Many bacteria and viruses can cause arthritis without directly invading the joint space. The diseases that result are highly varied and are the focus of this chapter. These processes include reactive arthritis, which occurs after genitourinary or enteric bacterial infections, post-streptococcal reactive arthritis (PSRA), Lyme disease, and viral and post-viral arthritis (including transient synovitis).
Bacterial infection of the joint, with the recovery of the causative organism from the synovial fluid, is called septic arthritis and is addressed in Chapter 105. Acute rheumatic fever (ARF), which can also cause arthritis, is addressed separately (Chapter 57).
Reactive arthritis is the name given to an aseptic arthritis that follows a gastrointestinal or genitourinary infection. It is associated with certain bacteria; specifically, Chlamydia trachomatis, Shigella, Salmonella, Yersinia, or Campylobacter, but recent reports have also implicated atypical organisms as diverse as Giardia lamblia and Clostridium difficile.1 Although by definition reactive arthritis is a sterile arthritis, modern PCR techniques have identified bacterial DNA in synovial tissue.2 The significance of this finding is unclear.
Reactive arthritis is part of a group of diseases called spondyloarthritides (arthritis that affects primarily the axial skeleton), which includes psoriatic arthritis, enthesitis-related arthritis, and ankylosing spondylitis. They have a strong association to human leukocyte antigen B27 (HLA-B27) and share common extra-articular features including enthesitis, uveitis, and inflammatory bowel disease.
The pathogenesis of reactive arthritis is still not well understood. Newer evidence suggests that the arthritis that results is caused by an abnormal innate immune response to bacterial antigens in the joint space, or to mechanical trauma.3
Post-streptococcal reactive arthritis (PSRA) may be caused by antistreptococcal antibodies that cross-react with proteins expressed in the joint cartilage and synovial lining.4
Lyme disease is the most common vector-borne infection in North America. It is caused by the spirochete Borrelia burgdorferi and transmitted to humans by infected Ixodes scapularis and I. pacificus ticks. The disease is endemic in the northeast and north-central regions of the United States, and its incidence is increasing dramatically.5
Although it cannot be cultured from the synovium of patients with Lyme arthritis, B. burgdorferi DNA is detectable in the synovial fluid via PCR. The spirochete does not secrete any toxins but is thought to cause a strong host inflammatory response that leads to arthritis.6 Phagocytosis of live B. burgdorferi by monocytes appears to induce the release of pro-inflammatory cytokines such as type I interferons that induce joint inflammation.7
Viruses cause arthritis by various mechanisms, including the stimulation of pro-inflammatory cytokines, inducing the formation of antibodies that cross-react with joint structures, increasing the activation of lymphocytes that are autoreactive, or via direct infection of synovial cells.8
Consideration for infection-associated arthritis first requires the presence of arthritis; that is, inflammation of the joints. The history of inflammatory joint disease is that of a child with significant morning stiffness that improves with activity and worsens with rest. This is in contrast to mechanical joint pain, which is worsened with activity and relieved with rest. Examination of an arthritic joint reveals the cardinal features of inflammation including swelling, warmth, tenderness, and limited range of motion. The timing of symptom onset, number and pattern of joints involved as well as extra-articular signs and symptoms, provide clues that help to differentiate among these infection-associated arthritides. Clinical features of infection-associated arthritis are shown in Table 152-1.
| Disease | Timing | Joint Involvement | Typical Age of Presentation | Associated Features |
|---|---|---|---|---|
| Reactive arthritis | 1–4 weeks after GI or GU infection | Acute painful oligoarthritis of lower extremities | 8–12 y | Enthesitis, dactylitis, fever, weight loss, HLA-B27 |
| Post-streptococcal reactive arthritis | 1–2 weeks after streptococcal infection | Mono- oligo- or polyarthritis of the lower extremities | 8–14 y | Pharyngitis |
| Acute rheumatic fever | 2–3 weeks after streptococcal infection | Painful migratory arthritis of large joints | 6–15 y | Carditis, chorea, erythema marginatum, subcutaneous nodules, fever |
| Lyme arthritis | Weeks to months after infection | Oligoarthritis of the knee | 5–9 y | Residence in or travel to endemic areas |
| Viral (e.g. parvovirus B19) | Concurrent with infection or up to 2 weeks later | Varied | Any | Fever, “slapped cheek” rash, other viral symptoms |
| Transient synovitis | Follows URI | Painful hip with limp | 3–10 y (male-to-female ratio 2:1) | Afebrile or low-grade fever, appear well |
Reactive arthritis occurs 1 to 4 weeks after gastrointestinal or genitourinary infections. Not all infections are symptomatic, so the diagnosis of reactive arthritis may be difficult to make in some cases, as the inciting event is not readily identified. Chlamydial infection, the most common cause of reactive arthritis in adults, tends to be asymptomatic in most patients that develop reactive arthritis.9 Reactive arthritis usually presents as an acute, painful, sometimes erythematous oligoarthritis (four or fewer joints involved), usually of the lower extremities, most typically in the knees and ankles. A characteristic of reactive arthritis is enthesitis, or inflammation of the attachment of ligaments and tendons to bone. This commonly occurs in the patellar and Achilles tendons as well as in the plantar fascia.2 Dactylytis, or sausage digits, may also be present. As a form of spondyloarthritis, stiffness and pain of the back and neck may be present. Systemic features may include fever, weight loss, and fatigue during the disease course. Extra-articular features may include painless oral ulcers, urethritis, and conjunctivitis. Patients with reactive arthritis will often have a relapsing course, especially in the setting of repeated infections with the same organism.
Post-streptococcal reactive arthritis represents a heterogeneous group of diseases, classified as arthritis that occurs 1 to 2 weeks after streptococcal infection in the setting of incomplete diagnostic criteria for acute rheumatic fever. It occurs with equal frequency in males and females, and commonly affects children ages 8 to 14.10 Joint involvement is usually not migratory, in contrast to the arthritis that occurs in ARF. PSRA primarily affects the large joints of the lower extremities, and there is an equal incidence of patients with mono-, oligo-, and polyarthritis. The arthritis typically resolves within a few weeks, although it can last for a few months. Pharyngitis may be present in two-thirds of patients, and one-third report low-grade fever or rash.11 Glomerulonephritis, a recognized complication of streptococcal infection, occurs in some patients. Around 8% of children with PSRA subsequently develop valvular heart disease,12 which raises the question of whether PSRA is a distinct entity from ARF. In contrast, carditis is not seen in adults with PSRA.12
Most patients infected with B. burgdorferi are asymptomatic, but in symptomatic patients, Lyme disease may affect the skin, joints, nervous system, and heart. Lyme disease is most commonly seen in children ages 5 to 9 years, a finding likely related to the frequency and intensity of tick exposure. The majority of patients have onset of disease in June, July, or August, but they may present throughout the year.5
Most symptomatic children present with early Lyme disease, manifested as erythema migrans (EM), an enlarging, erythematous, painless rash at the site of the tick bite. The rash expands peripherally and may have central clearing. This usually appears days to weeks after infection. EM may be accompanied by flu-like symptoms including chills, fevers, arthralgias, headaches, myalgias, and fatigue. Early Lyme disease may also be accompanied by a lymphocytic meningitis and Bell’s palsy.13 Lyme carditis is uncommon in children but can present with atrioventricular block.
Another common presentation of Lyme disease is arthritis, a late manifestation of the disease. Lyme arthritis occurs months to years after infection, with an average of 4 months between infection and presentation.14 Most patients do not recall a tick bite. Of children who present with Lyme arthritis, 90% have knee involvement, although the hip and ankles may be involved in a minority of patients.14 Arthritis may present as a single episode of mildly painful swelling that may disappear without treatment. Untreated, half of children with Lyme arthritis may have recurrent episodes of arthritis lasting weeks to months. However, after appropriate antibiotic treatment, arthritis may recur within a year; most of these recurrences can be treated with nonsteroidal anti-inflammatory agents (NSAIDs) alone. Arthritis related to Lyme disease that occurs years after the initial episode appear to be the result of a new infection rather than relapse of the original infection.15
Most viral infections cause arthralgias (joint pain in the absence of inflammation) rather than arthritis, although a few viruses have characteristic involvement of the joints. Parvovirus B19 usually causes erythema infectiosum, or fifth disease. Although most often an asymptomatic infection, this pathogen may cause fever and nonspecific influenza-like symptoms during viremia. Two weeks later, a cutaneous eruption is seen on the cheeks (slapped cheeks), thought to be due to the formation and deposition of immune complexes in the skin.16 The arthritis that sometimes occurs in this disease is also thought to be related to immune-complex deposition within joints. Adults often develop arthritis after parvovirus infection, with the sudden onset of symmetric swelling of the small joints of the hands, mimicking rheumatoid arthritis. However, only a few children with parvovirus B19 infection will develop joint symptoms, usually manifested as mild and transient arthalgias. A small minority will develop a symmetric arthritis similar to what occurs in adults,17 but they can also develop oligoarthritis of large joints such as knees and ankles.18 Symptoms usually resolve within weeks to months, though treatment directed against the arthritis may be necessary.
Rubella infection, either naturally acquired or occasionally after vaccination with MMR, can cause arthralgias and arthritis, especially in girls. The distribution of involved joints is usually symmetric, appearing 2 weeks after infection or vaccination, or around the onset of the rash. The hands and knees are most often affected, and the arthritis usually resolves within 2 weeks.
Arthritis can also be seen in the setting of other common viral infections, including hepatitis C virus (HCV) infection, especially with the presence of cryoglobulins, with hepatitis B virus (HBV) infection in the presence of polyarteritis nodosa, and in HIV.
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