Reactive Arthritis

• Microbial-triggered immune activation: Following infection with arthritogenic organisms (most commonly Chlamydia trachomatis, Shigella, Salmonella, Yersinia, or Campylobacter), pathogen-associated molecular patterns (PAMPs) and bacterial antigens encounter mucosal-associated lymphoid tissue (MALT). Toll-like receptors (TLRs) on dendritic cells and macrophages recognize these PAMPs, initiating innate immune signaling through NF-κB and MAPK pathways. This leads to production of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6, along with IL-17 and IL-23, promoting Th1 and Th17 differentiation of CD4+ T cells. Mucosal barrier disruption by certain organisms may allow translocation of bacterial lipopolysaccharide (LPS) and lipoproteins into systemic circulation, amplifying inflammatory signaling.

• HLA-B27-mediated molecular mimicry and cross-reactivity: Approximately 60-80% of patients with reactive arthritis carry the HLA-B27 allele (compared to 5-8% in the general population), establishing HLA-B27 as the primary genetic susceptibility factor. The HLA-B27 molecule presents both foreign bacterial epitopes and self-antigens in a manner that promotes T cell cross-recognition. Molecular mimicry occurs when bacterial antigens derived from organisms like Chlamydia share amino acid sequence homology with HLA-B27 itself and other self-antigens, particularly those found in joint tissue. This leads to activation of autoreactive CD8+ T cells that recognize self-peptides presented by HLA-B27, resulting in target tissue destruction. Additionally, HLA-B27 forms pathogenic homodimers and free heavy chains in the endoplasmic reticulum that activate innate immunity via TLR4 signaling and promote IL-17 production via IL-23-responsive T cells. The longer, less efficient peptide-loading properties of HLA-B27 may also favor presentation of cryptic self-epitopes.

• Bacterial persistence and antigen retention: Rather than complete organism clearance, reactive arthritis appears to involve persistence of bacterial antigens or viable but non-culturable organisms within synovial tissue. Bacterial DNA and lipopolysaccharides have been detected in synovial fluid years after the initial infection, and viable organisms have been recovered using sensitive molecular techniques. This persistent antigenic stimulus continually reactivates local T cell and B cell responses in the synovium. Neutrophil infiltration into synovial tissue occurs through CXCL8 (IL-8)-mediated recruitment, and these neutrophils contribute to tissue damage through release of proteolytic enzymes, reactive oxygen species, and additional pro-inflammatory mediators. The synovial barrier's immune-privileged status limits clearance of these antigens, perpetuating inflammation.

• Aberrant innate lymphoid cell (ILC) and mucosal immunity dysfunction: The initial infection disrupts normal intestinal barrier function and mucosal homeostasis, with loss of regulatory T cells (Tregs) and expansion of pathogenic Th17 cells. ILC3 cells, which normally promote protective IL-22 production and barrier integrity, become dysregulated. This allows persistent gut dysbiosis and reduced production of short-chain fatty acids (SCFA), which normally promote Treg differentiation and barrier function. The resulting breach in mucosal immune tolerance permits bacterial translocation and activation of gut-homing lymphocytes (expressing CCR9 and α4β7 integrin) that traffic to joint tissue. Altered microbiota composition itself may perpetuate inflammation through reduced production of anti-inflammatory metabolites.

• Synovial immunopathology and tissue-resident memory T cells: Within the joint, CD8+ T cells become activated and differentiate into tissue-resident memory cells (TRM) that persist locally even after systemic immune resolution. These TRM cells maintain high expression of TNF-α and IFN-γ, perpetuating chronic synovial inflammation. Synovial macrophages present persistent bacterial antigens via HLA-B27, maintaining local CD8+ T cell activation. B cells in the synovium produce anti-synovial antibodies and immune complexes that deposit in synovial tissue, activating complement and recruiting additional inflammatory cells. The accumulation of synovial fluid contains numerous neutrophils (often 2,000-50,000 cells/μL), imparting a "septic-appearing" synovitis that is nonetheless sterile.

• Preceding genitourinary infections: Chlamydia trachomatis is the most common sexually transmitted organism associated with reactive arthritis in developed nations, implicated in 60-80% of cases in some series. The organism's ability to establish persistent intracellular infection within epithelial cells of the urethra, cervix, and rectum may promote bacterial antigen retention and trafficking. Other sexually transmitted organisms including Ureaplasma urealyticum and Mycoplasma genitalium account for additional cases. Notably, reactive arthritis may develop even in the absence of symptomatic urethritis or cervicitis, with molecular evidence of infection detected through nucleic acid amplification testing (NAAT).

• Preceding gastrointestinal infections: Enteric pathogens are responsible for approximately 30-40% of reactive arthritis cases in developed countries and represent a larger proportion in developing nations. Bacterial dysentery caused by Shigella species (particularly S. flexneri and S. sonnei), Salmonella enteritidis, Campylobacter jejuni, and Yersinia enterocolitica are well-established triggers. These organisms cause acute inflammatory diarrhea, with some evidence suggesting that organisms with enhanced invasiveness and ability to breach the intestinal epithelium carry higher arthritis risk. Viral gastroenteritis caused by rotavirus and norovirus have been documented in case reports, though the association is less robust.

• HLA-B27 positivity: This represents the most important genetic risk factor, with >90% of HLA-B27 positive individuals who contract arthritogenic infections developing reactive arthritis, compared to 5-10% of HLA-B27 negative individuals exposed to the same organisms. However, only 1-3% of HLA-B27 positive individuals in the general population develop reactive arthritis, indicating that infection exposure is also necessary. HLA-B27 carries a relative risk of approximately 37-40 for developing reactive arthritis after exposure to enteric pathogens. Certain HLA-B27 subtypes (*B*27:05, *B*27:02) appear more strongly associated with arthritis than others.

• Host immunological factors: Deficiencies in mucosal immunity, including inadequate IgA responses or compromised intestinal barrier function, increase susceptibility. Patients with inflammatory bowel disease (IBD) carry increased risk due to baseline intestinal dysbiosis, increased intestinal permeability, and altered mucosal immunity. Initial acute infection severity and inadequate bacterial clearance predict chronicity and disease progression. Immunosuppression from HIV infection is associated with more severe and refractory reactive arthritis, though the advent of antiretroviral therapy has reduced both incidence and severity.

• Recent travel and epidemiologic exposures: Travel to areas with endemic enteric infections and poor sanitation increases exposure risk. Sexual history and number of partners influence exposure to sexually transmitted organisms. Food-borne infection exposure (consumption of contaminated poultry, unpasteurized dairy, contaminated water) establishes risk for gastrointestinal-triggered reactive arthritis.

• Oligoarthritis affecting large joints: The characteristic arthritis is asymmetric and oligoarticular, typically affecting 2-10 joints simultaneously (compared to monoarthritis in ~10% of cases). Lower extremities are predominantly involved, with the knees most commonly affected (70-80%), followed by ankles (60%), and feet (50%). The arthritis typically develops acutely over 24-48 hours after the preceding infection resolves (usually 1-4 weeks post-infection), and is often seronegative for rheumatoid factor and anti-CCP antibodies, distinguishing it from RA. Joint involvement may spread from one joint to another in a migratory pattern over days to weeks. Morning stiffness and joint swelling with warm, erythematous appearance occur due to synovial inflammation with associated effusions. Pain is often severe and limiting, and the joint aspiration characteristically yields turbid, inflammatory synovial fluid with predominant neutrophilic infiltration (2,000-50,000 white blood cells/μL), creating a "septic-appearing" picture despite negative cultures.

• Urogenital symptoms and urethritis: Dysuria and urethral discharge in males develop acutely and may precede or accompany arthritic symptoms. The discharge is typically seropurulent rather than the profuse, purulent discharge of gonococcal urethritis. In females, cervicitis with vaginal discharge and dysuria occurs. Asymptomatic urethritis is detected in up to 40% of cases via urinalysis or NAAT positivity without clinical symptoms, highlighting that the classic triad may be incomplete. Urinary frequency and nocturia are common. Prostatitis may develop, and urinary retention occasionally occurs. These symptoms typically resolve within 1-3 months even without specific treatment of the underlying infection.

• Ocular manifestations: Conjunctivitis is the most common extra-articular manifestation, occurring in 30-40% of patients, typically as the first extra-articular symptom or simultaneously with arthritis. The conjunctivitis is usually bilateral, mild, and non-purulent ("dry conjunctivitis"), often presenting as morning eye crusting and foreign body sensation. Most cases are self-limited and mild, though anterior uveitis develops in 3-10% of cases, potentially causing more significant morbidity with photophobia, anterior chamber inflammation, and iris adhesions if untreated. Keratitis and corneal erosions occur rarely. The conjunctivitis represents direct inflammatory response of the conjunctival mucosa rather than organism detection within the eye.

• Mucocutaneous lesions: Keratoderma blennorrhagicum develops in 15-30% of cases, presenting as hyperkeratotic, psoriasiform plaques on the palms and soles, often in clusters. The lesions are histologically indistinguishable from psoriasis and may persist for months to years. Oral ulcers (small, painless, superficial ulcerations on the hard palate, buccal mucosa, or tongue) develop in 10-20% of cases and are typically transient. Balanitis circinata (circinate, painless ulcerations or erosions of the glans penis) occurs in 25-40% of uncircumcised males and may be the only manifestation noted by patients due to painless nature. Subungual keratosis and nail ridging occasionally occur.

• Systemic and constitutional symptoms: Fever of 38-39°C frequently accompanies acute disease onset. Malaise, fatigue, and weight loss develop secondary to systemic inflammation and increased metabolic demands. Anorexia may contribute to nutritional impairment. These constitutional symptoms typically peak 1-2 weeks after disease onset and gradually improve over 2-12 weeks in most cases.

• Enthesitis and tendinitis: Beyond intra-articular synovitis, inflammatory involvement of tendon insertions (entheses) occurs, particularly at the Achilles tendon insertion and plantar fascia (causing heel pain that may be the presenting symptom). This represents the same pathological process as in other spondyloarthropathies and is mediated by HLA-B27 and local T cell activation at these fibrocartilage-bone junctions. Reactive arthritis can progress to ankylosing spondylitis in a subset of HLA-B27 positive patients (though this appears less common than historical descriptions), with development of sacroiliitis and spinal inflammation weeks to months after acute arthritis.

• Cardiovascular manifestations: Aortic regurgitation develops in 1-10% of cases due to aortitis with inflammatory involvement of the aortic root and valve cusps. Unlike endocarditis, blood cultures remain negative. Aortic root dilatation predisposes to aortic insufficiency, which may progress even after resolution of joint symptoms. Myocarditis and pericarditis are rare but documented complications presenting with chest pain and arrhythmias. The cardiovascular manifestations represent direct extension of the systemic inflammatory process and may be mediated by cross-reactive antibodies and T cells.

• Clinical variants based on preceding infection: Post-diarrheal reactive arthritis (triggered by enteric organisms) may include transient diarrhea at disease onset and occasionally exhibits more aggressive early inflammation. Post-venereal reactive arthritis (triggered by urogenital infection) may present more insidiously with gradual symptom progression over weeks. Some patients develop persistent, seronegative polyarthritis that transitions into a disease phenotype indistinguishable from seronegative spondyloarthropathy.

• Clinical diagnosis based on temporal sequence and symptom clusters: Reactive arthritis is fundamentally a clinical diagnosis supported by history of preceding infection 1-4 weeks prior to joint symptoms, acute oligoarticular arthritis affecting primarily large joints of the lower extremities, and absence of serological markers of autoimmune disease. The diagnosis rests on recognizing the temporal relationship between infection and arthritis rather than specific diagnostic markers. A patient presenting with acute knee and ankle swelling following an episode of diarrhea or urethritis should raise immediate clinical suspicion. The absence of rheumatoid factor and anti-CCP antibodies (seronegative pattern) further supports the diagnosis, as does negative HLA-DR4 when HLA-B27 is positive (the reverse is true in RA).

• HLA-B27 testing with appropriate interpretation: HLA-B27 positivity is present in 60-80% of reactive arthritis cases and serves to support the diagnosis when clinical suspicion is high, but is neither necessary nor sufficient for diagnosis (false negatives occur in ~20% of cases, and HLA-B27 positivity is present in 5-8% of the general population). HLA-B27 testing should be reserved for patients with established diagnosis of oligoarthritis or spondyloarthropathy to help with classification and risk stratification, not as a screening test. A negative HLA-B27 does not exclude reactive arthritis and should not be permitted to delay diagnosis if clinical suspicion remains high.

• Synovial fluid analysis: Joint aspiration and synovial fluid (SF) examination are critical for excluding bacterial infection and other arthropathies. Synovial fluid white blood cell count typically ranges from 2,000-50,000 cells/μL with predominant neutrophilic infiltration (70-90%), creating the appearance of septic arthritis. However, synovial fluid cultures are definitively negative (distinguishing reactive arthritis from septic arthritis, where organisms are cultured in 50-90% of cases). Synovial fluid protein is typically elevated (2-4 g/dL), and glucose is usually normal or mildly reduced (>50% of serum glucose), whereas in septic arthritis, synovial glucose is profoundly depressed (<50% of serum). Gram stain is negative. Polarized light microscopy shows absence of crystals, excluding crystal arthropathies.

• Serological testing and inflammatory markers: Rheumatoid factor and anti-CCP antibodies are negative, confirming seronegative pattern. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are markedly elevated in acute disease (ESR often 40-80 mm/hour, CRP often 3-10 mg/dL), reflecting acute phase response. These markers help distinguish systemic inflammation from mechanical arthritis but lack specificity. Ant

Before anything else — exclude septic arthritis

• Arthrocentesis first: an acutely hot, swollen joint with synovial neutrophilia is septic until cultures return. Never give intra-articular or systemic glucocorticoids before fluid is obtained; steroids into an infected joint accelerate cartilage destruction. Gonococcal arthritis is the key mimic, and disseminated gonococcal infection is treated per the CDC STI Treatment Guidelines with ceftriaxone.

First-line therapy

• NSAIDs (e.g., naproxen, indomethacin): full anti-inflammatory dosing, continued for weeks rather than as-needed analgesia. They blunt COX-2–derived prostaglandin amplification of synovitis and are the anchor drug in spondyloarthritis per the ACR/SAA/SPARTAN axial spondyloarthritis guideline.
• Intra-articular glucocorticoids (triamcinolone): for one or two persistently inflamed joints or for enthesitis, once infection is excluded. Delivers high local drug levels without systemic exposure.
• Antibiotics for the trigger, not the arthritis: if Chlamydia trachomatis is documented by NAAT, treat with doxycycline per the CDC STI Treatment Guidelines and treat sexual partners. Antibiotics do not shorten the arthritis, but eradication prevents reinfection and onward transmission. Post-enteric reactive arthritis does not warrant prolonged antibiotics — no benefit has been shown.

Escalation for disease persisting beyond about 3–6 months

• Conventional synthetic DMARD, typically sulfasalazine: preferred for persistent peripheral arthritis; methotrexate is an alternative. Note that csDMARDs do not control axial disease.
• TNF-α inhibitors (e.g., etanercept, adalimumab): for refractory or axial disease, extrapolating from ACR/SAA/SPARTAN axSpA recommendations. Screen for latent tuberculosis and hepatitis B before starting.
• Short systemic glucocorticoid course: reserved for polyarticular disease not controlled by the above.

Contraindicated or to avoid

• Systemic steroids before joint fluid culture, NSAIDs in advanced CKD, active peptic ulcer disease, or late pregnancy (ductal constriction), and TNF inhibitors with untreated latent TB or active infection. Topical steroids should not be self-started for a red eye — anterior uveitis needs ophthalmologic slit-lamp confirmation first.

Disease-related — emergencies first

• Acute anterior uveitis (EMERGENCY): HLA-B27–associated iridocyclitis; unilateral pain, photophobia, blurred vision, and ciliary flush rather than the bland bilateral conjunctivitis of the classic triad. Untreated it causes posterior synechiae, glaucoma, and permanent visual loss — same-day ophthalmology referral for slit-lamp exam and topical steroid/cycloplegic.
• Aortitis with aortic regurgitation and conduction block (EMERGENCY when symptomatic): inflammatory fibrosis of the aortic root extends into the membranous septum and AV node. Signals are a new early diastolic murmur, wide pulse pressure, or bradycardia/syncope from complete heart block requiring pacing. Blood cultures are negative, distinguishing it from endocarditis.
• Missed septic arthritis: the greatest diagnostic hazard, since reactive synovial fluid can be frankly purulent-appearing. Fever with a single deteriorating joint and positive culture is the discriminator.

Chronic disease-related

• Chronic or relapsing arthritis: roughly a third of patients have persistent symptoms; HLA-B27 positivity and chlamydial trigger predict chronicity.
• Progression to axial spondyloarthritis/ankylosing spondylitis: inflammatory back pain, sacroiliitis on imaging, loss of lumbar flexion on Schober test.
• Erosive joint damage and enthesophyte formation: heel spurs and Achilles enthesophytes on radiograph; persistent dactylitis.

Treatment-related

• NSAIDs: prostaglandin-dependent renal perfusion loss → AKI; gastric mucosal injury → GI bleeding (melena, drop in hemoglobin).
• Sulfasalazine: sulfa hypersensitivity, cytopenias, hemolysis in G6PD deficiency, and reversible oligospermia.
• Methotrexate: transaminitis, cytopenias from folate antagonism, and hypersensitivity pneumonitis (dry cough, hypoxemia).
• TNF-α inhibitors: granuloma destabilization → reactivation tuberculosis and invasive fungal infection; also demyelinating events and worsening of heart failure.
• Glucocorticoids: hyperglycemia, adrenal suppression, and masking of intercurrent infection.

• The mnemonic triad: "Can't see, can't pee, can't climb a tree" — conjunctivitis, urethritis, asymmetric lower-limb oligoarthritis appearing 1–4 weeks after GI or GU infection. The triad is present in a minority of patients; its absence does not exclude the diagnosis. The eponym Reiter syndrome has been abandoned in US practice.
• The single best next step in a hot joint is arthrocentesis, not HLA-B27 testing and not empiric steroids. Sterile inflammatory fluid with negative Gram stain and culture, no crystals, and near-normal synovial glucose is what confirms the picture.
• The association examiners test is HLA-B27, shared across the seronegative spondyloarthropathies (reactive arthritis, ankylosing spondylitis, psoriatic arthritis, IBD-associated arthritis). It is a supportive test, not a diagnostic one — it is neither sensitive nor specific enough to rule the disease in or out.
• Skin and mucosal buzzwords: keratoderma blennorrhagicum (psoriasiform palmoplantar plaques), circinate balanitis, painless oral ulcers, dactylitis ("sausage digit"), and Achilles enthesitis with heel pain.
• Classic distractor — disseminated gonococcal infection: also a sexually active young adult, but expect migratory polyarthralgia, tenosynovitis, pustular skin lesions, and a positive culture or NAAT, treated with ceftriaxone per the CDC STI Treatment Guidelines. Reactive arthritis fluid is sterile.
• Antibiotics treat the trigger, not the joint: document and treat Chlamydia with doxycycline and treat partners (CDC), but prolonged antibiotics do not shorten post-dysenteric arthritis.
• Therapeutic ladder: NSAIDs → intra-articular glucocorticoid → sulfasalazine for persistent peripheral disease → TNF-α inhibitor for refractory or axial disease, per ACR/SAA/SPARTAN spondyloarthritis principles.
• Check an HIV test in severe, refractory, or florid keratoderma cases — advanced HIV is associated with unusually aggressive disease.