Beyond the Markers: Understanding and Managing Seronegative Arthritis

Abstract

Joint pains are among the most common symptoms encountered by any clinician in the clinical practice of any medical field, and therefore, the clinician almost always suspects rheumatoid arthritis. However, a proportion of such patients present with polyarthritis without the presence of the signature serological markers such as rheumatoid factor (RF) or anti-cyclic citrullinated peptide (anti-CCP) antibodies. These patients fall into the seronegative group of arthritis. The challenge in diagnosis is to differentiate seronegative rheumatoid arthritis (SNRA) from other conditions, including seronegative spondyloarthropathies (SpA), psoriatic arthritis (PsA), reactive arthritis (ReA), and other forms of undifferentiated arthritis. The article deals with the complexity of seronegative arthritis, discusses different presentations and classified states of this particular disease, presents the criteria for diagnosis, and gives some insights into the therapeutic management of this controversial group of arthritic disorders.

Introduction

These include joint pain, stiffness, and inflammation. Together, these define the disease known as arthritis, affecting millions worldwide. For decades, the presence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP) in the blood was used to make a presumptive diagnosis of RA, a systemic autoimmune disease characterized by symmetrical polyarthritis. However, not all patients with inflammatory joint pain test positive for these markers. This subgroup is referred to as seronegative arthritis and poses a challenging diagnostic problem for clinicians.

Seronegative arthritis is a generic term that encompasses other entities, such as seronegative rheumatoid arthritis (SNRA), seronegative spondyloarthropathies (SpA), psoriatic arthritis (PsA), reactive arthritis (ReA), and few others. The clinical characteristics include inflammation of the joint and are seronegative, meaning they are usually not associated with serological markers, as in rheumatoid arthritis. The diagnosis and treatment of seronegative arthritis require an all-inclusive knowledge of the various clinical patterns and pathological processes.

In this article, we take on the challenge to explore the diagnostic challenge of seronegative arthritis, look at the diverse forms it may take, and discussing evidence-based treatment strategies to manage these conditions well.

Seronegative Arthritis: Defining the Disorder

Seronegative arthritis is a variety of arthritis that occurs in the absence of detectable rheumatoid factor or anti-CCP antibodies. A patient with such arthritis can present clinically with symptoms very similar to RA, including joint swelling, pain, and morning stiffness. However, seronegative arthritis encompasses a heterogeneous spectrum of diseases and presentation may vary widely according to the nature of the underlying process.

Seronegative Rheumatoid Arthritis (SNRA)

SNRA is a seronegative subtype of RA in which there are no RF and anti-CCP antibodies. Despite the loss of serological markers, a patient may appear with the same aspect of joint manifestation seen in seropositive RA in the form of symmetrical polyarthritis, mainly involving the small joints of the hands and feet. It is comparatively difficult to diagnose SNRA because of its seronegative profile, thus delaying diagnosis and misleading the clinician.

It should be noted that systemic involvement can be less pronounced in patients with SNRA, whereas joint damage and progression of the disease can be as aggressive as in seropositive RA. Imaging studies, including ultrasound and MRI, establish synovitis and joint erosion and help make the diagnosis.

Seronegative Spondyloarthropathies (SpA)

Spondyloarthropathies (SpA) are a group of inflammatory joint diseases that primarily affect the axial skeleton but can also involve peripheral joints. These conditions include ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis, psoriatic arthritis (PsA), reactive arthritis (ReA), and arthritis associated with inflammatory bowel disease (IBD).

A key feature of SpA is the absence of RF and anti-CCP antibodies, making it a seronegative disorder. SpA typically presents with inflammatory back pain, enthesitis (inflammation at the sites where tendons and ligaments attach to bone), and dactylitis (swelling of an entire digit). HLA-B27, a genetic marker, is often present in patients with SpA, particularly in those with ankylosing spondylitis, but not all cases are HLA-B27 positive.

Psoriatic Arthritis (PsA)

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis, a chronic skin condition characterized by red, scaly patches. PsA can affect the peripheral joints and the spine, causing pain, swelling, and stiffness. Unlike RA, PsA often presents with an asymmetric pattern of joint involvement and is typically seronegative for RF and anti-CCP.

Patients with PsA may exhibit nail changes, such as pitting or onycholysis, and can develop enthesitis and dactylitis. PsA can be difficult to diagnose in the absence of overt skin manifestations, as joint symptoms may precede the appearance of psoriasis.

Reactive Arthritis (ReA)

Reactive arthritis (ReA) is a form of inflammatory arthritis that develops in response to an infection, typically gastrointestinal or genitourinary. It is part of the SpA family and shares many clinical features with other seronegative spondyloarthropathies. ReA is characterized by acute onset of arthritis, often involving the lower limbs, as well as enthesitis, conjunctivitis, and urethritis.

Unlike RA, ReA is transient in most cases, but chronic forms can develop. The diagnosis is primarily clinical, based on a history of preceding infection and typical clinical features. Serological markers for RA are usually absent, and HLA-B27 may be present in some cases.

Undifferentiated Seronegative Arthritis

Some patients with inflammatory joint pain may not fit neatly into any of the above categories. These cases are classified as undifferentiated seronegative arthritis. Patients with undifferentiated arthritis may have early manifestations of an evolving condition, such as PsA or SpA, or they may have a distinct but undefined form of arthritis. These patients require careful monitoring for disease progression and changes in clinical presentation over time.

Diagnostic Challenges in Seronegative Arthritis

Diagnosing seronegative arthritis is often more complex than diagnosing seropositive RA due to the absence of definitive serological markers. Clinicians must rely on clinical presentation, imaging studies, and the exclusion of other diseases to make an accurate diagnosis.

Clinical Features

The clinical presentation of seronegative arthritis can vary widely depending on the underlying condition. Patients may present with symmetrical or asymmetrical joint involvement, axial or peripheral joint pain, and extra-articular manifestations such as enthesitis, dactylitis, or uveitis. A detailed history and physical examination are critical in identifying characteristic patterns of joint involvement and associated symptoms.

Imaging Studies

Imaging is a valuable tool in diagnosing seronegative arthritis. X-rays may show characteristic changes in conditions such as ankylosing spondylitis or psoriatic arthritis, including sacroiliitis, syndesmophytes, or joint erosion. However, early disease may not be visible on X-ray, making advanced imaging techniques such as MRI and ultrasound important for detecting synovitis, enthesitis, and other early changes.

Genetic Testing

HLA-B27 testing can aid in the diagnosis of spondyloarthropathies, particularly ankylosing spondylitis. However, it is important to note that not all patients with SpA are HLA-B27 positive, and a positive result is not diagnostic on its own.

Differential Diagnosis

Given the absence of serological markers, the differential diagnosis of seronegative arthritis is broad and may include conditions such as osteoarthritis, gout, fibromyalgia, or even malignancy. A comprehensive workup, including the exclusion of other causes of joint pain, is essential for accurate diagnosis.

Therapeutic Approaches to Seronegative Arthritis

Management of seronegative arthritis depends on the underlying diagnosis but generally follows the principles of treating inflammatory arthritis: reducing inflammation, preventing joint damage, and maintaining function. Treatment is often multidisciplinary, involving rheumatologists, physical therapists, and sometimes dermatologists or gastroenterologists for conditions such as PsA or IBD-associated arthritis.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs are commonly used to relieve pain and inflammation in seronegative arthritis, particularly in SpA and PsA. They are often the first line of treatment for patients with mild to moderate disease. However, long-term use of NSAIDs can lead to gastrointestinal and cardiovascular side effects, so their use should be carefully monitored.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

Traditional DMARDs, such as methotrexate and sulfasalazine, are commonly used in the treatment of seronegative arthritis, particularly PsA and peripheral SpA. These drugs help slow disease progression and reduce joint damage. Methotrexate is often preferred for its efficacy in treating both joint and skin manifestations of PsA.

Biologic Therapies

Biologics have revolutionized the treatment of inflammatory arthritis, including seronegative forms. Tumor necrosis factor (TNF) inhibitors, such as infliximab, etanercept, and adalimumab, are effective in treating SpA, PsA, and SNRA. For patients who do not respond to TNF inhibitors, other biologics targeting interleukins (such as IL-17 and IL-23) or Janus kinase (JAK) inhibitors may be considered.

Physical Therapy and Rehabilitation

Physical therapy plays a crucial role in maintaining joint mobility and function, particularly in patients with axial involvement, such as those with ankylosing spondylitis. Regular exercise, stretching, and physical therapy can help prevent stiffness and maintain posture and flexibility.

Monitoring and Follow-Up

Seronegative arthritis is often a chronic, progressive condition requiring ongoing monitoring. Regular follow-up with a rheumatologist is essential to assess disease activity, adjust medications, and monitor for side effects. Imaging studies may be repeated periodically to evaluate for joint damage.

Conclusion

Seronegative arthritis forms a diverse category of inflammatory joint diseases presenting significant challenges both in terms of diagnosis and treatment. Thus, absent the presence of rheumatoid factors and anti-CCP antibodies, the cause will have to be identified by clinical features, imaging, and the process of excluding other diagnoses. Despite the difficulty in the diagnosis of seronegative arthritis, advances in imaging and biological therapies have improved their management and prognosis. The practice is multi-disciplinary, and the treatment plan is individualized for optimal outcomes for these patients with seronegative arthritis.