Gonococcal Arthritis

Gonococcal arthritis is caused by infection with the gram-negative diplococcus N gonorrhoeae, a highly infectious organism that exclusively infects humans; it is capable of colonizing diverse mucosal surfaces. The risk of infection from a single contact with N gonorrhoeae is estimated to be 60-90% for women and 20-50% for men.[1] Common sites of infection include the urethra, cervix, pharynx, and rectum. Infection may be asymptomatic in some patients.

There have been reports of gonococcal arthritis in toddlers and young children. Sexual abuse should be considered as a possible cause of the infection in pediatric cases.[3]

Hematogenous spread of the mucosal infection occurs in 0.5-3% of cases,[4] and disseminated infection is thought to play a major role in the pathogenesis of gonococcal arthritis. Patients with DGI may present with dermatitis-arthritis syndrome (60% of cases) or with a localized septic arthritis (40%). These presentations may represent different phases of a disease continuum.

The risk of dissemination after mucosal infection depends on both the ability of the patient’s immune system to control the infection and the virulence of the organism. Factors that correlate with an increase in this risk have been identified for both the host and the organism. Host-related risk factors for disseminated infection include the following[2] :

• Female sex
• Pregnancy
• Menses
• Systemic lupus erythematosus
• Complement deficiency
• Low socioeconomic or educational status
• Intravenous drug use
• HIV infection
• Multiple sexual partners

Organism-related risk factors for DGI include the following[1, 2, 4, 5] :

• Antigenic variation of pili
• Protein Por B _1A on the outer membrane – This inhibits host factor H and C4-binding protein, making host complement cascade less effective
• Lack of protein Por B _1B
• Strains with nutritional requirements for arginine, hypoxanthine, and uracil (ie, AHU strains) – These are often associated with protein IA
• Colony opacity (Opa) protein-independent invasion - Opa proteins are adhesins crucial to the process of N gonorrhoeae attachment to host cells, particularly avoidance of carcinoembryonic antigen-related cell adhesion molecule-3 (CEACAM3) ^[6]

United States statistics

According to the Centers for Disease Control and Prevention (CDC), gonorrhea is the second most commonly reported notifiable disease in the United States, with 616,392 cases reported in 2019.[5]

The rate of reported gonorrhea cases in the US has been increasing since 2010, after declining from their peak of 467.7 cases per 100,000 population in 1975 to an historic low of 98.1 cases per 100,000 population in 2009. In 2018-2019, gonorrhea rates increased by 5.7%. As of 2019, the national rate of gonococcal infection was 188.4 cases per 100,000 population.[5] Within the United States, however, rates of infection vary by region (highest in the South and lowest in New England) and by demographics (see below).

International statistics

The World Health Organization (WHO) estimates that 87 million cases of gonococcal infection occur annually.[7] The incidence of gonococcal infection is lower in Europe than in North America. In Sweden in 1992, for example, it was lower than 5 per 100,000 population, whereas in the United States in 1995, it was 150 per 100,000.[2] Gonococcal infection is common in developing countries, partly because of limited public health infrastructure and limited access to health care.

A 3-year retrospective study from France of 21 cases of disseminated gonococcal infection, which included 14 cases of arthritis, found that the number of cases increased from to 2009 to 2011. Men were at higher risk than women.[8] In a study of indigenous people in central Australia, the incidence of gonococcal arthritis was 911 of 100,000 gonococcal notifications. Cases were significantly more likely to occur in young (≤29 years) indigenous women than young indigenous men; risk was almost twice as high in women than in men.[9]

Age-, sex-, and race-related demographics

In the United States, the highest rates of gonorrheal infection are in persons aged 20-24 years. However, rates are also high in those ages 25-29. In addition, during 2019 the gonorrhea rate increased in all age groups.  The rates per 100,000 population by age group are as follows[5] :

• Age 15–19 years: 442.6 
• Age 20–24 years: 742.0 
• Age 25–29 years: 576.0 
• Age 30–34 years: 397.5
• Age 35–39 years: 248.5 
• Age 40–44 years: 154.0 

In 2019, the rate of reported gonorrhea cases was higher in men than in women (224.4 versus 153.6 cases per 100,000 same-sex population).  Rates in women fell in 2012-2014, from 107.9 to 100.4 per 100,000, but have been rising since then; rates in men have increased steadily since 2012, when the rate was 105.0 per 100,000.[5]

Gonococcal infection is most common in African Americans.[5] Cases per 100,000 by race/ethnicity were as follows in 2019:

• Blacks -  581.0
• American Indians/Alaska Natives - 355.8
• Native Hawaiians/Other Pacific Islanders - 198.9
• Hispanics - 118.3
• Multirace persons- 121.1
• Whites - 73.9
• Asians - 38.2

For patients with septic arthritis resulting from gonococcal infection, proper antibiotic treatment and joint drainage typically leads to full recovery. For patients with more severe manifestations of DGI, the prognosis varies, depending on complications or comorbidities. For example, patients with acute endocarditis may require valve surgery and can expect to undergo at least 4-6 weeks of antibiotic therapy. DGI-associated morbidity has decreased dramatically in the antibiotic era. Complications are rare (1-3% of cases).[1]

Patient education is an integral part of proper therapy. Patients should learn about the sexual transmission of the disease and be informed regarding barrier methods of preventing it (condoms). In addition, education regarding specific risk factors or high-risk behaviors may help prevent further gonococcal infections or more severe sexually transmitted diseases (eg, HIV infection). Also important are identification, examination, and treatment of patients’ sexual partners.

For patient education resources, see the Sexual Health Center and the Arthritis Center, as well as Gonorrhea and Sexually Transmitted Diseases.

The clinical presentation of disseminated gonococcal infection (DGI) is typically divided into a bacteremic form and a septic arthritis form. Approximately 60% of patients present with symptoms consistent with the bacteremic form, and the remaining 40% present with symptoms of more localized infection. Although each form has its own symptom complex, the overlap can be considerable. The time from initial infection to initial manifestations of disease ranges from 1 day to 3 months.[1]

Bacteremic form

In the bacteremic form (arthritis-dermatitis syndrome), symptoms are typically present 3-5 days before diagnosis.[10]

Migratory arthralgias are the most common presenting symptom in persons with DGI and are usually polyarticular. The arthralgias are typically asymmetric and tend to involve the upper extremities more than the lower extremities. The wrist, elbows, ankles, and knees are most commonly affected. Symptoms resolve spontaneously in 30-40% of cases or evolve into a septic arthritis in 1 or several joints.

Pain may also be due to tenosynovitis. The tenosynovitis of DGI is asymmetric and most commonly occurs over the dorsum of the wrist and hand, as well as over the metacarpophalangeal joints, ankles, and knees. Diffuse involvement of fingers can result in dactylitis.[1]

The rash associated with the bacteremic form of DGI may be overlooked by patients because it is painless and nonpruritic and consists of small papular, pustular, or vesicular lesions. Other cutaneous lesions of DGI that have been reported are abscesses, cellulitis, petechiae, purpuric macules, necrotizing fasciitis, and vasculitis.[11]

Nonspecific constitutional manifestations may include myalgias, fever, and malaise.

Septic arthritis form

Joint signs and symptoms begin within days to weeks of gonococcal infection.[10] Patients may experience pain, redness, and swelling in 1 joint (or sometimes multiple joints), most commonly in a knee, wrist, ankle, or elbow.[1]

Bacteremic form

The bacteremic form of gonococcal arthritis comprises the classic triad of migratory polyarthritis, tenosynovitis, and dermatitis.[10] Migratory arthritis has an asymmetric distribution, most commonly affecting wrists, ankles, and elbows. About 70% of patients have 1-3 joints with clear inflammatory signs after just a few days. Symmetric polyarthritis is less common but may occur in approximately 10% of patients.

Tenosynovitis is asymmetric, usually affecting the dorsum of wrists, hands, and ankles. Tenosynovitis of the fingers may result in dactylitis.

Dermatitis occurs in 40-70% of patients and typically involves the extremities. Lesions are usually tiny maculopapular, pustular, or vesicular lesions on an erythematous base. The center may become necrotic or hemorrhagic. Despite their appearance, these lesions are painless and nonpruritic. They tend to disappear within a few days after treatment is initiated. Usually, 4-50 lesions are reported. Rarely, the lesions may resemble erythema nodosum or erythema multiforme.

Fever rarely involves a temperature higher than 39°C.

Other presentations of DGI include the following, which now occur in only 1-3% of cases[1, 12] :

• Fitz-Hugh-Curtis syndrome (gonococcal perihepatitis)
• Sepsis with Waterhouse-Friderichsen syndrome
• Gonococcal endocarditis (rare in the antibiotic era)
• Gonococcal meningitis (very rare in the antibiotic era)
• Paravertebral abscess

Septic arthritis form

Septic arthritis is characterized by acute arthritis with signs of joint effusion, warmth, tenderness, decreased range of motion, and marked erythema. It most commonly involves the wrists, hands, knees, and elbows. Chronic arthritis with joint destruction is rare when appropriate antibiotic therapy is provided.

As a rule, complications of gonococcal arthritis are rare. When they do occur, they may include any of the following:

• Permanent joint damage
• Pericarditis
• Perihepatitis
• Pyomyositis
• Glomerulonephritis
• Meningitis
• Endocarditis
• Osteomyelitis

A complete blood count (CBC) should be obtained; most patients with gonococcal arthritis have mild leukocytosis. The erythrocyte sedimentation rate (ESR) is elevated in most cases.

Cultures of likely sites of gonococcal infection are the most important tests to perform for the diagnosis of disseminated gonococcal infection (DGI) and consequent gonococcal arthritis. Synovial fluid cultures are positive for N gonorrhoeae in no more than 50% of cases[1] and alone are insufficient to establish the diagnosis. Cultures of blood, cervix, rectum, urethra, and pharynx should be obtained.[13] Positive culture results help confirm the diagnosis and provide antibiotic sensitivities for the particular infecting strain of the organism.

Patients should be tested for other sexually transmitted infections, including Chlamydia trachomatis, HIV, syphilis, Mycoplasma genitalium, and herpes simplex virus. If risk factors are present, consider further testing for hepatitis B and C. The CDC recommends that the initial laboratory testing for HIV be an HIV-1/2 antigen/antibody combination immunoassay..

Point-of-care ultrasound in the emergency department can aid in diagnosis by identifying tenosynovitis and excluding arthritis or simple soft-tissue swelling.[14] Plain radiography findings of the affected joint are usually normal. However, they may be indicated to exclude articular damage and to rule out other processes, such as fracture. 

Biopsy of skin lesions shows dermal vasculitis with perivascular neutrophils. Neutrophilic infiltration of the epidermis may also be seen in pustular lesions.

Arthrocentesis is mandatory in cases of suspected septic arthritis. Laboratory tests typically performed on synovial fluid include cell count, crystal analysis, Gram stain, and culture.

The cell count is usually higher than 50,000 WBC/µL (with polymorphonuclear leukocytes [PMNs] typically accounting for more than 90%). Synovial fluid with this much inflammation may appear purulent. Gram-negative intracellular organisms may be demonstrated, albeit in less than 25% of synovial fluid aspirates. Synovial fluid should be cultured on prewarmed chocolate agar for highest yield (findings are positive in only 50% of patients with gonococcal arthritis and 25-30% of those with DGI).

Repeat arthrocentesis should be performed when inflammatory synovial effusions recur in order to remove inflammatory mediators, debris, and purulence. Surgical drainage may be needed in joints refractory to drainage via arthrocentesis; however, it is rarely necessary in patients with gonococcal arthritis.

Yield is highest if the culture is obtained from the primary infection site. Findings are positive in more than 80% of cases. When obtained from the primary site of infection, 90% of results are positive in cervical samples, 50-75% in male urethral samples, 20% in pharyngeal samples, and 15% in rectal samples.[1]

The pharynx is an important site of infection in pregnant women and in men who have sex with men. For a rectal culture, the swab is inserted approximately 2.5 cm into the canal (ie, to the crypts of Morgagni, a frequent focus of infection). Mucosal surface cultures should be placed on prewarmed selective plates (ie, Thayer-Martin or modified New York media) and blood agar for identification of other possible organisms.

Urine culture is noted to produce a higher yield if the sample is the first-void urine from the first 20 mL of the void.

Bottled blood culture media containing sodium polyethylene sulfate inhibits growth.

Nucleic acid amplification tests (NAATs) may be used as an adjunct to cultures and can be performed on samples from the cervix, urethra, rectum, urine, pharynx, synovial fluid,[15] and skin.[16] These tests can help to confirm a diagnosis of DGI when cultures are negative.[15, 16, 17] However, an important limitation of polymerase chain reaction (PCR) and other NAATs is they do not provide antibiotic sensitivities to guide choice of antibiotic for treatment.

When septic arthritis is suspected, empiric antibiotics directed against likely pathogens should be used until confirmatory laboratory data are available. Antibiotic coverage in healthy hosts should initially include gram-positive organisms, which account for approximately 80% of nongonococcal monoarthritis cases (Staphylococcus aureus, 60%; non–group A Streptococcus species, 15%; S pneumoniae, 3%). Gram-negative organisms (18%) should be covered in patients who are immunocompromised, elderly, or otherwise at risk.

Most patients with suspected acute infectious arthritis, including gonococcal arthritis, should be hospitalized to establish a diagnosis and to monitor for improvement or complications. Daily synovial fluid drainage is recommended for purulent effusions associated with gonococcal arthritis. Surgical drainage is needed when arthrocentesis is ineffective. The transition to oral antibiotics can usually be made 24-48 hours after clinical improvement.

Bed rest during hospitalization and brief immobilization of the septic joint aid in decreasing pain, especially when nonsteroidal anti-inflammatory drugs (NSAIDs) are not used.

Neisseria gonorrhoeae can develop resistance to antibiotics because it can mutate rapidly and acquire new genes.  Selection pressures allow antimicrobials to kill susceptible strains and resistant strains to survive; resistance genes then spread to other strains of gonococcus.  In the early 1990’s, fluoroquinolone resistance was noted in some strains of N gonorrhoeae.{ref 22}  By 2007, cephalosporins became the antimicrobials of choice to treat gonorrhea, but 2 years later, gonococcus began showing reduced susceptibility to them. 

Resistance to antimicrobials persists even after the antimicrobial is no longer used to treat gonorrhea.  Because of the resistance to oral cephalosporins in the United States, there is only one first-line regimen, which is dual treatment with ceftriaxone and azithromycin.

In addition, persons infected with N gonorrhoeae frequently are coinfected with Chlamydia trachomatis; this finding has led to the longstanding recommendation that persons treated for gonococcal infection also be treated with a regimen that is effective against uncomplicated genital C trachomatis infection, further supporting the use of dual therapy that includes azithromycin.[18]

Unfortunately, cases of ‘super-resistant gonorrhea’ strains (eg, H041) with resistance to ceftriaxone, and multi-drug–resistant strains have been identified around the world.{ref 24} This development highlights the importance of monitoring cases of antibiotic resistance in N gonorrhoeae with programs such as the CDC’s Gonococcal Isolate Surveillance Project (GISP) and developing new treatments.

Disseminated gonococcal infection (DGI) frequently results in petechial or pustular acral skin lesions, asymmetric polyarthralgia, tenosynovitis, or oligoarticular septic arthritis. Hospitalization and consultation with an infectious-disease specialist are recommended for initial therapy, especially for persons who might not comply with treatment, have an uncertain diagnosis, or have purulent synovial effusions or other complications. Examination for clinical evidence of endocarditis and meningitis should be performed.[18]

The CDC recommendations for disseminated gonococcal infection are[19] :

• Ceftriaxone 1 g IM/IV every 24 h plus a single dose of azithromycin 1 g PO
• Alternative regimens - Cefotaxime 1 g IV every 8 h or ceftriaxone 1 g IV every 8 h plus a single dose of azithromycin 1 g PO

When treating for the arthritis-dermatitis syndrome, the clinician can switch to an oral agent, with the choice guided by antimicrobial susceptibility testing, 24-48 h after substantial clinical improvement. The total treatment course should be at least 7 days.

Spectinomycin was once recommended in this setting but is no longer available in the United States.[20]

Patients should be advised to refer their sexual partners for evaluation and treatment, as partners of patients with DGI often have asymptomatic infections.

Patients with confirmed diagnosis of a localized gonococcal infection can probably be discharged with outpatient medications if they are considered reliable for follow-up care. Synovial effusions may require a longer duration of antibiotic therapy, but open drainage is rarely required. Intra-articular antibiotics have no known benefit.

Follow-up is important for patients who have been treated for gonorrhea, as they have a high incidence of reinfection. They should be retested 3 months later.

Daily aspiration with synovial fluid drainage has been recommended for purulent effusions associated with gonococcal arthritis. Open drainage or arthroscopy of infected joints is needed when arthrocentesis is insufficient.

Although patients with persistent joint effusion despite early antibiotic therapy may require frequent joint aspiration, joint effusions in gonococcal arthritis rarely result in permanent damage. Arthroscopic evaluation or surgical drainage that requires an orthopedic surgeon is rarely needed.

Patients with acute endocarditis secondary to gonococcal infection may require cardiothoracic surgery.

Measures that may help prevent gonococcal arthritis include the following:

• Patient education
• Identification and reduction of high-risk sexual practices
• Promoting use of protective barrier contraceptives (ie, condoms)
• Contacting the patient’s sexual partners for education, examination, and possible treatment

Consider consulting a rheumatologist for assistance in the evaluation and management of septic joints.

Consider consulting an infectious disease specialist for management of DGI cases and determination of optimal antibiotic therapy later in the course of the disease or if there is concern for treatment failure.

Consider consulting a cardiologist if acute endocarditis is suspected.

An orthopedic consultation may be required for arthroscopic or surgical drainage of an inaccessible joint (eg, the hip) or for failure of nonsurgical management (ie, daily aspiration).

Reevaluate patients to ensure resolution of illness. Reculture all known infected sites at least 5-7 days after the last dose of antibiotics. Due to high risk of reinfection, repeat testing for N gonorrhoeae 3 months after treatment.  Patients screened for syphilis and HIV should be screened again in 4-6 weeks.

Contact, examine, and treat the patient’s sexual partners, especially those with whom the patient has had sexual contact within the past 60 days. Encourage the patient to abstain from sexual activity for 7 days after treatment completion.{ref 23}

The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications. Gonococcal arthritis and disseminated gonococcal infection are treated with antibiotics.

Class Summary

Dual antibiotic regimens (preferably ceftriaxone plus azithromycin) are indicated for treatment of gonococcal infection.

Ceftriaxone (Rocephin)

Ceftriaxone is the drug of choice for disseminated gonococcal infection or gonococcal arthritis, according to guidelines developed by the Centers for Disease Control and Prevention (CDC). It exerts its bactericidal action through inhibition of cell-wall synthesis. It has no activity against Chlamydia.

Azithromycin (Zithromax, Zmax)

Azithromycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl transfer ribonucleic acid (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest. Azithromycin plus ceftriaxone constitutes the first-line preferred dual-drug regimen for disseminated gonococcal infections.

Cefotaxime (Claforan)

Cefotaxime is a third-generation cephalosporin used as an alternative to ceftriaxone for treatment of disseminated gonococcal infection or gonococcal arthritis. It exerts its bactericidal action through inhibition of cell-wall synthesis.