been proposed to contribute to higher interferon production and vascular dysfunction in patients with SLE 5556. Autoantibodies including antiphospholipid and antilipoprotein antibodies have been associated with abnormal vascular function and atherosclerosis in SLE 57.

Despite the evidence of a link between inflammation and atherosclerosis in SLE, multiple studies have failed to show any consistent association of coronary calcium scores or carotid plaques with markers of disease activity 515859. In patients with SLE, the proportion of noncalcified vulnerable plaque was shown to be increased compared with the calcified stable plaque, and correlated with measures of disease activity 60. Elevated homocysteine, asymmetric dimethylarginine, leptin and high-sensitivity C-reactive protein levels have been proposed as markers of accelerated atherosclerosis in SLE in some studies 61626364.

The management of atherosclerosis in SLE is currently limited to the control of traditional risk factors. Statins are believed to have anti-inflammatory properties, in addition to their lipid-lowering effects. However, two large randomized controlled trials failed to show any beneficial effects of 20 mg atorvastatin versus placebo in adult and pediatric SLE patients without clinical cardiovascular disease 6566. The use of statins in SLE patients should thus be limited to treat hyperlipidemia. Hydroxychloroquine was noted to have weak protective effects on cardiovascular risk in SLE 28. Mycophenolate reduced the atherosclerotic burden in mice models but failed to reduce progression of subclinical atherosclerosis in a large cohort study 6768. Several trials evaluating anti-interferon therapy in SLE are currently ongoing, and beneficial effects on atherosclerosis might become evident. However, no SLE treatment is currently of proven benefit to reduce the risk of or halt the progression of atherosclerosis in SLE.

Corticosteroids are the mainstay of therapy for SLE, with proven efficacy. The harm they cause in the short term and the long term, however, is one of the major issues in SLE management. Corticosteroids increase the traditional cardiovascular risk factors, including serum lipids, blood pressure, weight and glucose. Fifteen years after the diagnosis of SLE, the majority of permanent organ damage can be attributed to the corticosteroids. Although the risk of damage is higher with high doses, there is no safe dose for chronic use. Even small doses, if continued long enough, will significantly increase the morbidity 69. The cumulative dose of corticosteroids has significant association with cataracts and osteoporotic fractures. Both the current dose and the cumulative dose are associated with cardiovascular events 70. When adjusted for confounding by indication due to SLE disease activity, the hazard ratio for organ damage increases dramatically with prednisone doses of 6 to 12 mg/day (hazard ratio = 1.5), 12 to 18 mg/day (hazard ratio = 1.64) and >18 mg/day (hazard ratio = 2.51) 69. Every attempt should be made to minimize the dose and duration of corticosteroid exposure.

The QoL in patients with SLE is significantly lower than in healthy controls and patients with other chronic diseases 7172. Disease activity and organ damage did not consistently correlate with lower QoL in SLE. Instead, the major predictors of poor QoL in SLE are nondisease-specific variables including fatigue, chronic pain and mood disturbances 7172.

Fatigue is a common and often crippling symptom experienced by about 85 to 92% of patients with SLE, with 50% rating it as the most disabling symptom 73. Fatigue can significantly contribute to the poor QoL in SLE patients 72. The pathophysiological mechanisms of SLE-related fatigue are probably multifactorial, with a predominant role being played by the psychological domains. Psychosocial factors such as mood disorders, anxiety, poor sleep quality and chronic pain syndrome have shown consistent associations with fatigue in SLE 7475. Exercise programs have been shown to have a positive impact on fatigue among SLE patients 76. However, fatigue remains an unmet need, reflected by the finding that 81% of SLE patients feel that the healthcare service did not support them enough in the management of SLE-related fatigue 77.

Fibromyalgia is a chronic pain disorder characterized by widespread generalized pain, often associated with fatigue, anxiety and sleep disturbances. The prevalence of fibromyalgia is much higher in SLE patients, compared with the general population 78. Fibromyalgia in SLE contributes to the lower QoL and correlates with psychosomatic and affective variables but not with disease activity or damage 787980. The widespread pain of concomitant fibromyalgia can lead to diagnostic confusions and potential overtreatment if symptoms are mistaken for SLE disease activity.

Mood disturbances are very common in patients with SLE, with depression being the most prevalent affective symptom 8182. Depression contributes to the fatigue and cognitive dysfunction, and significantly correlates with lower QoL in patients with SLE 457183. Although psychological effects of dealing with a chronic disease may contribute to the high prevalence of depression, disease-specific mechanisms probably play a role. Associations with specific antibodies and alterations in cerebral blood flow have been reported in depressed SLE patients 8485. However, the data are not conclusive and depression in patients with SLE should be treated with conventional measures similar to the general population.

Despite advances in therapies, the control of disease activity in SLE remains suboptimal. Flares are common and sustained disease control is generally limited to a small fraction of patients 86. These findings suggest that, despite significant improvements in SLE treatment, conventional approaches have probably reached their maximal benefit and alternate options have to be considered. Multiple new agents with immunomodulatory effects have been investigated in recent years but limited success has been achieved. Two large randomized controlled trials evaluating rituximab for treatment of SLE failed to meet their primary endpoints, despite good efficacy data in open-label studies 2387. Only belimumab showed efficacy in randomized controlled trials and received US Food and Drug Administration approval for treatment of SLE 8889. These studies have raised important issues that should be addressed in future SLE research.

The heterogeneous nature of the disease makes it difficult to design clinical studies in SLE. In the absence of specific biomarkers, classification criteria are generally used to define study populations. Although these criteria encompass the breadth of the disease spectrum, patients with diverse manifestations and probably different pathogenic mechanisms will be grouped together. This limitation can be avoided by defining specific disease subgroups based on organ manifestations, such as renal disease. However, this would seriously limit the eligible patient population, however, stressing the need for multicenter collaborative projects. Limiting the inclusion in this manner may not be even a viable option if uncommon manifestations are considered. Currently, some degree of heterogeneity in study populations has to be accepted.

Another major issue in SLE research has been the choice of outcome measures. The US Food and Drug Administration draft guidance statement on SLE clinical trials suggested the use of disease activity indices to measure the efficacy of the intended intervention 90. Several such indices have been developed and validated for use in clinical trials. Some disease activity indices - such as the SLE Disease Activity Index (SLEDAI) and its variants (SLEDAI-2K, SELENA-SLEDAI) - measure overall disease activity, while others - such as the British Isles Lupus Assessment Group Index (BILAG) - measure organ-specific activity. Physician's global assessment uses the treating physician's overall assessment to assign a numerical value to the disease activity on a visual analog scale of 0 to 3 91. This assessment has been used to define flares (>1 point rise) in clinical trials 91. Physician visual analog scale rating was found to have high variability in a comparative study of outcome measures by the SLICC study group 92, but it has been successfully incorporated as part of the SLE Responder Index (SRI) 93. The SLE Responder Index is a composite index developed to incorporate the strengths of different disease activity indices. This index provides a comprehensive definition of meaningful clinical response and has been used to define the primary end point in clinical trials 93. The SLE Responder Index utilizes the SELENA-SLEDAI score to determine global improvement, British Isles Lupus Assessment Group Index domain scores to ensure no significant worsening in previously unaffected organ systems, and physician's global assessment to ensure that improvements in disease activity are not achieved at the expense of the patient's overall condition 93. The SLE Responder Index has been used successfully in the belimumab phase 3 trials and has the potential to serve as an outcome measure in the future SLE therapeutic trials.

The background immunosuppression used as the standard of care in SLE trials adds another confounder to the picture. Most studies have employed diverse background treatments in both the treatment and placebo groups, to which the candidate agent is added. In addition, treatment adjustments have been either mandated or at least allowed during the studies. However, these concomitant therapies may have their own effects, masking the efficacy of the target intervention. Examples include the failed LUNAR and EXPLORER trials, in which rituximab or placebo were added to background therapy including high-dose corticosteroids and immunosuppressive drugs such as mycophenolate 2387. Efficacy of rituximab over placebo was not found in these trials, despite a large body of evidence favoring rituximab in observational and cohort studies. In contrast, the belimumab trial design permitted early tapering of corticosteroids and may have contributed, at least partially, to the positive results 8889. However, designing a trial in SLE where the active arm receives only the experimental agent will be difficult and unethical. There is a need to develop a clearly defined standard of care control arm, against which the newer agents can be tested.

The field of SLE clinical and therapeutic research is advancing rapidly. Large international collaborations have resulted in development of new criteria, composite outcome indices and insights into disease pathogenesis. Multiple newer biologic agents targeting specific immune system pathways and effectors are undergoing evaluation 94. Hopefully, these efforts will lead to development of newer therapeutic agents in SLE, a dire need.

The management of SLE remains a challenge despite significant advances in the treatment. The new SLICC classification criteria with better sensitivity will probably help in better identification of patients, but we have not yet reached the stage where early diagnosis can be universally achieved. The field of disease biomarkers is rapidly evolving with many putative candidates. However, no biomarker has been successfully validated for use in the routine clinical setting. Instead of a single measure, a battery of markers may perhaps be developed in the future to predict different disease aspects in a heterogeneous disease such as SLE. Refractory disease manifestations and development of damage associated with disease and therapies remain outstanding issues. Premature mortality and higher morbidity from atherosclerosis in this predominantly young group of patients are a major concern. Fatigue is one of the most prevalent and disabling symptom in SLE, significantly contributing to the poor QoL. The quest for newer targeted therapies has met with limited success despite many clinical trials. Whether there is a true lack of efficacy or whether the trial designs in SLE are partly to blame is open to discussion. However, advances have been made in developing reliable outcome measures for clinical research. Future research will focus on the goals of increasing survival, limiting organ damage and improving QoL for patients with SLE.

ACR: American College of Rheumatology; IL: interleukin; NPSLE: neuropsychiatric lupus; QoL: quality of life; SLE: systemic lupus erythematosus; SLEDAI: SLE Disease Activity Index; SLICC: Systemic Lupus International Collaborating Clinics; TNF: tumor necrosis factor.

The authors declare that they have no competing interests.

This article has been published as part of Arthritis Research & Therapy Volume 14 Suppl 4, 2012: New therapeutic targets in systemic lupus erythematosus. The supplement was proposed and developed by the journal. Articles were commissioned by the journal, were independently prepared by the authors and have undergone the journal's standard peer review process. Publication of the supplement has been supported by an unrestricted educational grant from UCB. Completed articles underwent a data quality check by Darwin Healthcare Communications, funded by UCB