Approach Considerations
No curative treatment for reactive arthritis (ReA) exists. Instead, treatment aims at relieving symptoms and is based on symptom severity. Almost two thirds of patients have a self-limited course and need no treatment other than symptomatic and supportive care. As many as 30% of patients develop chronic symptoms, posing a therapeutic challenge. [95]
Physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), and intralesional corticosteroids may be helpful for joint, tendon, and fascial inflammation. Low-dose prednisone may be prescribed, but prolonged treatment is not advisable. Antibiotics may be given to treat underlying infection. Disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine and methotrexate may be used safely and are often beneficial. No specific surgical treatment is indicated.
Hospitalization of a patient with uncomplicated ReA is not usually indicated. Inpatient care may be considered for patients who are unable to tolerate oral administration of medications, who are unable to ambulate because of significant joint involvement, who have intractable pain, or who have concomitant disease necessitating admission.
Few treatment options exist for HIV-infected patients with severe ReA. Treatment of ReA in the setting of HIV infection poses special problems. However, potentially immunosuppressive therapies (eg, cyclosporine, methotrexate, and psoralen plus ultraviolet A [PUVA]) have been used in some cases, with variable success and relatively few severe complications. A case report from the United Kingdom suggests that antiretroviral therapy may be considered in HIV-infected ReA patients who are unresponsive to standard therapy. [96]
No dietary limitations are necessary unless the patient is receiving steroid therapy. Efforts should be made to maintain joint function with physical activity, joint protection, and suppression of inflammation. Physical therapy may be instituted to avoid muscle wasting and to reduce pain in severe cases. Although no limitations on physical activity need be imposed, symptoms of arthritis will usually limit patients’ activity to some extent.
Pharmacologic Therapy
NSAIDs (eg, indomethacin and naproxen) are the foundation of therapy for ReA. [97] Etretinate/acitretin has been shown to decrease the required dosage of NSAIDs. [71] Sulfasalazine or methotrexate may be used for patients who do not experience relief with NSAIDs after 1 month or who have contraindications to NSAIDs. In addition, sulfasalazine-resistant ReA may be successfully treated with methotrexate. [98]
In a series of 22 pediatric ReA patients from the Republic of China, NSAIDs and sulfasalazine were the mainstays of treatment, with cyclophosphamide used in 14 patients and methotrexate and corticosteroids added in a few. [99] Most achieved full remission within 6 months.
Antibiotic treatment is indicated for cervicitis or urethritis but generally not for postdysenteric ReA. In Chlamydia-induced ReA, some data suggest that prolonged combination antibiotic therapy could be an effective treatment strategy. [42]
Case reports exist that demonstrate the effectiveness of anti−tumor necrosis factor (TNF) medications, [59, 100] such as etanercept and infliximab. [101, 69] No published data are available on the effectiveness of selective cyclooxygenase (COX)–2 inhibitors; however, a COX-2 inhibitor may be tried in patients who do not tolerate NSAIDs and in whom no preexisting contraindication to COX-2 use exists.
Symptom-specific approaches
Arthritis and enthesitis
Joint symptoms are best treated with aspirin or other short-acting and long-acting anti-inflammatory drugs (eg, indomethacin, naproxen). In one report, a patient became asymptomatic after 3 months of aspirin at a dosage of 80 mg/kg/day; the dosage was gradually reduced and eventually discontinued. A combination of NSAIDs is reportedly effective in severe cases. No published data suggest that any NSAID is more effective or less toxic than another (controlled treatment trials are difficult to conduct with an uncommon disease).
Varying success in treating severe cases of ReA with other medications (eg, sulfasalazine, methotrexate, etretinate, ketoconazole, azathioprine, or intra-articular steroid injections) has been reported. In a refractory case or a patient with HIV-associated ReA, the anti−TNF-α agent infliximab may be successful. [102] Depending on the culture results, a short course of antibiotics may be needed; however, treatment may not affect the disease course. Longer-term administration of antibiotics to treat joint symptoms provides no established benefits.
Conjunctivitis and uveitis
Transient and mild conjunctivitis is usually not treated. Mydriatics and cycloplegics (eg, atropine) with topical corticosteroids may be administered in patients with acute anterior uveitis. Patients with recurrent ocular involvement may require systemic corticosteroid therapy and immunomodulators to preserve vision and prevent ocular morbidity. [103]
Urethritis and gastroenteritis
Antibiotics may be considered for urethritis and gastroenteritis, depending on the cultures used and their sensitivity. In general, urethritis may be treated with a 7- to 10-day course of erythromycin or tetracycline. Antibiotic treatment of enteritis is controversial.
Mucocutaneous lesions
Only local care is necessary for mucosal lesions. Topical steroids may be needed for psoriasiform lesions; the use of hydrocortisone or triamcinolone may be beneficial. A topical keratolytic, such as 10% salicylic acid ointment, can be added if needed. Topical salicylic acid and hydrocortisone with oral aspirin has also been suggested. [81]
Hydrocortisone 2.5% cream and salicylic acid 10% ointment are effective in treating chronic keratoderma blennorrhagicum and circinate balanitis, though either condition may heal without medical treatment. Circinate balanitis usually responds to topical steroids; however, it can be recurrent and create a therapeutic challenge. Balanitis refractory to conventional therapy can be successfully treated with the complementary use of topical 0.1% tacrolimus. [26]
Systemic therapy, if required, consists of the administration of oral acitretin, PUVA, methotrexate, cyclosporine, or some combination thereof.
Nonsteroidal anti-inflammatory drugs
The choice of a specific NSAID depends on the individual response to treatment. Phenylbutazone may work in patients refractive to other NSAIDs. These agents should be used regularly to achieve a good anti-inflammatory effect. Patients must be instructed on compliance and the possible need to adjust the dosage or switch to another agent. Treatment must be continued for 1 month at maximum dosage before effectiveness can be fully evaluated.
NSAIDs may reduce the intensity and the frequency of recurrences of ocular inflammation and allow a decrease in the corticosteroid dosage, which helps decrease the chances of cataract formation and other associated corticosteroid effects.
The decreased awareness of pain sometimes seen with the use of NSAIDs may alter the patient’s recognition of recurrences. Patients should be examined whenever any change in symptoms occurs to evaluate for recurrence of an acute episode of inflammation. Ocular involvement may parallel systemic and joint disease relapses.
Corticosteroids
Corticosteroids may be given either via intra-articular injection or as systemic therapy. For ocular manifestations of ReA, they may also be given topically.
Joint injections can produce long-lasting symptomatic improvement and help avoid the use of systemic therapy. Sacroiliac joints can be injected, usually under fluoroscopic guidance. [104]
Systemic corticosteroids may be particularly useful in patients who do not respond well to NSAIDs or who experience adverse effects related to the use of NSAIDs. The starting dose is guided by a patient’s symptoms and objective evidence of inflammation. Prednisone can be used initially at a dosage of 0.5-1 mg/kg/day, tapered according to response.
Topical corticosteroids and mydriatics should be used early and aggressively to reduce tissue damage. Prolonged topical treatment is necessary for several weeks after the inflammation has cleared; early withdrawal of topical corticosteroids frequently results in the return of inflammatory changes. Keratolytics or topical corticosteroids may improve cutaneous lesions. Topical corticosteroids may be useful for iridocyclitis.
Antibiotics
The current view of the pathogenesis of ReA indicates that an infectious agent is the trigger of the disease, but antibiotic treatment does not change the course of the disease, even when a microorganism is isolated. In these cases, antibiotics are used to treat the underlying infection, but specific treatment guidelines for ReA are lacking.
However, in Chlamydia -induced ReA, studies have suggested that appropriate treatment of the acute genitourinary (GU) infection can prevent ReA and that treatment of acute ReA with a 3-month course of tetracycline reduces the duration of illness. Empiric antibiotics may be considered after appropriate cultures have been taken. Nongonococcal urethritis and other infections can be treated specifically with systemic antibiotics. In the absence of contraindications, treatment of urethritis is recommended, even if improvement is not certain.
Although urethritis and cervicitis are commonly treated with antibiotics, diarrhea generally is not. No evidence indicates that antibiotic therapy benefits enteric-related ReA or chronic ReA of any cause.
Long-term antibiotic therapy may be warranted in cases of poststreptococcal ReA; however, this is currently a controversial topic. [92, 93]
Lymecycline (a tetracycline available outside the United States) was studied in a double-blind placebo-controlled study of patients with chronic ReA for a treatment period of 3 months. [25] The duration of illness was significantly shorter in patients with Chlamydia -induced disease than in those with disease triggered by enteric infections.
Azithromycin was shown to be ineffective in a placebo-controlled trial. [105] Nevertheless, in another study, azithromycin or doxycycline in combination with rifampin for 6 months was reported to be significantly superior to placebo and significantly improved symptoms associated with Chlamydia-induced ReA. [106]
Quinolones have been studied because of their broad coverage, but no clear benefit has been reported. [107] In a randomized, double-blind, placebo-controlled study of 56 patients with recent-onset ReA, 3 months of treatment with a combination of ofloxacin and roxithromycin was not better than placebo in improving outcomes.
More studies are needed before definite recommendations can be made for the role of antibiotics in the management of ReA. [108]
Disease-modifying antirheumatic drugs
In patients who have chronic symptoms or have persistent inflammation despite the use of the agents mentioned above, other second-line drugs may be used. Clinical experience with these DMARDs has been mostly in rheumatoid arthritis and in psoriatic arthritis. However, DMARDs have also been used in ReA, though their disease-modifying effects in this setting are uncertain.
Sulfasalazine has been shown to be beneficial in some patients. The use of this drug in ReA is of interest because of the finding of clinical or subclinical inflammation of the bowel in many patients. Sulfasalazine is more widely used in ankylosing spondylitis. In a 36-week trial of sulfasalazine versus placebo to treat spondyloarthropathies, patients with ReA who were taking sulfasalazine had a 62.3% response rate, compared with a 47.7% rate for the placebo group in peripheral arthritis. [109]
Methotrexate may be used in patients who present with rheumatoidlike disease. Several reports have shown good response, but controlled studies are lacking. Reports also describe the use of azathioprine and bromocriptine in ReA, but again, large studies have not been published. [110, 111] Patients with ReA who have HIV infection or AIDS should not receive methotrexate or other immunosuppressive agents.
Case reports have demonstrated the effectiveness of anti-TNF medications, such as etanercept and infliximab, [59, 100, 102, 112] though there remains a need for randomized, double-blind trials. The high concentrations of TNF-α in the serum and joints of patients with persistent ReA suggest that this cytokine could be targeted in patients who do not respond to NSAIDS and DMARDs. Anti−TNF-α therapy has been demonstrated to be effective treatment for ReA, with a corticosteroid-sparing effect. [113]
However, TNF-α antagonists can increase the risk of serious infection, and it is important to conduct infectious screening and monitoring with a high index of suspicion, as well as preemptive treatment, when such medications are used. [9] Anti-TNF medications can also be associated with severe glomerulonephritis, so close monitoring of kidney function is recommended in patients treated with these agents. [15]
Interleukin (IL)-6 plays an important role in regulating immune response. Unregulated overproduction of IL-6, however, is pathologically involved in various immune-mediated inflammatory diseases, including ReA. Tocilizumab, a humanized anti–IL-6 receptor antibody, may provide clinical benefit in patients who are refractory to conventional therapy or anti-TNF therapy. [114] However, further clinical studies are required. Successful use of the IL-17A inhibitor secukinumab has been reported in two cases chronic severe ReA resistant to TNF antagonists. [115]
Surgical Intervention
No surgical therapy for ReA is recommended. However, surgical intervention may be warranted for certain ocular manifestations of the disease.
The posterior spillover of inflammatory material in the chronic iridocyclitis associated with ReA may result in persistent vitreous opacification. The cumulative effects of secondary involvement of the vitreous may result in visually disabling vitreous debris and opacification, making these eyes good candidates for vitrectomy. Although vitrectomy should be considered only after prolonged follow-up care and thorough planning, it appears to offer a definitive improvement in vision in certain cases.
Because of the intense episodes of recurrent inflammation, it is essential to render the eyes as quiet as possible before surgery by using topical, periocular, or systemic corticosteroids. At least 3 months of cell-free slit lamp examinations—6 months for younger patients and severe cases—should be documented before elective surgical intervention.
Preoperative ultrasonography is helpful in determining the degree of vitreous opacification, the thickening of the choroid, and the presence of a cyclitic membrane, which can create significant problems at surgery.
The major objective of surgery in patients with complicated uveitic cataract and vitreous opacification is to improve vision. Vitrectomy may favorably modify the dynamics of the uveitic process, though lensectomy-vitrectomy does not reduce the inflammatory reaction in all cases.
Cystoid macular edema is the major cause of decreased visual acuity after surgery; however, this is a common and serious complication of chronic uveitis even without surgery. Vitrectomy may actually reduce cystoid macular edema with gradual resolution over 1 year and an improvement in vision in some patients.
Prevention
In Chlamydia -induced ReA, studies have suggested that appropriate treatment of the acute GU infection can prevent ReA and that treatment of acute ReA with a 3-month course of antibiotics can reduce the duration of illness. Currently, there is no evidence to indicate that antibiotic therapy is effective for enteric-related ReA or chronic ReA of any cause.
Education on the prevention of the spread of sexually transmitted diseases with condoms has been associated with a decrease in the incidence of postvenereal ReA.
Consultations
Appropriate consultations should be obtained as necessary.
A rheumatologist may be consulted to discuss appropriate additional tests and medications for symptomatic relief and to ensure follow-up treatment. In particular, the consulting rheumatologist may be extremely helpful in suggesting an appropriate oral NSAID or immunosuppressive agent to augment topical and periocular corticosteroid therapy.
Consultation with a urologist may be necessary if particularly prominent genitourinary manifestations develop.
An ophthalmologist may be consulted to confirm the diagnosis and to treat the ophthalmologic manifestations of ReA.
Consultation with a dermatologist is often helpful. For example, dermatologic involvement may occur with several uveitic syndromes; an accurate description of these lesions may help establish the diagnosis in some cases.
Consultation with and treatment by a dentist, an oral surgeon, or a periodontist may be useful for patients with aphthous ulcers.
An internal medicine consultation should be sought when prolonged systemic corticosteroid therapy is anticipated, especially in patients with concomitant diabetes or hypertension.
An infectious disease consultation may be sought when empiric antibiotic therapy is being considered or when the patient has manifestations of coincident AIDS-defining illnesses.
In cases of poststreptococcal ReA, a cardiology consultation is necessary because serial echocardiography and long-term antibiotic therapy may be of benefit to the patient. It should be kept in mind that patients with ReA symptoms who have evidence of preceding streptococcal infection are likely meet the Jones criteria for acute rheumatic fever. Many cardiologists elect to place these patients on long-term penicillin treatment. [92, 93]
It should be noted that current data show no increased risk of valvular heart disease in adult poststreptococcal ReA. On the basis of these findings, routine long-term antibiotic prophylaxis is not recommended in adult poststreptococcal ReA. [39, 57, 47, 46] The above recommendation is valid in pediatric patients with ReA.
Physical and occupational therapists may be consulted for assistance with maintenance of function and gait.
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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.
