Early intervention benefits the treatment of rheumatic condition. Too often, delays are caused by lack of access to sophisticated testing procedures, says Tara Bruner. That is where laboratories can make a difference...

Autoimmune diseases affect more than 15 million people [1] in the U.S. alone yet remain chronically underdiagnosed. Rheumatoid Arthritis (RA) is the most prevalent, impacting approximately 1.3 million [2] Americans and 450,000 [3] in the UK.

The diagnostic journey is frequently prolonged and fragmented. Patients often present with vague, fluctuating symptoms including joint pain, stiffness, fatigue, and cognitive fog that evolve over time and mimic other conditions, contributing to the finding that up to 76% [4] experience at least one misdiagnosis.

Much of this challenge occurs early in the care pathway. Primary care providers (PCPs) are typically the first point of contact yet may not have access to structured testing approaches or decision-support tools needed to navigate diagnostically complex conditions. Laboratories play a critical role in strengthening the diagnostic process by providing advanced testing strategies, interpretive guidance, and clinically relevant insights that help clinicians better differentiate results and move toward a more accurate diagnosis.

Single markers: driving the gap

Blood-based markers are central to RA diagnosis, most commonly rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies. The process of how these markers is ordered and interpreted is as important as the tests themselves.

RF is the more commonly ordered of the two markers, but it is less specific. It can be elevated in chronic infections, liver disease, and other autoimmune conditions, which means a positive result on its own is not sufficient to confirm a diagnosis. Anti-CCP is considerably more specific to RA and can appear up to a decade before symptoms emerge, but approximately 20-30% [5] of RA patients never test positive for it. As a result, a negative anti-CCP result does not rule out RA and should not be viewed as a definitive answer in the diagnostic journey.

Seronegative RA remains one of the field’s most persistent diagnostic challenges. In the absence of reliable serologic markers, PCPs and even rheumatologists may face prolonged diagnostic uncertainty, which can delay treatment during a period when early intervention is most effective. Laboratories play a critical role in reducing this uncertainty by enabling early and accurate identification of seropositive patients. At the same time, appropriate interpretation of negative or inconclusive results is essential, particularly in suspected seronegative cases, to avoid false reassurance and further delays in diagnosis and care.

A single result, however accurate, rarely provides sufficient direction for clinical decision-making. Structured panels interpreted with the consideration of symptom history function more effectively as part of the diagnostic process.

Symptom-guided strategies

When RF and anti-CCP are measured together, diagnostic confidence can improve compared with either marker alone. Anti-CCP2 assays provide improved sensitivity over earlier-generation anti-CCP assays, and when combined with RF testing — including IgM and IgA isotypes — can provide a stronger serological basis for an RA diagnosis. The presence of multiple isotypes may indicate a more active immune response and offers additional context beyond any single biomarker. Together, anti-CCP2 and RF testing demonstrate a positive predictive value (PPV) approaching 100% [6], greater than either test alone.

For patients who test negative for standard RA markers, the diagnostic process is not entirely over as seronegative presentations may reflect overlapping connective tissue disease. Extended autoimmune screening can help identify conditions that would otherwise go undetected. Automated reflex protocols, triggered by initial results rather than requiring separate orders, keep the workflow efficient while ensuring these patients are not prematurely ruled out of a diagnosis.

Additionally, laboratory automation reduces operator variability in isotype-level testing, which is meaningful when serology requires precision across multiple analytes. Standardisation of methods and reporting across sites matters too: a result reported with interpretive context is more useful to a PCP than a bare numerical value. “RF elevated” is a raw data point; but when accompanied by interpretive context—such as the potential value of confirmatory testing like anti-CCP or isotype analysis—it becomes more useful for clinical decision-making.

Reporting becomes decision support

The evolving role of laboratories requires more than technological advancement; it demands structural and clinical support. By operating as active decision-support partners through interpretive guidance and clinician education, laboratories can meaningfully improve the quality and clinical utility of information available to providers. This is essential for primary care, which has absorbed more of the autoimmune diagnostic burden as the rheumatology workforce has contracted. National Health Services (NHS) Rheumatology wait times have been a pressure point for years; in many regions, patients often face wait times of several months [7] before reaching a specialist. A well-structured laboratory report with interpretive guidance can help a practitioner make a faster, more confident referral decision.

There is also a gender discrimination that laboratory practice is positioned to address. Various conditions, not just exclusive to autoimmune diseases, affect women at significantly higher rates: women are 66% [8] more likely than men to be misdiagnosed. Part of that disparity is often from symptoms being attributed to stress or hormonal changes rather than investigated systematically. Objective, standardised testing introduces a consistent and reproducible data layer into a diagnostic process that has historically relied heavily on clinical impression, helping to reduce this bias.

The shift from result reporting to clinical decision support is already underway in autoimmune disease diagnostics. For rheumatic disease specifically, where early intervention determines long-term outcomes, the lab's contribution is not incidental. A patient who receives a faster, more accurate diagnosis often does so because a better testing protocol helped stabilise diagnostic stability at the beginning of the journey. The lab professionals who design those protocols and guide the clinician through diagnosis are doing clinical work, even if they never see the patient.

Tara Bruner is manager, clinical education and physician associate at Thermo Fisher Scientific

Pic: Chaitali Chowdury (Inset: Tara Bruner)

Notes

1 https://www.jci.org/articles/view/178722

2 https://pmc.ncbi.nlm.nih.gov/articles/PMC8348893/

3 https://www.jci.org/articles/view/178722

4 https://pmc.ncbi.nlm.nih.gov/articles/PMC7197794/

5 https://pmc.ncbi.nlm.nih.gov/articles/PMC12821548/

6 https://onlinelibrary.wiley.com/doi/full/10.4061/2011/815038?msockid=20e83615bf17603c03682196be3e6111

7 https://pmc.ncbi.nlm.nih.gov/articles/PMC6429945/

8 https://www.soliant.com/blog/the-soliant-health-2024-state-of-healthcare-report/