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

Clinical Manifestations

SLE is a multisystem autoimmune disease[1,8] with considerable heterogeneity. This makes the diagnosis, assessment and monitoring a challenging process.[10,26–28,41] Delays in diagnosis are well recognized and remain a concern.[242] Some of the most typical features and their cumulative incidence are shown in Supplementary Table S3, available at Rheumatology Online.[7,10,26–29] It is important to ensure that the diagnosis of lupus is appropriate before considering treatment.[41,243] Given the variety of clinical manifestations that can occur, lupus should be considered in the differential diagnosis of many acute and sub-acute presentations, particularly, but not exclusively, in individuals at increased risk of the disease, such as women from African, South Asian or Chinese backgrounds.[2,244] Lupus can also affect men, resulting in severe disease, including renal involvement and greater risk of damage compared with women in some but not all reports.[15,16,30,31]

Renal and neurological involvement are major causes for morbidity and mortality in SLE.[2,7,15,16,32,33] Renal disease is clinically silent and must be actively sought to prevent renal damage as discussed below. A working party of the ACR distinguished 19 NP manifestations that may occur in SLE patients.[245] Not all are directly attributable to the SLE disease process, and the true incidence of these manifestations is hard to ascertain as most of them are uncommon.[23,246] Gastrointestinal and hepatic features occur in 39–67% of patients[42,247] and are often not recognized as being due to lupus. As with cardiorespiratory features, they must be distinguished carefully from infection, adverse events from drugs and co-morbid conditions. Ophthalmic manifestations of lupus are rare, but potentially sight-threatening, and need careful evaluation by an experienced ophthalmologist.[248–250]

Serological (Immunological) Manifestations

The clinical features of acute lupus are mostly due to inflammatory processes triggered by the formation of immune complexes involving autoantibodies and complement consumption, although thrombosis associated with aPLs may contribute to the pathogenesis in some patients.[1,8,10] With a clinical suspicion of SLE, an initial autoantibody screen should be performed. Approximately 95% of lupus patients are ANA positive, and 98% of patients will have positive ANA and/or anti-dsDNA antibodies.[26,36,37] ANA tests, although sensitive, are not specific for the diagnosis of lupus, and ANAs can occur in a variety of other conditions, including SS, SSc, DM, viral infections (e.g. infectious mononucleosis) and malignancy.[36,41] The ANA test can increase in titre over time or can become negative in treated patients, and the results can vary with different assays.[34,37]

If patients have a strong clinical likelihood of having lupus, anti-dsDNA antibody testing should be done.[38] Anti-dsDNA and anti-Sm antibodies are much more specific for lupus, being very rare in other conditions[36] but they are less sensitive than ANA (Supplementary Table S3, available at Rheumatology Online).[10,26–29,251] Both the Farr and the ELISA methods are acceptable for measuring anti-dsDNA antibodies, with the former yielding higher sensitivity and specificity rates.[24,39,40] The Crithidia luciliae immunofluorescence test also has a high specificity for SLE. Additional routine serological tests are the complement C3 and C4 levels.[43] C3 generally has a higher sensitivity than serum C4 for active LN, but both tests have modest specificity and their clinical utility lies in their high negative predictive value (>90%) to exclude active disease, especially renal disease.[24,44–46]

Anti-Ro (SSA), anti-La (SSB) and anti-RNP antibodies are less specific markers for the presence of SLE, as they are found in other autoimmune rheumatic disorders.[41] Anti-Ro and anti-La are most strongly associated with primary SS but do occur in lupus patients, especially those with photosensitivity and subacute cutaneous lupus. Anti-Ro and anti-La antibodies can cause neonatal lupus syndrome including congenital heart block (CHB) in children born to mothers with these antibodies (see Recommendations for monitoring of SLE section).[64,65] Anti-RNP antibodies are found in overlap conditions such as MCTD.[41]

All lupus patients should be tested for aPLs because their presence indicates a group at increased risk of arterial/venous thrombotic events and adverse pregnancy outcomes.[241,252,253] As APS and SLE often overlap, and APS sometimes evolves in to SLE, the presence of APS should also prompt assessment for lupus. Confirmatory tests for APS are positive LA, aCL (IgG, IgM), and/or anti-beta-2 glycoprotein-1(IgG, IgM) antibodies on two occasions at least 12 weeks apart.[241,252] The LA test is the most specific of the three tests and is associated with a higher positive predictive value. The most high-risk aPL profile (triple positivity including positive LA, aCL and anti-β2-glycoprotein-I antibody) is associated with a cumulative incidence of thrombosis after 10 years of 37.1%.[254]

Classification Criteria for Lupus

Based on the ACR (previously the American Rheumatism Association) revised criteria for SLE published in 1982[255] and the 1997 modification,[256] a patient may be classified as having SLE if they have 4 or more of 11 criteria present (Table 4). However, not all patients who meet these criteria have lupus, and not all patients diagnosed clinically with lupus have four or more of these criteria, which may appear or disappear over time.[7,33,35,257] There has been a tendency to consider patients who meet the ACR classification criteria for lupus to have the disease, even if they only have certain clinical features without evidence of one or more of the immunological abnormalities that are the hallmark of this autoimmune disease. Conversely, sometimes the disease has been diagnosed on the basis of auto-antibodies and haematological features, without consideration of whether the whole clinical and serological picture is consistent with lupus being the most likely diagnosis.

To address these and some other issues, the SLICC group devised alternative classification criteria for lupus.[258] These criteria introduced a requirement for at least one clinical and one immunological criterion and two others from an expanded list of items (Table 5) compared with the ACR criteria (Table 4).[256] They also allowed biopsy-proven LN in the presence of ANA or anti-dsDNA antibodies to be classified as lupus, without the need for other criteria.[258] The serological criteria include low complement (C3 and/or C4), as this item reflects complement consumption due to the formation of immune complexes in active lupus disease.

These revised SLICC lupus criteria have been accepted by the European Medicines Agency, the US Food and Drug Administration and NHS England as being suitable for the inclusion of patients in clinical trials and in the commissioning policy for rituximab. They are more intuitive than the previous ACR classification criteria when considering a diagnosis of lupus, and allow a larger number of patients to meet criteria; however, diagnosis should not be restricted to patients who meet the classification criteria, as they can encompass other manifestations in the appropriate serological context.[259] The SLICC criteria have been tested in a number of cohorts and in most studies have shown an increase in sensitivity and reduced specificity, so care is needed if features are better explained by an alternative diagnosis.[260–263]

Conclusions

When considering a patient with a possible diagnosis of lupus, a detailed clinical history and examination is required in order to identify relevant clinical features, including assessment of haematological and renal parameters. The diagnosis should not be made without evidence of at least one autoantibody or low complement levels to support the diagnosis of this autoimmune disease, consistent with the SLICC classification criteria. The ACR (Table 4) and SLICC (Table 5) classification criteria are not diagnostic criteria but may be helpful when considering the diagnosis; however, they do not cover all the clinical manifestations of lupus. The LOEs and GORs for parameters supporting the diagnosis of lupus are shown in Table 1.

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