An overview of reactive arthritis

Abstract

Reactive arthritis, also known as Reiter syndrome, is a spondyloarthropathy that typically follows a urogenital or gastrointestinal infection, and is characterized by conjunctivitis, urethritis, and arthritis. The frequency of reactive arthritis in the United States is estimated at 3.5 to 5 patients per 100,000. Physician assistants (PAs) can manage the condition; therefore, they should be familiar with the disease's signs and symptoms, diagnostic criteria, and treatment regimens. Without proper management, reactive arthritis can progress to a chronic destructive arthritis. Prompt recognition of the condition is key to early intervention and a better patient outcome with fewer complications.

Box 1

Reactive arthritis is a rare condition that is easily missed in clinical practice because of the variability in its symptomatology and presentation. Prompt recognition and treatment can reduce progression to chronic arthritis and other poor outcomes. Given the shortage of rheumatologists in the United States and the large number of physician assistants (PAs) in the field, PAs should be able to diagnose and treat complex rheumatologic conditions such as reactive arthritis.¹

CAUSES

Reactive arthritis most commonly occurs up to several weeks after a gastrointestinal or urogenital infection.² It also can occur following certain upper respiratory infections and after Bacillus Calmette-Guerin (BCG) treatment for bladder cancer.^3,4 Organisms commonly associated with reactive arthritis include Chlamydia trachomatis, Shigella flexneri, Salmonella enteritidis, Campylobacter jejuni, Clostridium difficile, and Ureaplasma urelyticum. Less commonly associated infections include Escherichia coli, Borrelia burgdorferi, Neisseria gonorrhoeae, and Chlamydia pneumoniae.^2,4 See Table 1 for a complete list of causative organisms of reactive arthritis.

Box 1

FIGURE 1.: Conjunctivitis (A), skin lesions (B), and keratoderma blennorrhagica (C) are among the manifestations of reactive arthritis.Images A - B: © Clinical Photography, Central Manchester University Hospitals NHS Foundation Trust, UK/Science Source. Image C: CDC/ Dr. M. F. Rein

TABLE 1.: Causative organisms of reactive arthritis^2,3

The pathophysiology of reactive arthritis is unknown.⁴ One common similarity between each of these pathogens is that they are intracellular organisms and can reach the joints as a complete form or as fragments causing a sterile synovitis.^2,5 Additionally, inheritance of the HLA-B27 allele is strongly associated with the development of reactive arthritis. Patients with this gene have a 50% increased risk of developing reactive arthritis, although the exact association between the two is unclear.³ Current research includes theories of molecular mimicry between the gene and pathogen, which incites the immune response; the gene being a receptor for various pathogens; and the gene driving cross-reactivity between antigen and host.^5,6

SIGNS AND SYMPTOMS

The presentation of reactive arthritis varies significantly in severity, number of clinical features, and symptom onset.⁴ Patients can be asymptomatic or symptomatic with urogenital, rheumatologic, ophthalmologic, dermatologic, and visceral manifestations.^2,4 Studies have shown that symptom severity and frequency is increased in patients who are HLA-B27 positive.⁷ Onset typically is acute; patients may have symptoms such as malaise, fatigue, weight loss, and fever.⁵ Urogenital manifestations of reactive arthritis include urethritis, cervicitis, salpingitis, pelvic inflammatory disease, epididymitis, orchitis, and prostatitis. Common urologic symptoms include hematuria, dysuria, urinary urgency, urinary frequency, and urethral and/or vaginal discharge.⁸ About 90% of patients experience urethritis or cervicitis as a result of genitourinary system infection.⁴

The most common joint manifestation of reactive arthritis is asymmetrical polyarticular arthritis of no more than six large joints, with knees and ankles being most frequently affected. Patients often will complain of joint pain and pain in their heels and lower back. On physical examination their joints will be red, swollen, and tender.⁸ Up to 30% of patients also suffer from enthesitis, including plantar fasciitis and achilles tendonitis.⁵

Ophthalmologic manifestations

Conjunctivitis (most common), uveitis (second most common), episcleritis, scleritis, keratitis, optic neuritis, glaucoma, and retinal vasculitis are among the ophthalmologic manifestations of reactive arthritis.⁸ Symptoms of conjunctivitis include injected dry eyes with or without pain, edema, and purulent discharge. Symptoms of uveitis include pain, photophobia, vision impairment, scleral injection, and hypopyon.⁸

Dermatologic manifestations

These are less common, and include hyperkeratotic lesions on palms and soles, mucocutaneous lesions in the oral cavity and genitalia, and/or nail dystrophy.⁵

Other manifestations

Reactive arthritis rarely is associated with visceral involvement. It can present as cardiac conduction abnormalities in early disease and aortic insufficiency in late disease.⁴ It also has been associated with myelopathy and neurologic manifestations.⁴ In addition, patients with reactive arthritis may have gastrointestinal complications such as diarrhea and colitis.⁵

DIAGNOSIS

To date, there is no agreement on diagnostic criteria for reactive arthritis. The condition is classified as a seronegative spondyloarthropathy because patients have historically tested negative for rheumatoid factor.⁴ Similar to other spondyloarthropathies (such as psoriatic arthritis and ankylosing spondylitis), reactive arthritis is characterized by arthritis of the axial skeleton, enthesitis, asymmetric oligoarthritis, or symmetric polyarthritis of peripheral joints, and absence of rheumatoid factor. More specifically, reactive arthritis is classically recognized as the triad of conjunctivitis, peripheral arthritis, and urethritis or cervicitis and often is remembered by the adage: “Can't see, can't pee, can't climb a tree.”⁴

In 1999, the American College of Rheumatology (ACR) issued general guidelines for classifying and diagnosing reactive arthritis.⁶ For a definite diagnosis of reactive arthritis, patients must have both major criteria and at least one minor criterion. Patients with both major criteria, or one major and one minor criterion, meet the probable diagnosis for reactive arthritis.

Major criteria are:

• Arthritis, meeting two of the following three characteristics: asymmetric, mono- or oligoarthritis, and lower limb involvement
• Preceding symptomatic infection, meeting one of the following characteristics: enteritis, defined as at least 1 day of diarrhea occurring 3 days to 6 weeks before the onset of arthritis; or urethritis, defined as dysuria or discharge for at least 1 day occurring 3 days to 6 weeks before the onset of arthritis

Minor criteria are:

• Presence of a triggering infection, as evidenced by positive urine culture, cervical/urethral swab, or stool culture
• Presence of persistent synovial infection, as evidenced by positive immunohistology or PCR.⁶

The combination of elevated CRP, genitourinary symptoms, metatarsophalangeal joint involvement, and HLA-B27 involvement has been estimated to be predictive of reactive arthritis with a 69% sensitivity and 93.5% specificity.⁶

Laboratory testing can be of great value to the diagnosis of reactive arthritis, but it also can present some difficulties. This is due to factors such as delays in culturing infectious fluids, a failure to isolate infectious organisms during arthrocentesis, and a lack of specific serologic tests for some of the causative agents (such as Shigella).⁹ Laboratory testing of the inflammatory markers erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) also can be quite helpful in the diagnosis of reactive arthritis, especially in the acute phase. However, the absence of elevated inflammatory markers does not rule out reactive arthritis.⁶

Given the many clinical manifestations of reactive arthritis, clinicians must consider several differential diagnoses. Some of the most common conditions to distinguish from reactive arthritis are psoriatic arthritis, rheumatoid arthritis, septic arthritis, and gout.¹⁰ Although dermatologic manifestations appear similar in psoriatic arthritis and reactive arthritis, psoriatic arthritis more commonly has distal interphalangeal (DIP) joint involvement on radiography. As mentioned previously, reactive arthritis may present as a symmetric polyarthritis, which also is a classic presentation for rheumatoid arthritis. Although this may present a diagnostic challenge, rheumatoid arthritis, unlike reactive arthritis, typically does not affect the sacroiliac joints or lumbar spine. Additionally, rheumatoid factor often will be positive in patients with rheumatoid arthritis and negative in those with reactive arthritis.⁴

Septic arthritis can present similarly to reactive arthritis. Septic arthritis is monoarticular and can be distinguished from reactive arthritis with synovial fluid and Gram stain analysis. Synovial fluid analysis also can help differentiate gout from reactive arthritis. In gout, crystals will be present on synovial fluid analysis and patients may have uric acid tophi.¹⁰

Also consider the patient's age: Reactive arthritis usually occurs in young adults, with a peak incidence in patients ages 20 to 29 years; however, many cases have been reported in children.⁴ The frequency of reactive arthritis in the United States is estimated to be 3.5 to 5 patients per 100,000.⁵ The risk is equal between men and women after enteric infections; however, reactive arthritis is more common in men than women after genitourinary infections, with a 9:1 ratio.¹¹ The condition also is more common in whites, as the presence of the HLA-B27 gene is higher in whites than in patients of other ethnicities.⁶

TREATMENT AND PROGNOSIS

Reactive arthritis has no cure; therefore, treatment focuses on alleviating pain and inflammation, reducing long-term deficits, and limiting disease progression.³ Two-thirds of patients have a self-limiting course.⁸ Nonpharmacologic treatments include rest during the acute phase and local cold treatment to affected joints.^3,8 Patients with enthesitis can use orthotics, insoles and heel supports to help reduce pain and increase mobility. Strengthening exercises are important during treatment to prevent muscle wasting.³

Unlike in other rheumatic conditions, nonsteroidal anti-inflammatory drugs (NSAIDs), most commonly ibuprofen, indomethacin, or naproxen, are the first-line pharmacologic treatment for spondyloarthropathies and reactive arthritis.^2,3 NSAIDs are beneficial for their analgesic, anti-inflammatory effects and also for slowing the development of syndesmophytes.² Patients should take these agents for at least 2 to 4 weeks before trying more powerful medications.³ In addition to NSAIDs, consider intra-articular glucocorticoid injections for patients with reactive arthritis affecting one or more joints.³ Dermatologic manifestations of reactive arthritis, such as hyperkeratotic lesions, can be treated with topical corticosteroids.¹⁰ Low to moderate doses of systemic corticosteroids may be used in patients who have had little response to NSAIDs or glucocorticoid injections, or those who have many affected joints. To avoid adverse reactions, taper systemic corticosteroid doses to the lowest dose possible to control symptoms.^2,10,12

Disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine also have shown to be effective for peripheral manifestations and should be continued until patients are in remission.^2,3 In patients with severe or refractory reactive arthritis, anti-tumor necrosis factor (TNF) agents such as etanercept and infliximab may be effective.^9,13 Anti-TNF therapy is associated with symptom improvement and has led to remission in one-third of patient cases.¹⁴ Antibiotic therapy for reactive arthritis is controversial, as evidence shows that it does not alter the disease course.^8,9

The course of reactive arthritis, including disease duration, frequency of relapses, and severity of relapses, is highly variable. Mild cases typically last 3 to 5 months and may spontaneously resolve or progress to chronic disease.^4,11 An estimated 30% to 63% of patients develop chronic reactive arthritis lasting more than 6 months.¹⁵ Symptomatic relapses can occur years after disease onset.¹¹ Recurrent exacerbations may include urethritis, uveitis, and arthralgias.⁴ Rarely, reactive arthritis can cause disability due to chronic, destructive arthritis.¹¹ Patients who are HLA-B27 positive are at risk for more severe disease manifestations and progression.⁴ Predictors of worse prognosis include HLA-B27 positivity, Chlamydia-induced infection, spondyloarthropathy family history, and chronic bowel inflammation.^4,11,15

PREVENTION

To reduce the chance of developing reactive arthritis, patients should be given appropriate antibiotics at the time of initial infection or if the antecedent infection remains active.^11,16 In patients with chronic reactive arthritis, routine follow-up and screening are crucial to prevent further manifestations. For example, ECG, echocardiogram, and ophthalmologic referral are recommended. Furthermore, patients diagnosed with reactive arthritis should continue to follow up with a rheumatologist as indicated for maintenance and prevention of long-term complications.³

CONCLUSION

Reactive arthritis can develop into a serious and chronic disease if not diagnosed and treated promptly. The diagnosis is easy to miss because of the similarity between clinical manifestations of other diseases and variability in the disease course itself. Clinicians should be aware of the ACR general guidelines and consider the possibility of reactive arthritis in patients presenting with urethritis, cervicitis, conjunctivitis, uveitis, and arthritis following a recent infection.