The British Society for Rheumatology Guideline for the Management of Systemic Lupus Erythematosus in Adults

Caroline Gordon; Maame-Boatemaa Amissah-Arthur; Mary Gayed; Sue Brown; Ian N. Bruce; David D'Cruz; Benjamin Empson; Bridget Griffiths; David Jayne; Munther Khamashta; Liz Lightstone; Peter Norton; Yvonne Norton; Karen Schreiber; David Isenberg

Disclosures

Rheumatology. 2018;57(1):e1-e45. 

In This Article

Rationale

Frequency of Monitoring Lupus/Follow-up Visits

There are no randomized controlled trials (RCTs) comparing different monitoring strategies in terms of frequency and details of assessments performed; however, data from various cohort studies have informed our expert opinion and previous guidelines in this respect.[22,71,74,278] Patients should be told to report to clinicians if they develop any new or significant worsening of clinical manifestations. In most patients with active clinical disease, clinic visits should be approximately every 4 weeks initially, reducing gradually down to about 3-monthly reviews as the disease comes under control. There remains a significant risk of flare and the development of damage, even for patients who achieve early remission.[72] For most patients with mild features, including those who are clinically quiet but serologically active, 3-monthly visits are adequate.[77] Review should become more frequent if the disease becomes more active, especially if there is renal involvement, as the patients will require clinical, renal and serological evaluation (see below).[285] For patients with inactive disease, without previous renal involvement or organ damage (that can predict increased risk of further active disease and damage), review may be less frequent, for example every 6 months providing treatment is stable and suitable drug monitoring is in place.[74] Patients should be seen more regularly, however, if treatment is being withdrawn or has been stopped, due to the risk of disease flare, even if they appear to be in remission.[72]

Reasons for Clinical Monitoring in Lupus Patients

Regular monitoring of clinical and laboratory features of active disease should take place, with additional investigations as necessary (Table 6), to assess and monitor changes in disease activity, the development of chronic damage, and to detect the presence of (and changes in) co-morbid conditions that may be confused with lupus (such as FM, hypothyroidism, iron deficiency anaemia, infection), and drug-induced conditions.[22,74,265] LOEs for the laboratory parameters are shown in Table 1. Proteinuria (and renal function in particular[24]), high DAS,[16,48,73,286] new and different types of cutaneous lesions,[50] arthritis,[72] NP disease[16,51] and cytopenias[52,53] have been shown to correlate with disease severity and can predict future flares and the development of damage.[11,32,49,54,55] Only measurement of proteinuria and renal function have been shown to have strong predictive value for outcome.[22,24,56] Chest X-ray, ECG and other specific tests such as lung function, echocardiography and neurophysiology should be repeated during the course of the disease as necessary. When major organs are involved, additional imaging (such as brain MRI) and pathology (renal/skin biopsy) can add significant prognostic information, particularly renal biopsy, and may need to be repeated to assess response to treatment.[22–24,287,288]

Interpretation of Haematological, Renal and Other Biochemical Parameters

Lymphopenia is a common manifestation of lupus (Supplementary Table S3, available at Rheumatology Online), and some patients will have leucopenia and neutropenia regularly with active disease.[53] This needs to be remembered when monitoring patients on cytotoxic therapy, as a fall in cell counts may signify the need to increase therapy for lupus rather than reduce or discontinue therapy if drug toxicity is suspected. It also means that the usual drug-monitoring limits of tolerance may need to be reviewed and personalized in the context of an individual with SLE. Thrombocytopenia may be acute and indicative of a disease flare, or low grade and chronic as part of of lupus and/or associated with APS.[57]

ESR is often raised in active SLE,[70] but can also reflect persistent polyclonal hypergammaglobulinaemia, and is not a reliable marker of disease activity. CRP is usually normal[66–68] or slightly elevated in the presence of serositis or arthritis.[69] A significantly raised CRP is more likely to indicate infection, and patients with raised CRP will need therefore to be thoroughly screened for infection, given that infection is the commonest cause of death in lupus patients. In contrast, a raised ESR does not discriminate between active lupus and infection.[69] Immune complexes of CRP and anti-CRP antibodies may form in lupus patients, possibly explaining the low levels of CRP observed with active disease.[67]

Proteinuria should be quantified using the urine protein:creatinine ratio or 24-h urine collection. Microscopic examination of the urine to look for red cells and red cell casts is useful for identifying active renal disease and renal flares, but the assessment of casts is now rarely done.[24,289,290] When assessing haematuria, it is important to exclude infection, menstrual blood loss and calculi. White cells in the urine are most often due to urine or vaginal infection and can be hard to interpret, but as an otherwise unexplained finding, are associated with active tubulointerstitial inflammation.

Serum immunoglobulins should be measured prior to starting drugs such as MMF, CYC and rituximab which have the most risk of inducing immunoglobulin deficiency that might increase the risk of infection. The initial repeat measurement of the serum immunoglobulins should take place about 3–6 months later and can then be spaced out to annual checks.[74,199,291,292,293] Specific antibodies, for example, pneumococcal antibodies, may be assessed (if tests are available) to assess the need for and response to immunization. Screening for chronic infections (such as TB, hepatitis B and C, HIV, HPV) is recommended before starting immunosuppressants and repeated if reactivation of infection is suspected.

It is important to measure creatinine kinase at baseline and to continue to follow it in patients with myositis or myalgias that might be due to lupus or statins used to prevent atherosclerosis.[75] Monitoring of cholesterol and of other lipids, and remaining vigilant for and treating the development of diabetes mellitus and features of the metabolic syndrome (which may increase cardiovascular risk, particularly in patients on glucocorticoids), are important and should be as successful as in the general population.[71,74,76] Additional monitoring investigations should include Vitamin D3, which is often low as a consequence of sun avoidance and/or chronic kidney disease.[294] Vitamin D is required for optimal bone health, especially in patients on chronic glucocorticoid therapy and/or following the menopause.[295] Clinicians should have a low threshold for assessing thyroid function, as hypothyroidism can present with similar features to lupus; it co-exists with lupus in ~7% of patients, and thyroid antibodies are found in 14%.[296–298]

Monitoring of Lupus Autoantibodies and Complement

Serial anti-dsDNA antibodies and C3 and C4 levels are useful because rising, high anti-dsDNA antibodies and falling, low complement levels are associated with flare,[49,58] particularly in patients with LN.[24] In general, concomitantly rising anti-dsDNA titres[39,43,46,49,59,60] and decreasing C3 and/or C4 levels[43–46] are more important predictors of current or impending flares than the absolute levels, and levels of anti-dsDNA antibodies may actually fall at the time of flare.[299]

It can be helpful to combine a sensitive but less specific anti-dsDNA antibody assay (e.g. ELISA) with one that only measures more specific, high affinity or high avidity antibodies (such as Farr radioimmunoassay or the Crithidia test), because only tests measuring high affinity and high avidity antibodies are strongly associated with renal disease; however, other ELISAs can be used to monitor disease activity.[40] Stable active serology without clinical features does not necessarily warrant therapy,[71] but patients need to be followed closely, with individual care decisions made to prevent over- or undertreatment. Many physicians would avoid reducing therapy in this situation as patients may develop renal disease,[300] but the serological tests do not always predict flare.[61,62,71] About 40% of lupus patients do not have anti-dsDNA antibodies, so for this group of patients, they are not useful for monitoring disease activity.[63] Some patients are heterozygous for the C4 allele and due to a null allele have a persistently low C4 level (at about 50% of normal), without having active disease, but C4 levels can still fluctuate with disease activity.

ANA, anti-Sm and anti-RNP antibodies tests should be carried out at baseline and do not need to be repeated at each visit, as levels do not fluctuate with disease activity. Anti-Ro and anti-La antibodies should be measured in women planning pregnancy or in early pregnancy, as they may be transferred across the placenta and are associated with CHB in ~1–2% of babies.[64,65] Fetal heart-rate monitoring should be instituted from week 16 of pregnancy and continued throughout pregnancy in women with either of these antibodies. Neonatal lupus rash develops in ~10% of babies born to mothers with these antibodies (especially if exposed to UV light), and laboratory abnormalities (cytopenias and abnormal liver function tests) have also been observed in babies exposed to these antibodies.[64]

aPLs should be assessed at baseline and, if previously negative, they should be re-evaluated in the presence of a new vascular event, adverse pregnancy outcome or other new manifestation that might have a thrombotic component, as well as prior to a planned pregnancy.[47,241,252,253] Positive tests for APS include LA, aCL (IgG, IgM) and/or anti-beta-2 glycoprotein 1(IgG, IgM), and these tests should be repeated after 12 weeks to confirm positivity,[241,252] although LA cannot be evaluated if anticoagulation has been started, as this would interfere with the assay.

Monitoring for the Development of Co-morbidities

Patients with lupus are at increased risk of co-morbidities,[71,74] such as infection, premature cardiovascular and peripheral vascular disease, osteoporosis, avascular necrosis and some malignancies (non-Hodgkin's lymphoma, cervical, vulval, lung and thyroid cancer[301,302]). The management of these issues is beyond the scope of this guideline and should follow national/international guidelines for each condition and include appropriate vaccinations.[22,71,74,278] Nevertheless, screening for and managing these conditions is an integral part of the assessment and regular monitoring of lupus patients, as described in the EULAR recommendations for monitoring patients with SLE in clinical practice and in observational studies.[74] A preventative approach should be adopted, since the commonest causes of death in lupus patients in the UK are infection and cardiovascular disease, followed by malignancy.[15,16,18] Modifiable risk factors for co-morbidities to address include vaccination status, hypertension, dyslipidaemia, diabetes, high BMI and smoking. These should be reviewed at baseline and at least annually thereafter.[22,24,71,74] These co-morbidities may occur at a younger age than in the normal population, and clinicians should screen regularly for them, even though there are no RCTs to suggest that more intense screening than that applied in the general population improves outcome in lupus patients.[22,24,71,74] Routine cancer screening (particularly for cervical cancer, given the increased risk of HPV infection in lupus patients[303]) should not be forgotten due to emphasis on lupus disease management.[304]

Monitoring of Drugs

This should be similar to that for drugs used in other rheumatic diseases, but due to the occurrence of cytopenias and abnormal renal and liver function possibly caused by lupus disease itself, monitoring tests may need to be undertaken more frequently, and the interpretation of laboratory results is more difficult. Adherence to drugs may be confirmed by measuring drug levels (e.g. of ciclosporin, tacrolimus, mycophenolate[171] and HCQ[80]), but these tests are not widely available (except that for tacrolimus, which is tested in order to guide optimal dosing and to prevent renal toxicity). There is little lupus-specific data about target drug levels, and detailed discussion is beyond the scope of these recommendations, but this topic has been reviewed for rheumatic diseases in general[78] as well as for lupus.[305] It should be noted that, like other chronic conditions, adherence levels are suboptimal in lupus, and therefore specific consideration of this issue is needed in patients showing poor response to therapy.[79]

Conclusions

It is important to monitor lupus patients regularly to assess and monitor changes in disease activity, chronic damage, and in drug-induced and co-morbid conditions that may be confused with lupus and that are associated with an increased risk of death. The LOEs and GORs for the main components of monitoring of lupus patients are shown together in Table 1, and a suggested protocol is shown in Table 6.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....