Pitfalls of Potential Lupus Diagnosis

Spotting the signs of autoimmunity as early as possible is often viewed as a positive goal for rheumatologic research. The premise: Patients may begin treatment years before their disease is active and destroying joints and tissue.

Although much progress has been made in identifying early stages of rheumatoid arthritis pathogenesis, the clues are not as clear in systemic lupus erythematosus (SLE). Many patients who test positive for autoantibodies that could be signs of potential SLE, such as antinuclear antibodies (ANA), never actually develop the disease. Describing a patient as having potential SLE could cause unnecessary anxiety and medication prescription in these individuals, say two lupus researchers.

“Previous reports have shown that only about 20% of patients with potential SLE go on to develop definite SLE. So if we use potential SLE as a diagnosis, we would be over-treating the majority of these patients,” say Graciela S. Alarcón, MD, MPH, MACR, Jane Knight Lowe Emeritus Professor of Medicine at the University of Alabama at Birmingham, and Manuel F. Ugarte-Gil, MD, a rheumatologist at the Hospital Nacional Guillermo Almenara Irigoyen in Lima, Peru, in a joint, written response to questions from The Rheumatologist.

Unnecessary Treatment

In an editorial published in Arthritis Care & Research in March 2016, “Incomplete Systemic Lupus Erythematosus: Early Diagnosis or Overdiagnosis?” Drs. Alarcón and Ugarte-Gil urged caution in describing patients who may never develop lupus with such terms as incomplete lupus, potential lupus, pre-lupus or latent lupus.¹ An earlier paper in the same journal, “We Need Better Classification and Terminology for ‘People at High Risk of or in the Process of Developing Lupus,’” prompted them to speak up about the risks of attempting early diagnosis of SLE when specific biomarkers for the disease are still unknown.²

“This over-diagnosis leads to at least two main problems. First, as these patients are treated with glucocorticoid and immunosuppressive drugs, they are at risk of presenting adverse events related to their use,” say Drs. Alarcón and Ugarte-Gil. “These include infections, metabolic disorders like diabetes, osteoporosis and osteonecrosis. Second, as SLE is a disease that portends shortened survival and the occurrence of several complications over its course, patients and their families may become quite concerned about receiving this diagnosis. This may lead to significant psychological distress, and the occurrence of anxiety and/or depression.”

SLE can present acutely in some patients, with clinical manifestations occurring over just a few days. Or they may accrue over months or years, say Drs. Alarcón and Ugarte-Gil.

According to the Systemic Lupus International Collaborating Clinics’ 2012 classification, four or more of the criteria must be met, including at least one clinical sign and one laboratory result. Biopsy-proven lupus nephritis accompanied by a positive ANA or anti-DNA test is also confirmed lupus. These signs don’t have high sensitivity or specificity, though, making early diagnosis challenging.

“At the present time, there are no laboratory tests [that] allow distinguishing patients who will evolve into definite lupus and those who will not. Of course, it will be of great value to identify biomarkers that may allow such an identification,” they say.

Dr. Alarcón

One serious concern is that a patient’s diagnosis of potential or pre-lupus may be misconstrued by a primary care or other provider who’s not as knowledgeable about SLE as a rheumatologist. In their editorial, Drs. Alarcón and Ugarte-Gil refer to a 2004 study that showed that, out of 476 patients referred to an autoimmune disease center at the University of Florida, 203 had been misdiagnosed.³ Of these, 39 patients who were seropositive for ANA but had no autoimmune disease, had been treated with glucocorticoids, some as high as 60 mg a day.

Pretest Predictive Probability

Many patients who are being tested for lupus have a very low pretest predictive probability of actually having the disease. They may have non-specific clinical manifestations of SLE, such as myalgia, fatigue or arthralgia. A primary care provider may treat these symptoms and refer them for lupus testing, but the chances of these patients having lupus is actually quite low, say Drs. Alarcón and Ugarte-Gil.

“That will not be the case for patients with clear-cut manifestations of SLE, such as malar rash, nephritis and the like. If we request a test in a patient with a very low pretest probability of lupus, a positive result does not necessarily mean the patient has SLE. This is particularly true when we use ANA,” they say.

To determine possible scenarios with a higher pretest probability for SLE, Drs. Alarcón and Ugarte-Gil looked at patients from the LUMINA (Lupus in Minorities: Nature Versus Nurture) cohort who developed lupus gradually, and within that group, those who had met three criteria for a while before achieving a fourth.⁴

“Within this group, the most frequent combination was malar rash with photosensitivity plus arthritis plus ANA, followed by arthritis plus a hematologic criterion plus ANA, and photosensitivity plus buccal ulcers plus arthritis,” they say. “Whether such patterns may be helpful in other settings remains to be determined.”

‘At the present time, there are no laboratory tests that allow distinguishing patients who will evolve into definite lupus & those who will not.’ —Drs. Alarcón & Ugarte-Gil

To Test or Not to Test

A lack of adequate biomarker identification means that referring a patient for testing without other clinical signs of SLE could lead to fuzzy or incorrect conclusions. Costly tests cannot be justified unless certain clinical signs are present, too, say Drs. Alarcón and Ugarte-Gil.

In fact, rheumatologists cited the testing of ANA subserologies without a positive ANA and clinical suspicion of immune-mediated disease as one of their top five concerns in the 2013 Choosing Wisely survey conducted by the American College of Rheumatology as part of a wider American Board of Internal Medicine campaign.⁵

Dr. Ugarte-Gil

“If we ask for a test in a patient without a clinical suspicion of an immune-mediated disorder, we may end up with over-diagnosis of SLE,” say Drs. Alarcón and Ugarte-Gil. “In addition to the risk of overtreatment and the psychological impact of this over-diagnosis, these tests would lead to an increase in the cost of care for both the health system and the patient without any tangible benefit.”

There is an unmet need to identify patients who are either at high risk of developing SLE or just early in the process due to the presence of genetic or environmental factors, they say. Rheumatologists should use terms like “potential lupus” with extreme caution until we have a better understanding of SLE pathogenesis.

Complement tests may one day help identify at-risk patients, say Drs. Alarcón and Ugarte-Gil. While these tests seem to be more useful for SLE diagnosis than previous approaches, they are not widely available and used right now.

A two-tier methodology for SLE diagnosis comparing cell-bound complement (Cd4) activation products on erythrocytes, B cells, and other specific autoantibodies proposed by a group of lupus researchers in a 2014 paper in the online journal Lupus Science & Medicine may help identify patients who are at higher risk of SLE, but it’s too soon to say for sure.⁶

“Two-tier methodology has a higher sensitivity and specificity than previous strategies for SLE diagnosis, but it has been tested only in U.S. patients, mainly Caucasians,” they say. “Its specificity and sensitivity could vary among patients from other ethnic groups. Additionally, only 304 patients were included in this study, and probably, patients with less frequent manifestations were not included.”

At this time, rheumatologists’ understanding of lupus still lags behind that of RA, which has extensive literature to identify at-risk patients, say Drs. Alarcón and Ugarte-Gil. As clues to SLE pathophysiology emerge, clinicians will be better equipped to identify which individuals need series of laboratory tests to confirm disease and which ones merit a wait-and-see approach.

Susan Bernstein is a freelance medical journalist based in Atlanta.

References

1. Alarcón GS, Ugarte-Gil MF. Incomplete systemic lupus erythematosus: Early diagnosis or overdiagnosis? Arthritis Care Res. 2016 Mar;68(3):285–287.
2. Costenbader KH, Schur PH. We need better classification and terminology for ‘people at high risk of or in the process of developing lupus.’ Arthritis Care Res. 2015 May;67(5):593–596.
3. Narain S, Richards HB, Satoh M, et al. Diagnostic accuracy for lupus and other systemic autoimmune diseases in the community setting. Arch Intern Med. 2004 Dec 13–27;164(22):2435–2441.
4. Ugarte-Gil MF, Pons-Estel GJ, Molineros J, et al. Disease features and outcomes in United States lupus patients of Hispanic origin and their Mestizo counterparts in Latin America: A commentary. Rheumatology (Oxford). 2016 Mar;55(3):436–440.
5. Yazdany J, Schmajuk G, Robbins M, et al. Choosing Wisely: The American College of Rheumatology’s top 5 list of things physicians and patients should question. Arthritis Care Res. 2013 Mar;65(3):329–339.
6. Putterman C, Furie R, Ramsey-Goldman R, et al. Cell-bound complement activation products in systemic lupus erythematosus: Comparison with anti-double-stranded DNA and standard complement. Lupus Sci Med. Published online 2014;1(1):e000056.