What is Reactive Arthritis? Believe it or Not, it is Often a Result of the Resent Onset of Food Poisoning!

Reactive Arthritis: A Comprehensive Scientific Review, with a Focus on Post-Infectious Onset Due to Recent Food Poisoning Cases

Introduction

Reactive arthritis (ReA) is a form of inflammatory arthritis that occurs following an infection, often affecting the joints, eyes, and genitourinary or gastrointestinal systems. It belongs to the family of diseases known as seronegative spondyloarthropathies, which are characterized by the absence of rheumatoid factor and a strong association with the HLA-B27 gene. Reactive arthritis can develop after infections in the gastrointestinal tract, urogenital tract, or, less commonly, the respiratory tract. Gastrointestinal infections, particularly those resulting in food poisoning caused by pathogens such as Campylobacter, Salmonella, Shigella, and Yersinia, are common triggers of this form of arthritis.

In this review, we will provide a detailed overview of reactive arthritis, with a focus on cases related to foodborne illnesses. We will cover the epidemiology, pathogenesis, clinical presentation, diagnosis, treatment, and prognosis, as well as recent research into its underlying mechanisms and prevention strategies.

Epidemiology

Reactive arthritis is relatively rare, with an estimated incidence ranging from 30 to 40 cases per 100,000 people per year. Its occurrence varies depending on the population studied and the pathogen involved. The prevalence of ReA following foodborne illness is highest in developed countries where bacterial food poisoning is more likely to be diagnosed and reported. Individuals between the ages of 20 and 40 are most commonly affected, and the condition is seen more frequently in males than in females, particularly when associated with urogenital infections. The risk of developing ReA is strongly associated with the presence of the HLA-B27 gene, which is found in up to 70-80% of patients with the condition.

Post-Food Poisoning Reactive Arthritis

Gastrointestinal infections are a common cause of reactive arthritis, with Campylobacter jejuni being the most frequent pathogen responsible. Other bacterial pathogens that have been implicated in post-food poisoning ReA include Salmonella, Shigella, and Yersinia. After an episode of foodborne illness, reactive arthritis typically develops within 1-4 weeks, although in some cases the onset may be delayed. Estimates suggest that up to 15% of individuals who experience gastroenteritis from one of these pathogens may develop ReA, though rates vary widely depending on factors such as the infecting organism and the host’s genetic predisposition.

Pathogenesis

Reactive arthritis is thought to result from an aberrant immune response to a preceding bacterial infection. Although the inciting infection typically resolves by the time arthritis develops, the immune system continues to target joint tissues due to molecular mimicry, where bacterial antigens resemble components of the host’s joint or connective tissues. In genetically susceptible individuals, particularly those who carry the HLA-B27 allele, this autoimmune reaction leads to inflammation in the joints, entheses (tendinous insertions), and other tissues.

Role of HLA-B27

The HLA-B27 gene, which encodes a protein involved in presenting antigens to the immune system, plays a central role in the pathogenesis of reactive arthritis. Individuals who are positive for HLA-B27 are at a significantly higher risk of developing ReA following an infection than those without the gene. While the exact mechanism by which HLA-B27 contributes to disease is not fully understood, several hypotheses have been proposed:

• Molecular mimicry: Bacterial antigens, particularly from pathogens such as Campylobacter and Salmonella, may resemble self-antigens that are normally presented by HLA-B27 on the surface of immune cells. This molecular mimicry can lead to cross-reactivity, where the immune system attacks not only the bacterial antigens but also host tissues, resulting in inflammation and arthritis.
• Misfolding of HLA-B27: Some research suggests that HLA-B27 may misfold during its synthesis, leading to endoplasmic reticulum stress and triggering an inflammatory response. This abnormal immune activation may contribute to the chronic inflammation seen in reactive arthritis and other spondyloarthropathies.
• Altered antigen presentation: HLA-B27 may present bacterial antigens in a way that promotes prolonged or excessive immune responses, contributing to the development of chronic inflammation even after the original infection has cleared.

Pathogen-Specific Mechanisms

Different gastrointestinal pathogens that cause food poisoning have distinct mechanisms by which they trigger reactive arthritis:

• Campylobacter jejuni: This is the most common bacterial cause of post-infectious reactive arthritis. Campylobacter invades the epithelial cells of the gut, causing diarrhea, fever, and abdominal pain. The immune system’s response to Campylobacter infection, particularly in individuals with HLA-B27, can lead to an overactive inflammatory response and the development of arthritis.
• Salmonella spp.: Reactive arthritis following Salmonella infection, often referred to as post-salmonella ReA, is also common. Salmonella infection leads to an intense immune response, with cytokines and immune cells targeting bacterial antigens that can persist in the gut or elsewhere in the body. This ongoing immune activation can result in joint inflammation.
• Shigella spp.: Infections with Shigella bacteria cause a severe inflammatory response in the gut, leading to dysentery. The immune response to Shigella can trigger systemic inflammation, including arthritis. In particular, Shigella flexneri has been closely linked to reactive arthritis.
• Yersinia enterocolitica and Yersinia pseudotuberculosis: These bacteria cause gastroenteritis and can persist in mesenteric lymph nodes, leading to chronic immune stimulation. In HLA-B27-positive individuals, this can result in reactive arthritis and other inflammatory conditions, such as erythema nodosum.

Clinical Presentation

Reactive arthritis typically manifests 1 to 4 weeks after the onset of the triggering infection, and patients may not always make the connection between the initial illness and subsequent joint symptoms. The clinical presentation of ReA is characterized by a triad of symptoms: arthritis, urethritis, and conjunctivitis, though not all patients present with all three. This classic triad was previously known as “Reiter’s syndrome,” but this term has fallen out of favor due to its association with a historical figure with controversial ties. The clinical manifestations of ReA vary, depending on the individual, the severity of the preceding infection, and whether extra-articular involvement is present.

Articular Symptoms

The hallmark feature of reactive arthritis is arthritis, which is typically asymmetric and predominantly affects the lower extremities. Key features of the arthritis associated with ReA include:

• Oligoarthritis: ReA typically presents as an oligoarthritis (affecting 4 or fewer joints), with the knees, ankles, and feet being the most commonly involved joints.
• Enthesitis: Inflammation of the entheses, the sites where tendons or ligaments insert into bone, is common in ReA. This may manifest as pain at the Achilles tendon or plantar fascia, leading to heel pain and difficulty walking.
• Dactylitis: “Sausage digit” or dactylitis, characterized by swelling of an entire finger or toe, is a typical feature of reactive arthritis.
• Axial involvement: In some cases, particularly in HLA-B27-positive individuals, reactive arthritis can involve the spine, leading to inflammatory back pain. Sacroiliitis (inflammation of the sacroiliac joints) is a common feature in patients with axial involvement.

Extra-Articular Symptoms

In addition to joint symptoms, patients with reactive arthritis may experience a variety of extra-articular manifestations, including:

• Conjunctivitis and Uveitis: Eye involvement occurs in approximately 20-30% of cases and may include conjunctivitis (inflammation of the conjunctiva) or uveitis (inflammation of the uveal tract). Conjunctivitis is usually mild and self-limiting, whereas uveitis can be more serious and may require treatment to prevent complications.
• Urethritis and Genitourinary Symptoms: Urethritis, or inflammation of the urethra, can occur, particularly in cases of reactive arthritis following urogenital infections. Dysuria (painful urination), urinary frequency, and discharge may be present. Men may also develop prostatitis, while women may experience cervicitis or vaginitis.
• Mucocutaneous Lesions: Reactive arthritis may cause a variety of skin and mucosal lesions, including keratoderma blennorrhagicum (a rash that resembles pustular psoriasis, usually on the palms and soles) and circinate balanitis (a painless ulcerative lesion on the glans penis).
• Gastrointestinal Symptoms: While gastrointestinal symptoms such as diarrhea and abdominal pain are typically part of the initial infection, they may persist in some individuals even after the infection has resolved. Chronic gastrointestinal inflammation is particularly common in reactive arthritis triggered by Yersinia infections.

Diagnosis

The diagnosis of reactive arthritis is primarily clinical, based on the characteristic history of a preceding infection, the pattern of joint involvement, and the presence of extra-articular manifestations. There are no specific laboratory tests or imaging studies that can definitively confirm the diagnosis of ReA, but several investigations can be helpful in supporting the diagnosis and ruling out other conditions.

Laboratory Tests

• Acute phase reactants: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are typically elevated in patients with active reactive arthritis, reflecting systemic inflammation.
• HLA-B27 testing: Testing for the HLA-B27 gene may be useful, particularly in cases of recurrent or chronic reactive arthritis, though its presence is not necessary for diagnosis.
• Stool cultures: In cases where gastrointestinal infection is suspected as the trigger for ReA, stool cultures may identify the causative pathogen. However, by the time arthritis develops, the infectious agent may no longer be detectable in stool samples.
• Synovial fluid analysis: Joint aspiration and synovial fluid analysis can help differentiate reactive arthritis from septic arthritis, gout, or other inflammatory joint conditions. In ReA, synovial fluid analysis typically reveals an inflammatory pattern, with elevated white blood cell counts, but no infectious organisms.

Imaging Studies

• X-rays: Radiographs of affected joints are usually normal in the early stages of reactive arthritis. However, in cases of chronic or recurrent disease, radiographic changes such as joint space narrowing, periostitis (inflammation of the periosteum), and new bone formation at the entheses may be seen.
• MRI: Magnetic resonance imaging (MRI) can be useful in identifying soft tissue inflammation, such as enthesitis or sacroiliitis, particularly in cases where axial involvement is suspected.

Treatment

The treatment of reactive arthritis is aimed at controlling inflammation, relieving pain, and preventing long-term joint damage. While the course of reactive arthritis is often self-limiting, with symptoms resolving within 3 to 6 months in most cases, some patients may develop chronic or recurrent arthritis. The management of ReA involves a combination of pharmacological therapies and supportive measures.

Pharmacological Treatment

• Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs are the first-line treatment for reactive arthritis and are effective in reducing inflammation and relieving pain. Commonly used NSAIDs include ibuprofen, naproxen, and indomethacin. NSAIDs are generally well-tolerated, but long-term use may be associated with gastrointestinal, renal, and cardiovascular side effects.
• Corticosteroids: In cases of severe or refractory arthritis, intra-articular corticosteroid injections may provide relief from joint inflammation. Systemic corticosteroids (e.g., prednisone) may be used for patients with widespread or severe disease, though their use is typically limited due to the risk of side effects with long-term use.
• Disease-modifying antirheumatic drugs (DMARDs): In patients with chronic or recurrent reactive arthritis, DMARDs such as sulfasalazine or methotrexate may be used to control inflammation and prevent joint damage. These drugs are typically reserved for cases where NSAIDs and corticosteroids are insufficient to control symptoms.
• Biologic therapies: In patients with refractory reactive arthritis, biologic agents such as tumor necrosis factor (TNF) inhibitors (e.g., etanercept, adalimumab) may be considered. These drugs are effective in reducing inflammation and preventing joint damage in patients with chronic spondyloarthropathies, though their use in reactive arthritis is less well-studied.

Antibiotics

While antibiotics are effective in treating the underlying bacterial infection that triggers reactive arthritis, they are not typically used to treat the arthritis itself. However, in cases where the triggering infection is still active (e.g., persistent Chlamydia infection in urogenital ReA), antibiotic therapy may be indicated. There is no evidence to support the routine use of antibiotics in treating reactive arthritis that develops after gastrointestinal infections, as the bacterial infection has usually resolved by the time arthritis develops.

Supportive Measures

• Physical therapy: Physical therapy and exercise are important components of the management of reactive arthritis. Regular exercise can help maintain joint mobility and prevent stiffness, while strengthening exercises can improve muscle function and support affected joints.
• Orthotics and assistive devices: In cases of severe joint involvement, orthotics (such as shoe inserts for plantar fasciitis) or assistive devices (such as crutches or canes) may be needed to support affected joints and improve mobility.

Prognosis

The prognosis of reactive arthritis is generally favorable, with most cases resolving within 3 to 6 months. However, approximately 15-30% of patients may develop chronic or recurrent arthritis, particularly those who are HLA-B27-positive. Chronic reactive arthritis can lead to long-term joint damage and disability if not adequately managed. Extra-articular symptoms, such as uveitis or chronic skin lesions, may also persist in some patients.

Factors Associated with Poor Prognosis

Several factors have been associated with a worse prognosis in reactive arthritis, including:

• HLA-B27 positivity: HLA-B27-positive individuals are more likely to develop chronic or recurrent arthritis and are also more likely to experience axial involvement, such as sacroiliitis.
• Severe initial presentation: Patients with more severe joint involvement or multiple extra-articular manifestations at the onset of the disease are more likely to develop chronic symptoms.
• Delayed treatment: Early and aggressive treatment of inflammation with NSAIDs or corticosteroids may help prevent the development of chronic reactive arthritis.

Conclusion

Reactive arthritis is an inflammatory condition that can develop after gastrointestinal or urogenital infections, with foodborne pathogens such as Campylobacter, Salmonella, Shigella, and Yersinia being common triggers. The pathogenesis of ReA involves an aberrant immune response, particularly in individuals who carry the HLA-B27 gene. While the condition is typically self-limiting, some patients may develop chronic or recurrent arthritis, and treatment is aimed at controlling inflammation and preventing joint damage. Ongoing research into the immunological mechanisms underlying reactive arthritis may lead to more targeted therapies and prevention strategies in the future.