Pathogenesis

Reactive arthritis typically follows enteric infection with Salmonella, Shigella, Yersinia enterocolitica, Campylobacter jejuni, Cryptosporidium parvum, or Giardia intestinalis, or genitourinary tract infection with Chlamydia trachomatis or Ureaplasma. Though similar in some respects to reactive arthritis, acute rheumatic fever caused by group A streptococcus (Chapter 176.1), arthritis associated with infective endocarditis (Chapter 431), and the tenosynovitis associated with Neisseria gonorrhoeae are considered later.

Approximately 75% of patients with reactive arthritis are HLA-B27 positive. This association has led to the idea that reactive arthritis represents an autoimmune response involving molecular mimicry, whereby autoreactive T lymphocytes cross react with antigens (synovial, cartilaginous, glycosaminoglycan) in the joints presented by HLA-B27; however, this hypothesis remains unproven. Incomplete elimination of bacteria and bacterial products, such as DNA, has also been proposed. A relationship with clinical characteristics of specific infectious disorders is not present. In postinfectious arthritis, several viruses (rubella, varicella-zoster, herpes simplex, cytomegalovirus) have been isolated from the joints of patients. Antigens from other viruses (hepatitis B, adenovirus 7) have been identified in immune complexes from joint tissue.

Patients with reactive arthritis who are HLA-B27 positive have an increased frequency of uveitis and other extra-articular features. In addition, HLA-B27 is a risk factor for persistent gut inflammation following enteric infections, even after resolution of the gastrointestinal infection, and significantly increases the risk that the individual will eventually develop a chronic spondyloarthritis. Nevertheless, reactive arthritis does occur in HLA-B27–negative patients, indicating that other genes play a role in disease susceptibility.

Clinical Manifestations and Differential Diagnosis

Symptoms of reactive arthritis present approximately 2-4 wk following infection. The classic triad of arthritis, urethritis, and conjunctivitis (formerly referred to as Reiter syndrome) is relatively uncommon in children. The arthritis is typically oligoarticular, with a lower extremity predilection. Dactylitis may occur, and enthesitis (Fig. 151-1) is common (Chapter 150). Cutaneous manifestations can occur and may include circinate balanitis, ulcerative vulvitis, oral lesions, and keratoderma blennorrhagica, which is similar in appearance to pustular psoriasis (Fig. 151-2). Systemic symptoms may include fever, malaise, and fatigue. Early in the disease course, markers of inflammation—erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelets—may be markedly elevated.

Figure 151-1 Enthesitis—swelling of the posterior aspect of the left heel and lateral aspect of the ankle.

(Courtesy of Nora Singer, Case Western Reserve University and Rainbow Babies’ Hospital.)

Figure 151-2 Keratoderma blennorrhagica.

(Courtesy of Dr. M.F. Rein and The Centers for Disease Control and Prevention Public Health Image Library, 1976. Image #6950.)

Familiarity with other causes of postinfectious arthritis is vital when a diagnosis of reactive arthritis is being considered. Numerous viruses are associated with postinfectious arthritis (Table 151-1) and may result in particular patterns of joint involvement. Rubella and hepatitis B virus typically affect the small joints, whereas mumps and varicella often involve large joints, especially the knees. The hepatitis B arthritis–dermatitis syndrome is characterized by urticarial rash and a symmetric migratory polyarthritis resembling that of serum sickness. Rubella-associated arthropathy may follow natural rubella infection and, infrequently, rubella immunization. It typically occurs in young women, with an increased frequency with advancing age, and is uncommon in preadolescent children and in males. Arthralgia of the knees and hands usually begins within 7 days of onset of the rash or 10-28 days after immunization. Parvovirus B19, which is responsible for erythema infectiosum (fifth disease), can cause arthralgia, symmetric joint swelling, and morning stiffness, particularly in adult women and less frequently in children. Arthritis occurs occasionally during cytomegalovirus infection and may occur during varicella infections but is rare after Epstein-Barr virus infection. Varicella may also be complicated by suppurative arthritis, usually secondary to group A streptococcus infection. HIV is associated with an arthritis that resembles psoriatic arthritis more than juvenile idiopathic arthritis (JIA).

Post-streptococcal arthritis is a postinfectious arthritis that may follow infection with either group A or group G streptococcus. It is typically oligoarticular, affecting lower extremity joints, and mild symptoms can persists for months. Post-streptococcal arthritis differs from rheumatic fever, which typically follows a course with painful migratory polyarthritis of brief duration. Because valvular lesions have occasionally been documented by echocardiography after the acute illness, some clinicians consider post-streptococcal arthritis to be an incomplete form of acute rheumatic fever (Chapter 176.1). Certain HLA-DRB1 types may predispose children to development of either post-streptococcal arthritis (HLA-DRB1*01) or acute rheumatic fever (HLA-DRB1*16).

Transient synovitis (toxic synovitis), another form of post-infectious arthritis, typically affects the hip, often after an upper respiratory tract infection (Chapter 670.2). Boys from 3 to 10 yr of age are most commonly affected and have acute onset of severe pain in the hip, with referred pain to the thigh or knee, lasting approximately 1 wk. The ESR and white blood cell count are usually normal. Radiologic or ultrasound examination may confirm widening of the joint space secondary to effusion. Aspiration of joint fluid is often necessary to exclude septic arthritis and results in dramatic clinical improvement. The trigger is presumed to be viral, although responsible microbes have not been identified.

Nonsuppurative arthritis has been reported in children, usually adolescent boys, in association with severe truncal acne. Patients often have fever and persistent infection of the pustular lesions. Recurrent episodes may also be associated with a sterile myopathy and may last for several months. Infective endocarditis can be associated with arthralgia, arthritis, or signs suggestive of vasculitis, such as Osler nodes, Janeway lesions, and Roth spots. Post-infectious arthritis, perhaps because of immune complexes, also occurs in children with N. gonorrhoeae, Neisseria meningitidis, H. influenzae type b, and Mycoplasma pneumoniae infections.

Diagnosis

A recent genitourinary or gastrointestinal infection may suggest the diagnosis of reactive arthritis, but there is no diagnostic test. Although stool or urogenital tract cultures can be performed in an attempt to isolate the triggering organism, the offending agent is not typically identified by the time arthritis is present. Imaging findings are nonspecific or normal. Similarly, documenting previous streptococcal infection may help to diagnose post-infectious arthritis.

Because the preceding infection can be remote or mild and often not recalled by the patient, it is also important to rule out other causes of arthritis. Acute arthritis affecting a single joint suggests septic arthritis, mandating joint aspiration; osteomyelitis may cause pain and an effusion in an adjacent joint but is more often associated with focal bone pain over the site of infection. The diagnosis of postinfectious arthritis is often established by exclusion, after the arthritis has resolved. Arthritis associated with gastrointestinal symptoms or abnormal liver function test results may be triggered by infectious or autoimmune hepatitis. Arthritis or spondyloarthritis may occur in children with inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis (Chapter 328). When two or more blood cell lines progressively decrease in concentration in a child with arthritis, parvovirus infection, macrophage activation (hemophagocytic) syndrome, and leukemia should be strongly considered. Persistent arthritis (>6 wk) suggests the possibility of a chronic rheumatic disease, including JIA (Chapters 149 and 150) and systemic lupus erythematosus.

Treatment

Specific treatment is unnecessary for most cases of reactive or postinfectious arthritis. Nonsteroidal anti-inflammatory agents are often needed for management of pain and functional limitation. Unless ongoing Chlamydia infection is suspected, attempts to treat the offending organism are not warranted. If swelling or arthralgia recurs, further evaluation may be necessary to exclude active infection or evolving rheumatic disease. Intra-articular steroid injections may be utilized for refractory or severely involved joints once acute infection has been ruled out. Systemic steroids or disease-modifying antirheumatic drugs (DMARDs) are rarely indicated but may be considered for chronic disease. Participation in physical activity should be encouraged, and physical therapy may be needed to maintain normal function and prevent muscle atrophy. For post-infectious arthritis due to streptococcal disease, current recommendations include penicillin prophylaxis for at least 1 yr; duration of prophylaxis is controversial.

Complications and Prognosis

Postinfectious arthritis following viral infections usually resolves without complications unless it is associated with involvement of other organs, such as encephalomyelitis. Children with reactive arthritis after enteric infections occasionally experience inflammatory bowel disease months to years after onset. Both uveitis and carditis have been reported in children diagnosed with reactive arthritis. Reactive arthritis, especially after bacterial enteric infection or genitourinary tract infection with Chlamydia trachomatis, has the potential for evolving to chronic arthritis, particularly spondyloarthritis (Chapter 150). The presence of HLA-B27 or significant systemic features increases the risk of chronic disease.