Systemic Lupus
Erythematosus

Historical perspective

In 1851, Pierre Alphée Cazenave, a French dermatologist, described the facial (butterfly) rash that is archetypal of the disease, naming it lupus érythémateux:

“In some circumstances [lupus] manifests itself at first as a violet rubefaction on this or that part of the face, and mainly on the nose, which at the same time is rather swollen: over many months the colour rises little by little; the surface becomes animated; a small ulcer forms and on top of it, a scab, which then thickens and covers the ulcer, which becomes progressively deeper. Lastly, the skin may get thinner in imperceptible stages and adopt the appearance of a scar, without there being tubercles or ulcers, and without displaying worse injuries than a livid colour and, from time to time, a light and barely perceptible peeling.”

Figure 1. Wax representation of lupus erythematosus (1894) housed in the Federal Pathologic-Anatomical Museum in Vienna. Patzak B. Moulage: "Lupus erythematosus". Dermatol Pract Concept. 2011 Jan 31;1(1):1. doi: 10.5826/dpc. dp0101a01. PMID: 24396710; PMCID: PMC3881073. Copyright ©2011 Patzak.

Moritz Kaposi and Sir William Osler are generally credited with recognising lupus affecting internal organs, in particular, renal and CNS lupus. Descriptions of pulmonary, cardiac and haematological manifestations followed. Keil proposed a single disease that included Discoid Lupus Erythematosus and Systemic Lupus Erythematosus in 1937.

Evolution of diagnosis

As clinical descriptions extended and recognition improved, the incidence of this disorder, recognised in at least one pre-Colombian mummy and possibly linked to Jane Austen, grew. LE cells were described in 1948, followed by an increasing array of autoantibodies, which were generally indicative and sometimes diagnostic. The advent of laboratory tests increased diagnostic capabilities, leading to increased recognition of less serious cases and a dramatic rise in both incidence and prevalence (Felten & al., 2022).

Diagnostic challenges

Lupus remains both a diagnostic and scientific challenge, which sometimes appears to deepen as knowledge expands. The disease we call lupus has multiple presentations within and between patients, may affect one or many organs or tissues, and has a variable course and prognosis. Given this heterogeneous clinical picture, diagnostic assessment will inevitably be equally complex. Since the 1982 American College of Rheumatology (ACR) Revised Criteria for the Classification of Systemic Lupus Erythematosus, circulating autoantibodies have risen in diagnostic importance. Antibodies to native DNA and Sm antigens were added to the criteria, along with the “false-positive serological test for syphilis,” later shown to be anti-cardiolipin antibody.

This set of clinical and laboratory criteria improved diagnostic performance in both sensitivity (83% vs 78%) and specificity (89% vs 87% against a cohort of scleroderma and myositis patients) (Tan & al., 1982). Antinuclear antibody (ANA) by Indirect Immunofluorescence (IIF) was also introduced; however, even then, it was noted to have low specificity, despite being identified in 174 out of 175 SLE patients selected from specialist clinics, demonstrating high sensitivity. Thus, from its earliest inclusion, ANA was proposed as an entry criterion rather than a diagnostic test.

Advances in classification criteria

The ACR criteria were updated in 1997 and remained the reference criteria until the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria update. In 2019, the European Alliance of Associations for Rheumatology (EULAR)/ACR classification criteria for SLE were developed. As previously, the need to report homogeneously and consistently in clinical research settings drove the development of classification criteria that have become de facto diagnostic criteria. These latest collaborative criteria have been validated in both adult and paediatric populations (sensitivity 92% and 89%, respectively) and have increased the sensitivity of the 2012 SLICC criteria while protecting the specificity achieved by the 1997 ACR criteria.

Using this standard, positive ANA (at a titre of 1:80) is still defined as an entry criterion, as at this titre, 98% of cases are captured, although its specificity is not sufficient for use as a diagnostic test. ANA at less than 1:80 is seen in other autoimmune disorders, notably in autoimmune hepatitis, where it contributes to the IAIHG simplified scoring system for the detection of autoimmune hepatitis (European Association for the Study of the Liver, 2015).

Delayed diagnosis and disease progression

The clinical diagnosis of lupus is, as stated, complex and is frequently delayed. Rees et al. showed that in the UK, between 1/1/1999 and 31/12/2012, patients who were eventually diagnosed with lupus presented to their general practitioners a median of 9.2 times per annum during the 5 years preceding diagnosis for symptoms associated with lupus, compared to 3.8 times per annum for case-based controls (Rees, 2017). Additionally, it has been known for several years that some autoantibodies, including anti-dsDNA, can be identified in the serum of individuals who are clinically well but who would later be diagnosed with lupus (Arbuckle, et al., 2001).

As with anti-CCP antibody in rheumatoid arthritis, the concentration of antibody increases proximate to the development of clinical disease. Perhaps unsurprisingly, in a disorder that presents with a range of severity, milder and more frequent cases initially present to family practitioners, while cases that present directly to specialists with greater experience of this nebulous disease tend to be more severe. Nikopolous et al. demonstrated that, for Caucasian patients with a disease duration of at least a year, approximately 55% had a mild phenotype at diagnosis, but nearly half of those progressed to more severe disease. After three years, there was a more than 20-fold increased risk of accrued irreversible tissue damage (Nikolopoulos, et al., 2020). In their study, high-risk patients were men, those with positive anti-dsDNA or those with neuropsychiatric disease.

Ethnic and age-related variation

Epidemiological differences in disease frequency and severity have been well documented. Pons-Estel et al. (2010) summarised that lupus is 2-4 times more frequent and severe in non-white populations. Although lupus most commonly affects women of childbearing age or later, it tends to be more severe in men, paediatric patients (<17 years at diagnosis) and late-onset patients (> 50 years at diagnosis).

EULAR/ACR classification criteria

The EULAR/ACR criteria were published in the Annals of the Rheumatic Diseases (Aringer, 2019) and a guide to the relevance of common ANA patterns was published by Lazar in 2023 (see below). All laboratory investigations listed in the EULAR/ACR criteria are available at Clinical Labs.

Table 1. Guide to the relevance of common ANA patterns

Abbreviations: AIM, autoimmune myositis; DM, dermatomyositis; JIA, juvenile idiopathic arthritis; MCTD, mixed connective tissue disease; PBC, primary biliary cirrhosis; SARD, systemic autoimmune rheumatic disease; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; SjS, Sjogren’s syndrome; SSc, scleroderma; UCTD, undifferentiated connective tissue disease.
Copyright © 2023 by the author(s) (Lazar & J., 2023)

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