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Systemic lupus erythematosus

An update on treat-to-target

Roberts, Amy Lynn PA-C; Rizzolo, Denise PA-C, PhD

Journal of the American Academy of PAs: September 2015 - Volume 28 - Issue 9 - p 22–28
doi: 10.1097/01.JAA.0000470432.76823.93
CME: Rheumatology
Free
CME

ABSTRACT Systemic lupus erythematosus involves many organ systems, and its vague and multisystem manifestations make early diagnosis and treatment difficult. However, early diagnosis and treatment offer the best chance of reducing end-organ damage and achieving remission. This article describes a new strategy called treat-to-target that may help patients achieve remission.

Amy Lynn Roberts practices at the Sisselman Medical Group in Massapequa, N.Y., and is a recent graduate of the Pace Completion Program in New York City. Denise Rizzolo is an associate professor in the PA program at Seton Hall University in South Orange, N.J., an assistant clinical professor in the Pace completion program in New York City, and practices urgent care in Springfield, N.J. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Earn Category I CME Credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at http://cme.aapa.org. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of September 2015.

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Box 1

Box 1

Systemic lupus erythematosus is a chronic inflammatory disease affecting multiple organ systems as a result of immune system dysregulation, and can be fatal. The cause of lupus is not fully understood but is believed to be multifactorial.1 Early diagnosis and treatment are important in preventing tissue and organ damage and achieving remission. Reaching these goals can increase long-term patient survival and improve quality of life. The treatment of rheumatic disorders such as lupus has been a struggle: because numerous organ systems are involved, patients must take multiple medications. Although some treatments work well for certain symptoms, they can worsen others, prompting the need for further intervention.

An emerging treatment concept, treat-to-target (T2T), is being successfully applied to the treatment of rheumatoid arthritis (RA) as well as other chronic diseases.2-5 Previous clinical trials that focused on RA demonstrated how T2T better supports disease control and remission.2-5 Due to the success of this research, T2T is now being explored for patients with lupus.

In T2T, the patient and clinician mutually decide on an attainable target or level of disease and use aggressive treatments and modifications to reach the target.2,3,5 Each patient's target is individualized by their disease stage and severity. For some, the goal is to control pain or fatigue; for others, the goal is to use the lowest possible corticosteroid dose. The overall objective is remission. However, this can be difficult due to lupus' effect on multiple organ systems and the obstacles clinicians commonly encounter when trying to make an early diagnosis. This article provides a brief update on lupus and describes the benefits and challenges of using T2T.

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PATHOGENESIS

Lupus is caused by a culmination of factors, including sex, age, ethnicity, and genetics.1 Environmental exposures such as ultraviolet light, medications (Table 1), and infectious agents also are thought to have an association with lupus development.6,7

TABLE 1

TABLE 1

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EPIDEMIOLOGY

An estimated 51 per 100,000 people with lupus are living in the United States, and 2 to 8 new cases per 100,000 population are diagnosed each year in North America, South America, and Europe.1,6 Lupus is most common in black, Hispanic, and Asian patients ages 15 to 44 years.1,6 Research suggests lupus is 9 to 10 times more common in women, which suggests that hormones may be a contributing factor in its development.1,6,8 Siblings of patients with lupus are 30 times more likely to develop the disease, confirming a genetic predisposition.6

In the 1950s, about half of patients with lupus were still alive 10 years after diagnosis; as of 2000, the 10-year survival rate was over 90%.5,9 The rise in survival rate could possibly be due to increased provider awareness, leading to an earlier diagnosis and treatment.

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DIAGNOSIS AND CLASSIFICATION

Before appropriate T2T goals can be established, lupus must be appropriately diagnosed using a combination of signs, symptoms, and laboratory studies. Because the signs and symptoms of lupus are nonspecific, patients typically seek medical attention from their primary care provider first, so being able to recognize the vague signs and symptoms and make a timely diagnosis is crucial. Some of the elusive symptoms include malar or discoid rash, photosensitive rash, oral ulcers, fever, hair loss, fatigue, anemia, leukopenia, and hematuria.8 Early recognition can reduce the patient's risk for organ damage, prolong the time between relapses, and may reduce time to remission.

Criteria are available to help with classifying lupus, but are only intended for use in scientific research. A lupus diagnosis is very difficult to make, so clinicians may refer to these classification systems for guidance.

One of the most commonly used systems for diagnosing lupus was developed in 1971 by the American College of Rheumatology (ACR) and is known as the ACR SLE classification criteria. This system was revised in 1982 and again 1997 (Table 2).10,11 The presence of four of the 11 criteria (concurrently or consecutively on two separate occasions) yields a sensitivity of 86% and a specificity of 93% for diagnosing lupus.10,11

TABLE 2

TABLE 2

In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group, an international group dedicated to lupus research, modified and validated the ACR criteria and came up with new criteria called the SLICC criteria. The reason for the modification was due to many drawbacks that became apparent with the ACR criteria.12 One of these concerns included duplication of highly associated terms such as malar rash and photosensitivity. The criteria also failed to include other cutaneous and neurologic symptoms of lupus, or exclude low complement levels in its immunologic criteria.12 In addition to these limitations, the ACR criteria were never validated. Overall the revision's goal was to make the criteria more consistent with lupus' evolving pathogenesis.

SLICC criteria require the patient to meet at least four criteria, including one clinical criterion and one immunologic criterion, or the patient must have confirmed lupus nephritis via a biopsy with positive antinuclear (ANA) antibodies or anti-double-stranded-DNA (anti-dsDNA) antibodies (Table 3).12 A study that evaluated the SLICC and ACR lupus criteria revealed that, “In the derivation sample researchers concluded the SLICC misclassified fewer cases and had higher sensitivity (94%) but lower specificity (92%) compared with the ACR criteria 86% and 93%. In the validation sample the SLICC had a sensitivity of 97% and specificity of 84% compared with ACR, which was 83% and 96%.”12 To date, no one set of criteria has taken precedence.12

TABLE 3

TABLE 3

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SERUM MARKERS

Some of the more notable serologic markers supporting the diagnosis of lupus are ANA and anti-dsDNA antibodies. ANA tests have a low specificity and can be positive for many rheumatologic conditions.6,13 Only 11% to 13% of patients with positive ANA tests have a confirmed diagnosis of lupus.14 ANA also can be positive in 3% to 15% of healthy patients of all ages, and in 10% to 37% of healthy patients over age 65 years.14

The two most popular ANA tests are the indirect immunofluorescence assay (IFA) and the enzyme-linked immunosorbent assay (ELISA). The IFA is the gold standard for ANA detection because of its higher specificity, although the ELISA is more sensitive.15 Some experts recommend screening for ANA with ELISA if the clinician has a strong suspicion of a connective tissue disorder based on the patient's signs and symptoms, then confirming the results with an IFA.15

The presence of ANA in healthy people has raised many questions. The assay system used to detect ANA and intrinsic immunologic disturbances may cause positive results.13,16 ANA appears to be more prevalent among women, older adults, and blacks, and less common in patients who are obese.17

An extractable nuclear antigen (ENA) panel can be used when the ANA is positive and the clinician strongly suspects lupus. This test includes anti-ribonucleoprotein, anti-Smith, anti-SS-A (Ro), and anti-SS-B (La) autoantibodies.18 When positive, these markers may be associated with certain lupus manifestations. For example, anti-SS-A (Ro) has been linked to serositis, cutaneous lupus, and hematologic symptoms.19 Anti-RNP has shown correlation with arthritis and Raynaud syndrome.19 Ro and La antibodies can cross the placenta and cause neonatal lupus.20 Anti-Sm antibodies usually reflect the severity and activity of renal involvement.21

Patients with false-positive diagnostic test results may be at risk for lupus or other autoimmune diseases, and should be followed closely because antibody positivity can precede symptoms.22 Careful monitoring can help patients obtain early aggressive treatment and reduce the likelihood for a severe course if they develop the disease.

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ORGAN DAMAGE AND COMORBIDITIES

Lupus-related organ damage is defined as any irreparable tissue damage occurring since the diagnosis of lupus and lasting at least 6 months.23 Damage can result from the disease or its treatments, and tends to accrue over time. One area that is still under deliberation is whether disease-induced damage or treatment-induced damage should be categorized as different measures or as one.2,3 Lopez and colleagues found that age, renal activity, immunosuppressant use, and preexisting burden of organ damage were major predictive factors of irreparable organ damage and mortality.24 The SLICC Inception Cohort determined that increasing age, male sex, black Americans, and Hispanic residents of Mexico all had a higher risk of damage accrual.25

Lupus also is associated with many comorbid conditions, including cardiovascular disease (CVD), nephritis, and osteoporosis; T2T strategies hope to target these conditions.

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CVD

The chronic inflammation caused by lupus appears to cause coronary microvascular dysfunction.26 Women with lupus have twice the risk of CVD as women without lupus; pericarditis is one of the most common cardiac complications in patients with lupus.27,28 Myocarditis, endocarditis, and coronary artery disease also are common in patients with lupus.27

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Lupus nephritis

Characterized by proteinuria, hematuria, rising anti-dsDNA levels, and low complement levels, lupus nephritis affects 40% of patients and is more common in women, blacks, and Hispanics.29,30

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Osteoporosis

This common comorbidity can be attributed to the recommendation for patients with lupus to avoid sun exposure, the association between the disease and renal impairment, the overall inflammatory component of the disease, and patients' chronic use of corticosteroids.31 Corticosteroids pose a clinical challenge because they successfully treat lupus, but cause adverse reactions and contribute to organ damage.3 Because of the association between corticosteroids and organ damage, using the lowest corticosteroid dose possible is an important T2T goal.2,3

Patients with lupus who develop these or other comorbidities may have a more complicated disease course and decreased survival, making early diagnosis, treatment, and follow-up critical to preventing organ damage.

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CURRENT TREATMENTS

The goal of treatment for rheumatic conditions, including lupus, is to suppress the immune system, reduce inflammation, decrease disease activity, prevent flares, and achieve remission. Lupus has a varied course depending on the patient, so treatment goals vary. Treatment is continuing to evolve and improve; however, lupus has no cure.

Belimumab, the newest drug for lupus, was approved in 2011.32 Previously, the only approved drugs for lupus were hydroxychloroquine, corticosteroids, and aspirin.32 Belimumab is a biologic that inhibits the B-lymphocyte stimulator, a pathological factor in patients with lupus.33-35 Patients with low complement levels, anti-dsDNA positivity, and more severe disease appear more responsive to belimumab in combination with standard therapy than to standard therapy alone.33

Rituximab, another biologic that targets B cells, was unsuccessful at achieving and maintaining a major clinical response (maintaining stable mild or inactive disease without a moderate or severe flare by week 52).36,37 However, patients receiving rituximab did have a significant improvement in their anti-dsDNA and complement levels, which correlated with reductions in proteinuria.38 Patients taking biologics as the primary treatment must receive appropriate vaccinations (such as an annual influenza vaccine and pneumococcal pneumonia vaccine) at baseline due to the risk of immunosuppression. However, patients should avoid live vaccines while taking immunosuppressants, and should be monitored closely for signs of infection.

The antimalarial drug hydroxychloroquine was found to exert a protective effect on survival in addition to controlling flares and disease activity in patients with lupus.39 Antimalarial drugs usually have anti-inflammatory and antithrombotic properties, and are added to the regimen to reduce the dosages of other required medications.39,40 One of the advantages of hydroxychloroquine is its high tolerability compared with corticosteroids; hydroxychloroquine usually is given for the length of the disease, and can be taken by pregnant women without harming the fetus.39-41 Dosages may need to be adjusted for patients with kidney damage or low body weight.41 Although this drug causes few adverse reactions, rarely, patients may develop retinal toxicity, so the ACR recommends that all patients starting hydroxychloroquine have a baseline ophthalmologic examination within the first year of treatment.41,42

Corticosteroids control the inflammation associated with lupus and suppress the immune system. They can be administered orally, intramuscularly, topically, or IV (for high doses over a short period of time).43 Higher doses usually are reserved for patients with more severe complications, such as nephritis or myocarditis. Because of concern over the long-term adverse reactions to corticosteroids, a goal of T2T is to have patients on the lowest effective dose of corticosteroids.37,44 Patients taking long-term corticosteroids should be monitored for osteoporosis and cataracts.

Medications that are used off-label for lupus (due to the complexity of treating the disease) include rituximab, azathioprine, mycophenolate, and methotrexate.45

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T2T GOALS FOR LUPUS

Using T2T for rheumatic conditions is more complicated than using it for diabetes or hypertension because the goal is a reduction in disease activity or remission, rather than a numeric target such as A1C or BP.5 The T2T recommendations for lupus were developed by a working group of specialists proficient in research and treatment of lupus and an international expert panel.3 The recommendations are steppingstones that providers can use, along with clinical judgment, to apply T2T to lupus.3 Primary T2T goals should be to achieve remission, prevent damage accrual, and improve health-related quality of life to reduce patient morbidity and mortality.2,3 When remission is not feasible, the target should be the lowest possible disease activity.3 These targets have been the primary endpoints of many studies of T2T for rheumatoid arthritis, and can be measured by the various disease activity/damage indices discussed below.

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Remission

The main obstacle to using remission as a target is that the task force and other researchers have been unable to agree on a definition of remission from lupus.3 One study defined complete remission as clinical and laboratory dormancy in a patient no longer taking corticosteroid, antimalarial, or immunosuppressive treatment.46 However, patients could be taking nonsteroidal anti-inflammatory therapy. Prolonged remission was defined as remission for 5 years. However, this study determined that both prolonged and complete remissions were rare. Prolonged remission only occurred in 1.7% of patients and 6.5% of patients achieved complete remission for at least 1 year.46

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Preventing organ damage

Because of its large effect on prognosis and the connection between organ damage and subsequent impairment, preventing damage accrual is a key treatment target.3 Predicting and preventing lupus-related organ damage has always been a major obstacle for clinicians and researchers.24 Research demonstrates that damage accrual was associated with higher disease activity and corticosteroid use.24,25 Ruiz-Arruza found that 21% of patients on no prednisone accrued organ damage, compared with 30% on low doses (7.5 mg/day or less) and 53% on medium (7.5 to 30 mg/day) to high doses (more than 30 mg/day). The primary damage observed in these patients was cataracts, osteoporotic fractures, avascular necrosis, and diabetes.43 The task force was unable to come up with a safe dose of corticosteroids so the recommendation is to have patients on the lowest effective dose.3

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Improving health-related quality of life

Fatigue, depression, and pain can have devastating effects, so health-related quality of life is another primary T2T target. Although treatment decisions are based on remission, low disease activity, and damage prevention, factors that improve quality of life also must be considered as patients achieve long-term survival.3

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Reducing disease activity

Because remission is not always possible, low disease activity is a more realistic target. Disease activity, which can be reversed by treatment, can be relapsing-remitting, chronically active, or long quiescent.2 (Damage, in contrast, is irreversible.2) Lower disease activity has been associated with a reduction in damage accrual and improved prognosis.47 Because disease activity is a major therapeutic target, researchers are trying to develop a validated index to assess disease activity in clinical trials. Clinicians now use clinical expertise to evaluate disease activity in routine clinical practice.2

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ASSESSING T2T GOALS

Assessing disease activity, organ damage, and quality of life are important to monitor response to therapy, predict future organ damage, and determine if T2T goals are being met. No one instrument has been confirmed as the standard measurement system. Some available assessment tools are described below; health-related quality of life assessments also can be used.48-50

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Physician Global Assessment (PGA)

Considered by many as the gold standard measurement tool for disease activity, the PGA can be used to determine if T2T goals are being met.48,49 This tool uses a visual analog scale to assess activity globally and by organ system.49 The tool is quick and easy to use, but many providers have varying opinions on its level of importance.49

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SRI

One of the newer disease activity indices, SRI combines three disease assessments: Safety of Estrogen in Lupus: National Assessment-SLE Disease Activity Index, British Isles Lupus Assessment Group Scale, and PGA, and assesses disease improvement and treatment responsiveness.51 Because of the time needed for this tool, it is mostly used in clinical trials.51

Health-related quality of life is assessed via questionnaires such as the Lupus Quality of Life (LupusQoL), Systemic Lupus Erythematosus-Specific Quality-of-Life, and SLE Quality of Life.52 The LupusQoL is the most validated of these tools.53

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CONCLUSION

After a sudden decrease in mortality among patients with lupus, mortality has plateaued in the last 30 years.47 This triggered the need for other approaches such as T2T, which are aimed at achieving complete remission possible and ultimately stopping the acceleration of end-organ damage.

Because lupus has such an unpredictable and inconsistent progression, a standardized way is needed to assess disease activity and flares in order to develop T2T goals, formulate appropriate treatment plans, and determine if the targets are being reached. Treatment guidelines are still evolving to incorporate a T2T model; however, the research on T2T is still in the nascent phases. T2T has shown great success in the treatment and prognosis of rheumatoid arthritis, diabetes, spondyloarthritis, and other chronic conditions, so the future of using this strategy to effectively manage lupus has great potential.2

Until adequate evidence supports the T2T approach in patients with lupus, providers must work collaboratively following the current standard of care to help control this disease. Like many other diseases, early intervention and diagnosis is key to reducing morbidity, mortality, and healthcare-related costs.54

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REFERENCES

1. Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus. 2006;15(5):308–318.
2. Mosca M, Boumpas DT, Bruce IN, et al. Treat-to-target in systemic lupus erythematosus: where are we today. Clin Exp Rheumatol. 2012;30(4 suppl 73):S112–S115.
3. van Vollenhoven RF, Mosca M, Bertsias G, et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann Rheum Dis. 2014;73(6):958–967.
4. Pincus T, Castrejón I. Evidence that the strategy is more important than the agent to treat rheumatoid arthritis. Data from clinical trials of combinations of non-biologic DMARDS, with protocol-driven intensification of therapy for tight control or treat-to-target. Bull Hosp Jt Dis. 2013;71(suppl 1):S33–S40.
    5. Doria A, Gatto M, Zen M, et al. Optimizing outcome in SLE: treating-to-target and definition of treatment goals. Autoimmun Rev. 2014;13(7):770–777.
    6. Bertsias G, Cervera R, Boumpas D. Systemic lupus erythematosus: pathogenesis and clinical. In: Bijlsma JWJ, ed. EULAR Textbook of Rheumatic Diseases. 1st ed. London: BMJ Group; 2012:476–505.
    7. Antonov D, Kazandjieva J, Etugov D, et al. Drug-induced lupus erythematosus. Clin Dermatol. 2004;22(2):157–166.
    8. American College of Rheumatology. Systemic lupus erythematosus (lupus). www.rheumatology.org/practice/clinical/patients/diseases_and_conditions/lupus.asp. Accessed June 10, 2015.
    9. Mak A, Cheung MW, Chiew HJ, et al. Global trend of survival and damage of systemic lupus erythematosus: meta-analysis and meta-regression of observational studies from the 1950s to 2000s. Semin Arthritis Rheum. 2012;41(6):830–839.
    10. American College of Rheumatology. 1997 Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus. https://www.rheumatology.org/Practice/Clinical/Classification/SLE/1997_Update_of_Revised_Systemic_Lupus_Erythematosus. Accessed June 10, 2015.
    11. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.
    12. Petri M, Orbai AM, Alarcón GS, et al. Derivation and Validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677–2686.
    13. Wichainun R, Kasitanon N, Wangkaew S, et al. Sensitivity and specificity of ANA and anti-dsDNA in the diagnosis of systemic lupus erythematosus: a comparison using control sera obtained from healthy individuals and patients with multiple medical problems. Asian Pac J Allergy Immunol. 2013;31(4):292–298.
    14. American College of Rheumatology. Antinuclear antibodies (ANA). https://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Antinuclear_Antibodies_(ANA)/. Accessed June 10, 2015.
    15. Copple SS, Sawitzke AD, Wilson AM, et al. Enzyme-linked immunosorbent assay screening then indirect immunofluorescence confirmation of antinuclear antibodies: a statistical analysis. Am J Clin Pathol. 2011;135(5):678–684.
    16. Pisetsky DS. Antinuclear antibodies in healthy people: the tip of autoimmunity's iceberg. Arthritis Res Ther. 2011;13(2):109.
    17. Satoh M, Chan EK, Ho LA, et al. Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum. 2012;64(7):2319–2327.
    18. Lab Tests Online. ENA Panel. American Association for Clinical Chemistry. http://labtestsonline.org/understanding/analytes/ena-panel/tab/test. Accessed June 25, 2015.
    19. Cozzani E, Drosera M, Gasparini G, Parodi A. Serology of lupus erythematosus: correlation between immunopathological features and clinical aspects. Autoimmune Dis. 2014;2014:321359.
    20. Lupus Foundation of America website. What are the laboratory tests for Lupus? www.lupus.org/answers/entry/lupus-tests. Accessed June 25, 2015.
    21. Migliorini P, Baldini C, Rocchi V, Bombardieri S. Anti-Sm and anti-RNP antibodies. Autoimmunity. 2005;38(1):47–54.
    22. Isenberg DA, Manson JJ, Ehrenstein MR, Rahman A. Fifty years of anti-ds DNA antibodies: are we approaching journey's end. Rheumatology (Oxford). 2007;46(7):1052–1056.
    23. Gladman DD, Urowitz MB, Goldsmith CH, et al. The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index in patients with systemic lupus erythematosus. Arthritis Rheum. 1997;40(5):809–813.
    24. Lopez R, Davidson JE, Beeby MD, et al. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology (Oxford). 2012;51(3):491–498.
    25. Bruce IN, O'Keeffe AG, Farewell V, et al. Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort. Ann Rheum Dis. [e-pub May 16, 2014].
    26. Knight JS, Kaplan MJ. Cardiovascular disease in lupus: insights and updates. Curr Opin Rheumatol. 2013;25(5):597–605.
    27. Lupus Foundation of America. How does lupus affect the heart and circulation? www.lupus.org/answers/entry/lupus-and-the-heart. Accessed June 25, 2015.
    28. Hak AE, Karlson EW, Feskanich D, et al. Systemic lupus erythematosus and the risk of cardiovascular disease: results from the nurses' health study. Arthritis Rheum. 2009;61(10):1396–1402.
    29. Lupus Foundation of America. How does lupus affect the renal (kidney) system? www.lupus.org/answers/entry/lupus-and-kidneys. Accessed June 25, 2015.
    30. Saxena R, Mahajan T, Mohan C. Lupus nephritis: current update. Arthritis Res Ther. 2011;13(5):240.
    31. García-Carrasco M, Mendoza-Pinto C, Escárcega RO, et al. Osteoporosis in patients with systemic lupus erythematosus. Isr Med Assoc J. 2009;11(8):486–490.
    32. US Food and Drug Administration. FDA approves Benlysta to treat lupus. www.fda.gov/newsevents/newsroom/pressannouncements/ucm246489.htm. Accessed June 25, 2015.
    33. van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012;71(8):1343–1349.
    34. Sanz I, Lee FE. B cells as therapeutic targets in SLE. Nat Rev Rheumatol. 2010;6(6):326–337.
    35. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61(9):1168–1178.
    36. Mosca M, van Vollenhoven R. New drugs in systemic lupus erythematosus: when to start and when to stop. Clin Exp Rheumatol. 2013;31(4 suppl 78):S82–S85.
    37. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62(1):222–233.
    38. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheum. 2012;64(4):1215–1226.
    39. Alarcón GS, McGwin G, Bertoli AM, et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis. 2007;66(9):1168–1172.
    40. Lupus Foundation of America. What medications are used to treat lupus? www.lupus.org/answers/entry/medications-to-treat-lupus. Accessed June 25, 2015.
    41. Lupus Foundation of America. Spotlight on hydroxychloroquine. www.lupus.org/magazine/entry/drug-spotlight-on-hydroxychloroquine. Accessed June 25, 2015.
    42. American Optometric Association. Retinal toxicity from hydroxychloroquine. www.aoa.org/optometrists/education-and-training/clinical-care/retinal-toxicity-from-hydroxychloroquine?sso=y. [account required]. Accessed January 24, 2015.
    43. Ruiz-Arruza I, Ugarte A, Cabezas-Rodriguez I, et al. Glucocorticoids and irreversible damage in patients with systemic lupus erythematosus. Rheumatology (Oxford). 2014;53(8):1470–1476.
    44. van der Goes MC, Jacobs JW, Boers M, et al. Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice. Ann Rheum Dis. 2010;69(11):1913–1919.
    45. Lupus Research Institute. Lupus treatments. www.lupusresearchinstitute.org/lupus-facts/lupus-treatments. Accessed June 30, 2015.
    46. Urowitz MB, Feletar M, Bruce IN, et al. Prolonged remission in systemic lupus erythematosus. J Rheumatol. 2005;32(8):1467–1472.
    47. Wangnoo SK, Sethi B, Sahay RK, et al. Treat-to-target trials in diabetes. Indian J Endocrinol Metab. 2014;18(2):166–174.
    48. Mosca M, Bombardieri S. Assessing remission in systemic lupus erythematosus. Clin Exp Rheumatol. 2006;24(6 suppl 43):S100–S104.
    49. Petri M. Measuring disease activity and severity in clinical trials and then the clinic: same or different? Treatment of SLE: bridging the gap from the clinical trials to practice. Annual Congress of the American College of Rheumatology, Washington, DC, November 11, 2012.
    50. Kiani AN, Strand V, Fang H, et al. Predictors of self-reported health-related quality of life in systemic lupus erythematosus. Rheumatology (Oxford). 2013;52(9):1651–1657.
    51. Luijten KM, Tekstra J, Bijlsma JW, Bijl M. The systemic lupus erythematosus responder index (SRI): a new SLE disease activity assessment. Autoimmun Rev. 2012;11(5):326–329.
    52. Romero-Diaz J, Isenberg D, Ramsey-Goldman R. Measures of adult systemic lupus erythematosus: updated version of British Isles Lupus Assessment Group (BILAG 2004), European Consensus Lupus Activity Measurements (ECLAM), Systemic Lupus Activity Measure, Revised (SLAM-R), Systemic Lupus Activity Questionnaire for Population Studies (SLAQ), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Arthritis Care Res (Hoboken). 2011;63(suppl 11):S37–S46.
    53. Yazdany J. Health-related quality of life measurement in adult systemic lupus erythematosus: Lupus Quality of Life (LupusQoL), Systemic Lupus Erythematosus-Specific Quality of Life Questionnaire (SLEQOL), and Systemic Lupus Erythematosus Quality of Life Questionnaire (L-QoL). Arthritis Care Res (Hoboken). 2011;63(suppl 11):S413–S419.
    54. Turchetti G, Yazdany J, Palla I, et al. Systemic lupus erythematosus and the economic perspective: a systematic literature review and points to consider. Clin Exp Rheumatol. 2012;30(4 suppl 73):S116–S122.
    Keywords:

    systemic lupus erythematosus; treat-to-target; T2T; autoimmune disease; cardiovascular disease; osteoporosis

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