History
Reactive arthritis (ReA) usually develops 2-4 weeks after a genitourinary (GU) or gastrointestinal (GI) infection (or, possibly, a chlamydial respiratory infection [15] ). About 10% of patients do not have a preceding symptomatic infection. The classic triad of symptoms—noninfectious urethritis, arthritis, and conjunctivitis—is found in only one third of patients with ReA and has a sensitivity of 50.6% and a specificity of 98.9%. [71] In postenteric ReA, diarrhea and dysenteric syndrome (usually mild) is commonly followed by the clinical triad in 1-4 weeks.
In a large percentage of ReA cases, conjunctivitis or urethritis occurred weeks before the patient seeks medical attention. Patients may fail to mention this unless specifically asked. Musculoskeletal disease is evident in many of these patients. [72] Vague, seemingly unrelated complaints may obscure this diagnosis at times. [73]
The onset of ReA is usually acute and characterized by malaise, fatigue, and fever. An asymmetrical, predominantly lower-extremity, oligoarthritis is the major presenting symptom. Myalgias may be noted early on. Asymmetric arthralgia and joint stiffness, primarily involving the knees, ankles, and feet (the wrists may be an early target), may be noted. Low-back pain occurs in 50% of patients. [71] Heel pain associated with Achilles enthesopathies and plantar fasciitis is also common.
Both postvenereal and postenteric forms of ReA may manifest initially as nongonococcal urethritis, with frequency, dysuria, urgency, and urethral discharge; this urethritis may be mild or inapparent. Urogenital symptoms, whether resulting from GU infection or from GI infection, are found in 90% of patients with ReA. [71]
An estimated 0.5-1% of cases of urethritis evolve into ReA. Urethritis develops acutely 1-2 weeks after infection through sexual contact and is similar to gonococcal urethritis. A purulent or hemopurulent exudate appears, and the patient complains of dysuria.
In men, chlamydial urethritis is less painful and produces less purulent discharge than acute gonorrhea does, making it difficult to notice. Findings from microscopic examination and cultures can be used to rule out Neisseria gonorrhoeae infection. Coinfection with Chlamydia and Neisseria organisms is common in some areas. In women, urethritis and cervicitis may be mild, with dysuria or slight vaginal discharge, or asymptomatic, which makes diagnosis difficult.
Often, the initial urethritis is treated with antibiotics (especially wide-spectrum tetracyclines or macrolides) when findings suggest gonorrhea. Despite an apparent early cure, the manifestations of the disease appear several weeks later, and the patient may not relate them to a previous episode of urethritis.
Lymphogranuloma venereum infection may be asymptomatic; screening should be considered in all men who have sex with men (MSM) presenting with acute arthritis, particularly if they are infected with HIV. [74]
In addition to conjunctivitis, ophthalmologic symptoms of ReA include erythema, burning, tearing, photophobia, pain, and decreased vision (rare).
Patients may have mild recurrent abdominal complaints after a precipitating episode of diarrhea.
Association with HIV infection
ReA is particularly common in the context of HIV infection. [75, 76] Accordingly, patients with new-onset ReA must be evaluated for HIV. The existing immunodepression in patients with AIDS poses special management problems.
HIV-positive ReA patients are at risk for severe psoriasiform dermatitis, which commonly involves the flexures, scalp, palms, and soles. Frequently, psoriasiform dermatitis is associated with arthritis that involves the distal joints in a destructive pattern. The disturbances of immune homeostasis in AIDS could account for this peculiar expression of psoriasis in these patients.
Physical Examination
Physical findings in ReA may involve the musculoskeletal system, the skin and nails, the eyes, the GU tract, the GI tract, and other systems (see below).
A scoring system for diagnostic points in ReA-like spondyloarthropathies exists. In this system, the presence of 2 or more of the following points (1 of which must pertain to the musculoskeletal system) establishes the diagnosis:
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Asymmetric oligoarthritis, predominantly of the lower extremity [77]
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Sausage-shaped finger (dactylitis), [71] toe or heel pain, or other enthesitis
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Cervicitis or acute diarrhea within 1 month of the onset of arthritis
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Conjunctivitis or iritis
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Genital ulceration or urethritis
Joints, axial skeleton, and entheses
Articular involvement in ReA is typically asymmetric and usually affects the weight-bearing joints (ie, knees, ankles, and hips), but the shoulders, wrists, and elbows may also be affected. In more chronic and severe cases, the small joints of the hands and feet may be involved as well. Dactylitis (ie, sausage digits) may develop. In children, joint involvement is oligoarticular in 69% of cases, polyarticular in 27%, and monoarticular in 4%.
Joints are commonly described as tender, warm, swollen (see the image below), and, sometimes, red. Symptoms may occur initially or several weeks after onset of other symptoms. Migratory or symmetric involvement is also reported. Periostitis and tendinitis may occur, especially involving the Achilles tendon, which produces pain in the heel. The arthritis is usually remittent and rarely leads to severe limitation of functional capacity. Muscular atrophy can develop in severely symptomatic cases.
Swelling of right knee with effusion caused by arthritis. Image courtesy of Gun Phongsamart, MD.
Enthesopathy, or enthesitis (ie, inflammation of ligament and tendon insertions into bone), is thought to be a characteristic feature of ReA. The Achilles insertion is the most common site; other sites include the plantar fascial insertion on the calcaneus, ischial tuberosities, iliac crests, tibial tuberosities, and ribs.
Sacroiliitis (see the image below) frequently occurs in adults who are positive for human leukocyte antigen (HLA)–B27 (though it is apparently less common in children). It is typically self-limiting. Whereas 50% of patients with ReA may develop low-back pain, most physical examination findings in patients with acute disease are minimal except for decreased lumbar flexion. Patients with more chronic and severe axial disease may develop physical findings similar to, or even indistinguishable from, those of ankylosing spondylitis.
Remarkable tenderness of left sacroiliac joint caused by sacroiliitis. Image courtesy of Gun Phongsamart, MD.
Skin and nails
Skin and mucocutaneous lesions are commonly observed in ReA. The dermal lesions are typified by keratoderma blennorrhagicum, [71] in which hyperkeratotic skin begins as clear vesicles on erythematous bases and progresses to macules, papules, and nodules—found on the soles of the feet (see the image below), palms, scrotum, trunk, or scalp—and eventually coalescing to form a hyperkeratotic erythematous dermatitis resembling pustular psoriasis. [59]
Distal involvement with painful and erosive lesions in the tips of the fingers (see the image below) and toes, with pustules and subungual pustular collections, also occurs.
In some patients, typical keratoderma blennorrhagicum develops 1-2 months after the onset of arthritis, with keratotic papules and plaques that are painful under pressure; sometimes, these can be disabling.
Erythematous macules and plaques, diffuse erythema, erosions, and bleeding can appear on the oral and pharyngeal mucosae in 30-60% of patients. [71] Circinate lesions on the tongue resemble geographic tongue (see the image below).
Erythema nodosum may develop but is uncommon.
Nail dystrophy is present in 20-30% of patients. The nails can become thickened and ridged and may crumble, in a manner resembling mycotic infection or psoriatic onychodystrophy, but nail pitting is not observed. Nail shedding is common.
Eyes
Conjunctivitis is a component of the original triad and is one of the hallmarks of the disease, reported to appear in 33-100% of patients. It tends to occur early in the disease, especially during the initial attack; it may be missed if patients are seen only during subsequent attacks.
An intense red, velvetlike conjunctival injection characterizes the conjunctivitis. Bilateral involvement is common. Edema and a purulent discharge are not rare. The conjunctivitis may be mild and painless or may cause severe symptoms with blepharospasm and photophobia. It usually resolves spontaneously within 2 weeks.
Anterior uveitis (including iritis, iridocyclitis, or cyclitis) is the second most common ocular finding. Iridocyclitis may be the initial ocular manifestation in some patients. Uveitis may occur in 12-37% [71] (or possibly as many as 50%) of patients with ReA and is more frequently found in patients with HLA-B27 and those with sacroiliitis. At clinical examination, redness, pain, impaired vision, and exudation with hypopyon can suggest iritis. Rarely, an ReA patient may have permanent visual loss from macular infarction or foveal scarring. [78]
A particularly serious ocular manifestation is recurrent nongranulomatous iridocyclitis. Recurrences are usually associated with an acute iridocyclitis that has a rapid onset with conjunctival and episcleral edema and injection. The corneal endothelium has cellular debris and poorly defined, small- to medium-sized keratic precipitates. Heavy flare and cells and a very early tendency toward formation of posterior synechiae are characteristic, more so than in most other forms of acute iridocyclitis.
Even the most aggressive pupil-dilation management is sometimes inadequate to prevent synechiae formation. A peripheral iridectomy may be necessary to prevent iris bombé and angle closure if the synechiae cannot be broken.
Heavy flare is sometimes so plasmoid that cells are immobile, and a fibrinlike clot may be seen in the pupillary opening as the inflammation resolves. An acute hypopyon may occur. Cells and inflammatory debris may be seen in the vitreous, and blurring of the disc margins and macular edema may occur with severe or prolonged episodes. Spillover vitreitis may be more common in patients with reactive arthritis than those with ankylosing spondylitis.
Other ocular findings that may be noted in ReA include the following:
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Scleritis
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Cataracts - Lens clouding and posterior subcapsular cataracts occur with prolonged or repeated episodes
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Hypotony - This may occur after a severe or prolonged course and may persist after resolution
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Glaucoma - Secondary open-angle glaucoma may occur because of the anterior chamber reaction and the trabecular obstruction or trabeculitis; it usually resolves with aggressive anti-inflammatory therapy; with repeated recurrences, damage to the trabecular meshwork may occur, resulting in secondary glaucoma
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Corneal ulceration
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Disc or retinal edema
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Retinal vasculitis
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Optic neuritis
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Dacryoadenitis (occurs rarely in the setting of chlamydial urethritis) [80]
Genitourinary tract
Urogenital symptoms may be primary or postdysenteric and may include the following [71] :
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Meatal edema and erythema and clear mucoid discharge
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Prostatitis causing tenderness (up to 80%) and vulvovaginitis
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Circinate balanitis (balanitis circinata)
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Cystitis
Circinate balanitis, consisting of small shallow painless ulcers of the urethral meatus or the glans penis (see the images below), is characteristic. The condition is characterized by circinate or gyrate white plaques that grow centrifugally and eventually cover the entire surface of the glans penis. The penile shaft and scrotum can be involved. On an uncircumcised penis, the lesions typically remain moist; on a circumcised penis, they may harden and crust, causing pain and scarring in 50% of patients. [71]
Balanitis circinata (circinate balanitis). Image courtesy of Gun Phongsamart, MD.
Circinate vulvitis is reported in women. Balanitis and vulvitis are rare in children; when they occur, they are suggestive of ReA. [81]
Prostatitis, cystitis, and pyelonephritis are rare but possible urogenital manifestations of reactive arthritis. Bartholinitis can be present in women. Proctitis caused by Chlamydia species can occur in both sexes after anal intercourse.
Urethritis is difficult to diagnose in children but is present in 30% of pediatric patients at onset. Obtaining a history of dysuria from children is difficult, possibly because the urinary abnormality is mild or absent. In patients with painless discharge, staining of the underpants may be evident. The recommended procedure is to obtain a detailed history and perform a careful clinical evaluation for urethritis, searching for pyuria, meatal inflammation, and small perimeatal ulcerations.
Gastrointestinal tract
Enteric infections may trigger ReA. Pathogens include Salmonella, Shigella, Yersinia, and Campylobacter species. The frequency of ReA after these enteric infections is about 1%-4%. Other enteric bacteria that have been associated with ReA include C difficile, [82] E coli, and Helicobacter pylori. [20] (See Etiology.)
Some patients with ReA continue with intermittent bouts of diarrhea and abdominal pain. Lesions resembling ulcerative colitis or Crohn disease have been described when ileocolonoscopy is performed in patients with established ReA. [82] Although enteritis is usually a prolonged diarrheal episode with frequent passage of bloody loose stools, it can also manifest as a 24-hour episode of increased bowel activity.
Other findings
Aortic regurgitation caused by inflammation of aortic wall and valve may occur. This proximal aortitis can be found in 1-2% of cases. [59] Aortitis may be accompanied by coronary inflammation, which can be fatal in rare cases. Transient conduction abnormalities may develop but are of little significance; rarely, patients may be affected by myocarditis or pericarditis. [59]
Other manifestations of ReA include mild renal pathology with proteinuria and microhematuria. In severe chronic cases, amyloid deposits and immunoglobulin A (IgA) nephropathy have been reported in association with reactive arthritis. [83] IgA nephropathy is the most common type of primary glomerulonephritis worldwide.
Complications
Complications of ReA include the following:
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Recurrent arthritis (15-50%)
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Chronic arthritis or sacroiliitis (15-30%)
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Ankylosing spondylitis (30-50% of HLA-B27–positive patients)
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Urethral stricture
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Aortic root necrosis
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Secondary glaucoma
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Cataracts
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Cystoid macular edema
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Posterior and anterior synechiae
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Cyclitic membrane
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Vitreous opacification
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Ankylosing spondylitis, psoriatic arthritis, and sacroiliitis
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Erythroderma (rare)
In severe cases, functional impairment may be severe, and a chronic and prolonged clinical course is followed by sequelae (eg, urethral stenosis, chronic arthritis, or ocular impairment).
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Balanitis circinata (circinate balanitis) in patient with reactive arthritis.
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Plaques on soles of patient with reactive arthritis.
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Painful erosions on fingers in patient with reactive arthritis.
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Plaques and erosions of tongue in patient with reactive arthritis.
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Radiograph of feet of 27-year-old man shows erosions in all left metatarsophalangeal (MTP) joints with subluxation and valgus deformity of most toes. Smaller erosions are also visible in fourth and fifth MTP joints of right foot.
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Lateral radiograph of foot reveals calcaneal spur and enthesitis.
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Radiograph of both hands shows small erosive changes in both first metacarpal heads associated with minimal subluxation. Bone density is normal.
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Radiography of pelvis reveals bilateral asymmetric sacroiliitis.
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Radiograph in 40-year-old man shows nonmarginal syndesmophytes predominantly in lower thoracic and upper lumbar spine.
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Swelling of right knee with effusion caused by arthritis. Image courtesy of Gun Phongsamart, MD.
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Remarkable tenderness of left sacroiliac joint caused by sacroiliitis. Image courtesy of Gun Phongsamart, MD.
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Balanitis circinata (circinate balanitis). Image courtesy of Gun Phongsamart, MD.
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Achilles tendinitis and swelling of retrocalcaneal bursa.
