Understanding Seronegative Rheumatoid Arthritis

Changing Perceptions & Criteria

Rheumatoid arthritis (RA) affects approximately 1% of the global population, with variations in prevalence across different regions. The disease’s classification primarily hinges on the presence of autoantibodies, notably rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), leading to a distinction between seropositive RA (SPRA) and seronegative RA (SNRA). This distinction is critical, as it influences both the perceived severity of the disease and the treatment approach. However, the evolving understanding of SNRA challenges some of the traditional views on its pathogenesis and clinical management.

Historically, RA classification has heavily relied on serological markers. The presence of RF and ACPA is considered indicative of a more severe disease course, which often prompts an aggressive treatment strategy. However, emerging research identifies additional antibodies, such as those against carbamylated proteins and malondialdehyde-acetaldehyde, which could potentially refine our understanding of RA pathophysiology, though these are not yet included in routine clinical criteria.

Despite these advances, approximately 20-30% of RA patients do not test positive for RF and ACPA. These SNRA patients present a unique challenge, as their disease may manifest with symptoms and progression rates similar to those of SPRA patients, questioning the binary classification based on seropositivity.

Clinical Presentation

The clinical presentation of SNRA can be deceptively mild compared to SPRA in some cases. Studies such as the ESPOR cohort have shown that while SNRA patients might have similar disease activity levels and quality of life to SPRA patients at a three-year follow-up, they often experience less radiographic progression and use fewer DMARDs and glucocorticoids. This could suggest a different underlying pathophysiological mechanism that might respond differently to conventional treatments.

However, discrepancies in findings across studies highlight the complexity of RA. For instance, some reports indicate that SNRA may be associated with more severe inflammatory activity at disease onset. These conflicting data underscore the need for a more nuanced approach to diagnosing and managing SNRA, potentially incorporating advanced imaging techniques like ultrasound and MRI, which can reveal inflammatory activity not evident in routine clinical assessments.

A Typically Long Road to Diagnosis

The time to diagnosis of SNRA can be significantly longer than for SPRA due to a variety of interconnected factors. One major challenge is the absence of the typical serological markers, RF and ACPA, which are often used to quickly identify and confirm RA. Without these markers, clinicians must rely more heavily on clinical symptoms and imaging findings, which can be ambiguous and overlap with other inflammatory and non-inflammatory joint disorders.

Additionally, the symptoms of seronegative RA can be quite mild and non-specific at the onset, such as mild joint pain and fatigue, which are easily attributed to more common and less severe conditions. This can lead to initial misdiagnosis or a wait-and-see approach. The variability in how the disease presents itself adds another layer of complexity; some patients may show atypical patterns of joint involvement or present with extra-articular symptoms that don’t immediately suggest RA.

Moreover, general awareness of seronegative RA among primary care providers may be lower compared to seropositive RA. This can result in delays in appropriate referrals to rheumatologists who are better equipped to diagnose complex cases of RA without serological markers. Access to specialised care plays a significant role as well; in regions with fewer healthcare resources or in systems where referrals to specialists are bottlenecked, diagnosis is inevitably delayed.

Psychological factors also contribute, as patients might downplay their symptoms or delay seeking medical advice due to fear, uncertainty, or other priorities. Thus, a confluence of clinical, systemic, and personal factors often leads to a longer diagnostic journey for patients with seronegative RA, emphasising the need for heightened vigilance and a comprehensive approach to diagnosis in primary care settings.

Treatment and Challenges

The current treatment paradigm for RA, which favours early and intensive intervention for seropositive patients, may need adjustment for SNRA. The evidence suggesting a good response to DMARDs in SNRA patients points to the efficacy of these treatments, though the lower use of biologics and glucocorticoids suggests a different treatment response profile. Personalising treatment based on more detailed phenotyping and perhaps a broader use of biomarkers could enhance outcomes for SNRA patients.

Both SNRA and SPRA patients carry an elevated risk of cardiovascular disease (CVD), which is exacerbated by systemic inflammation and possibly by the use of certain RA medications. The management of CVD risk in RA patients involves assessing traditional factors like lipid levels and diabetes, but also RA-specific factors such as sustained inflammation levels. Implementing comprehensive risk assessment models and integrating preventive cardiovascular care into the RA management plan is crucial.

Although the public profile for seronegative RA is increasing, there are many gaps in research and treatment guidelines for this disease, sparking the calling for clinicians and supporters to speak out with their experiences. As research evolves, it is imperative that medical professionals remain adaptable in their approaches, integrating new research findings and technologies into clinical practice. This will ensure that all RA patients, regardless of serostatus, receive optimised, personalised care that addresses both the articular and extra-articular manifestations of the disease. Ultimately we understand that early diagnosis and intervention in any disease leads to better outcomes, and seronegative RA is no different. 

Carbonell-Bobadilla N, Soto-Fajardo C, Amezcua-Guerra LM, Batres-Marroquín AB, Vargas T, Hernández-Diazcouder A, Jiménez-Rojas V, Medina-García AC, Pineda C, Silveira LH. Patients with seronegative rheumatoid arthritis have a different phenotype than seropositive patients: A clinical and ultrasound study. Front Med (Lausanne). 2022 Aug 16;9:978351. doi: 10.3389/fmed.2022.978351. PMID: 36052337; PMCID: PMC9424641.

Nikiphorou, E., Sjöwall, C., Hannonen, P. et al. Long-term outcomes of destructive seronegative (rheumatoid) arthritis – description of four clinical cases. BMC Musculoskelet Disord 17, 246 (2016). https://doi.org/10.1186/s12891-016-1067-y