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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Ann Rheum Dis. Author manuscript; available in PMC Jul 1, 2011.
Published in final edited form as:
PMCID: PMC2952401
NIHMSID: NIHMS240999

European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies

Abstract

Objectives

To develop recommendations for monitoring patients with systemic lupus erythematosus (SLE) in clinical practice and observational studies and to develop a standardised core set of variables to monitor SLE.

Methods

We followed the European League Against Rheumatism (EULAR) standardised procedures for guideline development. The following techniques were applied: nominal groups, Delphi surveys for prioritisation, small group discussion, systematic literature review and two Delphi rounds to obtain agreement. The panel included rheumatologists, internists, dermatologists, a nephrologist and an expert related to national research agencies. The level of evidence and grading of recommendations were determined according to the Levels of Evidence and Grades of Recommendations of the Oxford Centre for Evidence-Based Medicine.

Results

A total of 10 recommendations have been developed, covering the following aspects: patient assessment, cardiovascular risk factors, other risk factors (osteoporosis, cancer), infection risk (screening, vaccination, monitoring), frequency of assessments, laboratory tests, mucocutaneous involvement, kidney monitoring, neuropsychological manifestations and ophthalmology assessment. A ‘core set’ of minimal variables for the assessment and monitoring of patients with SLE in clinical practice was developed that included some of the recommendations. In addition to the recommendations, indications for specific organ assessments that were viewed as part of good clinical practice were discussed and included in the flow chart.

Conclusions

A set of recommendations for monitoring patients with SLE in routine clinical practice has been developed. The use of a standardised core set to monitor patients with SLE should facilitate clinical practice, as well as the quality control of care for patients with SLE, and the collection and comparison of data in observational studies.

INTRODUCTION

Assessment of patients with systemic lupus erythematosus (SLE) in clinical practice relies upon the experience of the treating doctor and thus is subject to great variability between centres and between doctors. Much of this variability concerns the assessment of organ involvement, complicating comparisons among practices and potentially leading to poor outcomes.1 2

The aims of the present study were to address aspects for monitoring patients with SLE in clinical practice and observational studies, and to develop a standardised core set of variables for the assessment of patients with SLE in routine clinical practice.

METHODS

These recommendations have been developed following the methodology proposed by the European League Against Rheumatism (EULAR).3 The following techniques were applied: nominal group, Delphi surveys for prioritisation, small group discussion and systematic literature review (SLR).

A first meeting was held, during which a list of questions for the SLR was agreed upon. The SLR results were discussed at the final meeting. Evidence was graded according to the levels proposed by the Oxford Centre for Evidence-Based Medicine, and agreement with each recommendation was collected by Delphi technique.4 Additionally, the panellists provided an estimation of the cost and safety of individual monitoring strategies (for more information on the methodology followed see the Supplementary material).

RESULTS

Scope, target population and definitions

These recommendations have been elaborated with the intention of helping specialists involved in the care of patients with SLE in their decisions. See the Supplementary material for the definitions of monitoring, active disease and remission referred to in this document.

Recommendations

Table 1 shows the list of recommendations with the level of evidence, grade of recommendation, agreement and cost/risk ratio. (See Supplementary material for further information in the discussion that led to specific recommendations.)

Table 1
List of recommendations with level of evidence and grade of recommendation, agreement, cost/risk ratio

Recommendation 1: patient assessment

The clinical picture of SLE is extremely variable and may be related to disease activity, organ damage, drug toxicity and quality of life (QoL).5 6 Several indices have been developed and validated to measure these parameters. Although there are some concerns about feasibility, the use of validated indices facilitates the collection of relevant data that otherwise may be overlooked. The evaluation of QoL in routine clinical practice by questionnaires appeared unlikely to be feasible, and therefore the Committee agreed on QoL routine evaluation based on the patient’s history or with a 0–10 visual analogue scale (VAS). Validated questionnaires should be used to compare QoL between centres.

Recommendation 2: cardiovascular risk factors

Patients with SLE have an increased prevalence of hypertension (11.5% to 75%) and dyslipidaemia (11.5% to 75%), and usually have a sedentary lifestyle, but they do not smoke more than the general population. Fewer data are available on whether the prevalence of diabetes or obesity is increased.712

Although data from the literature have shown that the increased incidence of cardiovascular disease (CVD) and of premature atherosclerosis in SLE cannot be fully explained by traditional CVD risk factors, at present agreement exists on the need for monitoring traditional CVD risk factors and treating modifiable risk factors according to the existing guidelines. 9 1012

In view of the potential of drugs to affect the occurrence of CVD risk factors, more frequent assessments may be required in certain situations, for example, corticosteroid therapy.7 9 12

Recommendation 3: other comorbidities

The prevalence of osteoporosis among patients with SLE varies from 4% to 24% and from 10% to 20% when premenopausal patients are evaluated. Vertebral fracture prevalence ranges between 7.6% and 37%. Additional risk factors for osteoporosis in SLE include treatment with glucocorticoids, as well as other medications that may impact bone mass, and reduced levels of vitamin D related to the avoidance of sun exposure or ethnicity.1315

Cancer incidence is increased in patients with SLE, particularly haematological malignancies, cervical cancer, breast cancer and lung cancer.16 17 An abnormal cervicovaginal cytology is reported in up to 16% of examined patients and an association with cyclophosphamide therapy has been suggested.17

However Bernatsky et al have found that patients with SLE undergo cancer screening (mammogram, faecal occult blood and cervical smear test) even less frequently than the general population. 18 Therefore patients with SLE should at least follow cancer screening recommended for the general population. However, taking in consideration the epidemiological and clinical characteristics of patients with SLE, the development of SLE specific guidelines might be considered.

Recommendation 4: infection risk

Patients with SLE do not have an increased incidence of HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.19 However, in view of the risks of infection reactivation following immunosuppressive therapy, particularly glucocorticoids, patients with any personal risk factor should be screened for HIV, HBV and HCV infections before administering these medications.

The frequency of tuberculosis (TB) among patients with SLE is higher than expected, varying with background incidence (2.5% to 13.8% in countries with endemic TB and 0% to 1.4% in countries with a low incidence of TB).20 Routine TB testing in patients with SLE is not recommended in non-endemic areas. However, TB testing before glucocorticoids and immunosuppressive drugs is recommended according to the US Centers for Disease Control and Prevention (CDC) recommendations.21

Cytomegalovirus (CMV) antigenaemia has been reported in 18% to 44% of patients. Antigen concentrations appear higher in patients treated with pulse methylprednisolone and pulse cyclophosphamide. As CMV infection may mimic active SLE and might be frequent with high dose corticosteroid therapy, testing for CMV (antigenaemia) should be considered particularly in patients with active disease undergoing therapy with high dose glucocorticoids.22 23

In view of the morbidity and mortality associated with infections, patients with SLE would greatly benefit from vaccination.2426 Some data show that vaccination may be associated with the development of autoimmunity, which has raised concerns about its safety in subjects with autoimmune diseases. Several studies have shown that flu vaccination is safe and does not lead to SLE flares, with the majority of patients developing protective antibodies. Similarly, vaccination against Pneumococcus appears safe, although reduced anti-pneumococcal antibody production has been reported. Hepatitis B vaccination of 28 patients with SLE with currently inactive SLE has been reported. All patients developed protective antibodies and no increase in SLE flares was observed. Tetanus toxoid administration was not associated with disease flares either, and 90% of patients developed protective levels of antibodies.

Inactivated live vaccines are contraindicated in patients taking immunosuppressive drugs and/or glucocorticoids at a dose >20 mg/day.

Lymphocyte counts of ≤1×109/litre and low levels of IgG3 (≤60 µg/ml) or IgG4 (≤20 µg/ml) have been associated with an increased risk of infections.27 28 Total IgG and subclass levels should be assessed at the patient first assessment and during follow-up visits particularly in patients taking immunosuppressive drugs.

Recommendation 5: frequency of assessments

No data are available in the literature to suggest an optimal frequency of clinical and laboratory assessment in patients with SLE. The committee arbitrarily agreed on the need to assess patients with inactive disease, in the absence of organ damage and comorbidities, every 6–12 months. During these evaluations, emphasis should be given to the discussion of preventive measures such as sun avoidance, adequate vitamin D and calcium intake, weight control and other measures to reduce cardio vascular risk, QoL, occupational problems and pregnancy planning. Patients in whom immunosuppressive therapy is being reduced need to be monitored for reactivation of disease, especially those with renal disease, which may recur without symptoms.

Recommendation 6: laboratory assessment

Changes in anti-double-stranded (ds)DNA antibody titres sometimes correlate with disease activity and active renal disease, and may be useful in monitoring disease activity. The available data, however, do not support the indication of treating patients with anti-dsDNA antibodies in the absence of clinical activity.2931 Few data are available on the association between anti-dsDNA and damage development.

Anti-Ro, anti-La and anti-ribonucleoprotein (RNP) antibodies may have prognostic value in SLE. Anti-Ro/Sjögren syndrome antigen A (SSA) and anti-La (SSB) antibodies have been associated with the occurrence of neonatal lupus.31

Anti-phospholipid (aPL) antibodies have been associated with general disease activity, thrombotic manifestations, damage development as well as pregnancy complications.3234 A possible role of aPL in early graft loss among patients with SLE undergoing kidney transplant has been suggested.35

Complement levels are sometimes associated with active disease, although no predictive value for the development of disease flares has been reported.36

Severe anaemia has been variably associated with organ involvement, disease progression and worse prognosis. Similarly, thrombocytopenia has been associated with renal disease, disease progression to end-stage renal disease and worse prognosis. Severe leucopenia and lymphopenia have been associated with the occurrence of infections.27 31

Serum albumin, creatinine, urinalysis and urine protein/creatinine ratio provide information on the presence and prognosis of renal involvement.31 3739

The significance of C reactive protein (CRP) in SLE remains controversial. Many authors reported that patients with SLE rarely have elevated CRP levels and, in the case of a significant increase along with clinical suspicion, a superimposed infection should be excluded, especially in the presence of very high values (>50 mg/litre).40

Recommendation 7: mucocutaneous involvement

Cutaneous manifestations of lupus erythematosus include LE-specific (acute cutaneous LE (CLE), subacute CLE, chronic CLE and intermittent CLE) and LE-non-specific lesions.41 42

The diagnosis of CLE may be difficult, as many conditions may mimic LE, and therefore may require evaluation by an experienced dermatologist and a skin biopsy for histological analysis.

Follow-up repeat biopsy is recommended if there is a change in the clinical morphology of the lesions or if there is a lack of response to treatment.

The use of Cutaneous Lupus Disease Area and Severity index (CLASI) in clinical practice might be considered, at least in patients with SLE with prevalent cutaneous manifestations.42

Recommendation 8: kidney

Serum creatinine, urine sediment analysis, proteinuria and blood pressure have a predictive value for the presence and outcome of kidney involvement and the occurrence of flares.39 4345 Relapses of kidney disease are common, being observed in up to 45% with a flare rate of 0.1–0.2 flares/patient/year. The risk of doubling serum creatinine ranges between 7.4% and 8.5% at 5 years and between 14.3% and 18.2% at 10 years.

The following variables have been associated with renal survival at 5 years: age, ethnicity, serum creatinine, hypertension, C3 complement, kidney biopsy, activity index and chronicity index.3138

Guidelines have been published for the monitoring of patients with chronic kidney disease (http://www.kidney.org).

Recommendation 9: neuropsychiatric manifestations

Neurological involvement (central, peripheral, autonomic) occurs frequently in SLE. The most frequent syndromes observed are headache, mood disorders, seizures, cognitive impairment and cerebrovascular disease.46 47

The assessment of neurological symptoms is difficult and no specific instrument has been evaluated in clinical practice. Therefore, it has been suggested that patients should be monitored by clinical history. Cognitive impairment may be assessed by evaluating memory, attention, concentration and word-finding difficulties.

Recommendation 10: eye assessment

The incidence of retinopathy among patients with SLE treated with antimalarial drugs is low (0.5%).48 49 Risk factors are age (above 60 years), presence of macular degeneration, retinal dystrophy, obesity, liver disease, renal insufficiency, duration of therapy >5 years, daily dose of hydroxychloroquine above 6.5 mg/kg, or chloroquine above 3 mg/kg.48 49

Recommendations on screening for antimalarial retinopathy include a baseline eye assessment according to published guidelines. 50 Thereafter, in low-risk patients, no further testing is required for the next 5 years; after the first 5 years of treatment, eye assessment is recommended yearly. In high-risk patients, an eye assessment is recommended yearly.50

Systemic glucocorticoids increase the risk of cataracts and of glaucoma. Authors have reported glaucoma in 19% of subjects with rheumatic diseases treated with >7.5 mg/day of prednisone versus 3% of those treated with 7.5 mg/day.15

In addition an eye assessment may be required if there are symptoms suggesting eye involvement by lupus.

Core set of variables for the assessment and monitoring of patients with SLE in clinical practice

In addition to the recommendations, other assessments were discussed and included in a core set of data to be collected in routine clinical practice (see Supplementary material). The core set is given as a paper chart that could serve as a guide for data collection (see Supplementary material).

DISCUSSION

We have developed a set of recommendations and a core set of variables that could be used for monitoring SLE in clinical practice. We do acknowledge the limitations of the present recommendations. First, these recommendations take into consideration only some aspects of the patients’ assessment. Some issues were not included or removed as these were felt to be standard good clinical practice or the panellists could not agree as the evidence was contradictory. Second, there was no direct evidence to support most recommendations directly, as studies on specific monitoring protocols are few. Finally while several aspects may be very important (for instance checking blood pressure at least once a year), others may be less essential (for instance checking blood glucose yearly in patients not on corticosteroid therapy). Another product of this study is the future research agenda. This should include the development of quality indicators, an update based on new data on biomarkers for activity, the development of specific guidelines for cancer screening and the development of specific guidelines for kidney biopsy.

An evidence-based guide to the minimum requirements for monitoring patients with lupus should decrease unwanted variability in clinical practice. In addition the use of a standardised core set may improve the quality of care offered to patients with SLE and provide data that could be used in observational studies.

Supplementary Material

appendix 1

appendix 2

appendix 3

methods

recommendations

Acknowledgements

We are thankful to Anja Schönbächler from EULAR for supporting the meetings and to Juan Antonio Martínez from the Spanish Society of Rheumatology for helping in the search strategies and in the creation of the data collecting forms.

Footnotes

Data Supplement "Web Only Data" http://ard.bmj.com/content/suppl/2010/06/11/ard.2009.117200.DC1.html

Provenance and peer review: Not commissioned; externally peer reviewed.

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