Inflammatory Arthritides

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory arthritis characterized by symmetric synovitis, progressive cartilage destruction, and marginal bone erosions. It classically affects women more than men, with a female:male ratio of approximately 2–3:1, and usually begins between ages 30–60 years. For USMLE Step 1, RA is best understood as an immune-mediated disease of the synovium, not primarily a disease of cartilage or bone.

Pathogenesis and Immunology

The central lesion in RA is proliferative synovitis. The normal synovium is a thin membrane that produces lubricating synovial fluid. In RA, it becomes hyperplastic and infiltrated by immune cells, forming a destructive granulation tissue called a pannus. The pannus grows over articular cartilage and erodes cartilage, subchondral bone, tendons, and ligaments.

• Genetic risk: Strong association with HLA-DRB1 alleles, especially those containing the “shared epitope.” PTPN22 polymorphisms also increase autoimmune risk.
• Environmental trigger: Cigarette smoking promotes citrullination of proteins in the lung and is a major risk factor, especially for anti-CCP–positive RA.
• Autoantigens: Peptidylarginine deiminase enzymes convert arginine residues to citrulline. These citrullinated proteins may be recognized as foreign.
• Adaptive immunity: CD4+ T cells activate macrophages, B cells, and synovial fibroblasts. B cells produce autoantibodies, especially rheumatoid factor and anti-cyclic citrullinated peptide antibodies.
• Cytokines: TNF-α, IL-1, and IL-6 drive synovial inflammation, fever, fatigue, hepatic acute-phase reactants, osteoclast activation via RANKL, and erosive bone disease.

Marker	Meaning	Approximate Test Characteristics
Rheumatoid factor	IgM antibody against Fc portion of IgG	Sensitivity ~70–80%; specificity ~70–85%; may be positive in hepatitis C, endocarditis, Sjögren syndrome, and aging
Anti-CCP antibody	Antibody to citrullinated peptides	Sensitivity ~60–75%; specificity ~90–98%; predicts erosive disease
ESR/CRP	Inflammation markers	Often elevated; normal CRP is typically <10 mg/L, but laboratory ranges vary

Clinical Features

RA presents with insidious onset of pain, swelling, warmth, and prolonged morning stiffness, classically lasting >1 hour and improving with activity. The typical pattern is symmetric polyarthritis of the MCP, PIP, wrists, and MTP joints. The DIP joints are usually spared, helping distinguish RA from osteoarthritis and psoriatic arthritis.

• Hand deformities: Ulnar deviation at MCP joints, swan-neck deformity hyperextension at PIP with flexion at DIP, and boutonnière deformity flexion at PIP with hyperextension at DIP.
• Subcutaneous nodules: Firm nodules over extensor surfaces; associated with seropositive disease.
• Pulmonary: Pleural effusions, interstitial lung disease, and Caplan syndrome pneumoconiosis plus RA pulmonary nodules.
• Hematologic: Anemia of chronic disease; Felty syndrome is RA with splenomegaly and neutropenia.
• Cardiovascular: Increased atherosclerotic risk due to chronic systemic inflammation.
• Cervical spine: Atlantoaxial subluxation from transverse ligament destruction; important before intubation because neck manipulation can injure the spinal cord.

Classification and Diagnosis

RA is a clinical diagnosis supported by serology, inflammatory markers, and imaging. The 2010 ACR/EULAR classification criteria classify definite RA with a score of ≥6 out of 10, after excluding better explanations such as lupus, psoriatic arthritis, viral arthritis, or crystal disease.

Domain	Scoring Concept
Joint involvement	Higher score for more joints; small-joint disease scores more heavily; up to 5 points
Serology	RF and anti-CCP negative 0; low-positive 2; high-positive 3
Acute-phase reactants	Abnormal ESR or CRP gives 1 point
Duration	Symptoms ≥6 weeks give 1 point

Synovial fluid in RA is inflammatory, typically with WBC count approximately 2,000–50,000 cells/µL, predominantly neutrophils, but without crystals or organisms. Radiographs may show soft tissue swelling, juxta-articular osteopenia, uniform joint-space narrowing, and marginal erosions. MRI and ultrasound detect earlier synovitis and erosions but are less emphasized on Step 1.

Treatment Principles and Pharmacology

Modern RA treatment follows a treat-to-target strategy: early disease-modifying antirheumatic drug therapy, frequent assessment, and adjustment to achieve remission or low disease activity. The TICORA trial demonstrated that tight control improved outcomes versus routine care. Current ACR guidance generally favors methotrexate monotherapy as initial therapy for moderate-to-severe RA unless contraindicated.

Drug/Class	Mechanism	High-Yield Dose/Monitoring
Methotrexate	Inhibits dihydrofolate reductase at high doses; in RA mainly increases extracellular adenosine, reducing inflammation	7.5–25 mg once weekly plus folic acid 1 mg daily; monitor CBC, LFTs, creatinine; adverse effects include hepatotoxicity, marrow suppression, pneumonitis, teratogenicity
NSAIDs	COX inhibition decreases prostaglandins	Symptom relief only; do not prevent erosions
Glucocorticoids	Broad inhibition of NF-κB-mediated cytokine transcription	Short-term “bridge” therapy; chronic use risks osteoporosis, diabetes, infection
TNF inhibitors	Neutralize TNF-α	Etanercept, infliximab, adalimumab; screen for latent TB and hepatitis B; risk of serious infection
Other biologics/JAK inhibitors	IL-6 blockade, CD80/86 costimulation blockade, B-cell depletion, or JAK-STAT inhibition	Tocilizumab, abatacept, rituximab, tofacitinib; infection risk is a class theme

Step 1 emphasis: RA is a type III/IV immune-mediated systemic synovitis with anti-CCP specificity, pannus formation, symmetric small-joint inflammatory arthritis, and disease-modifying therapy centered on methotrexate.

Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of chronic inflammatory arthritides defined by arthritis beginning before age 16 years, persisting for at least 6 weeks, with other causes excluded. The term “idiopathic” emphasizes that no single pathogen or autoantigen explains all subtypes. For USMLE Step 1, JIA is best understood as pediatric immune-mediated synovitis with subtype-specific patterns of joints, extra-articular disease, autoantibodies, and complications.

Pathogenesis and Basic Mechanisms

In most JIA subtypes, chronic synovial inflammation results from dysregulated innate and adaptive immunity. Activated dendritic cells, macrophages, T cells, and B cells produce inflammatory cytokines such as TNF-α, IL-1, IL-6, IL-17, and IL-23, leading to synovial hyperplasia, effusion, pain, morning stiffness, and impaired growth around affected joints. Compared with adult rheumatoid arthritis, erosive pannus is less universal, but it is important in RF-positive polyarticular JIA, which closely resembles adult seropositive RA.

Systemic JIA is mechanistically distinct and is often considered an autoinflammatory disorder: innate immune activation and cytokines, especially IL-1, IL-6, and IL-18, drive fever, rash, serositis, and macrophage activation syndrome rather than classic autoantibody-mediated disease.

Classification

Subtype	Core Features	High-Yield Associations
Oligoarticular JIA	≤4 joints in first 6 months, often knees/ankles; most common subtype	Young girls; ANA positive; high risk of chronic anterior uveitis
Polyarticular RF-negative	≥5 joints in first 6 months; RF negative	Symmetric small and large joint disease; variable ANA
Polyarticular RF-positive	≥5 joints; RF positive on at least 2 tests ≥3 months apart	Adolescent girls; anti-CCP may be positive; erosive RA-like disease
Systemic JIA	Arthritis plus quotidian fever for ≥2 weeks, with ≥3 days documented	Evanescent salmon-pink rash, lymphadenopathy, hepatosplenomegaly, serositis; risk of macrophage activation syndrome
Enthesitis-related arthritis	Arthritis and enthesitis, or either plus spondyloarthritis features	Male adolescents; HLA-B27; sacroiliitis; acute anterior uveitis
Psoriatic JIA	Arthritis plus psoriasis, or arthritis plus dactylitis/nail pitting/family history	Dactylitis, nail pitting, asymmetric arthritis

Clinical Manifestations and Complications

The hallmark is objective arthritis: joint swelling or limited range of motion with pain, warmth, or tenderness. Children may present with limp, refusal to use a limb, morning stiffness, or delayed motor activity rather than verbalized pain. Fever alone is not sufficient for diagnosis.

Chronic anterior uveitis is a classic Step 1 complication, especially in ANA-positive oligoarticular JIA. It may be asymptomatic until vision loss occurs; slit-lamp screening is therefore essential. In contrast, enthesitis-related arthritis is associated with acute symptomatic anterior uveitis presenting with red painful photophobic eye.

Macrophage activation syndrome (MAS) is a life-threatening hyperinflammatory complication most associated with systemic JIA. It resembles secondary hemophagocytic lymphohistiocytosis: uncontrolled macrophage and T-cell activation causes fever, cytopenias, liver injury, coagulopathy, and hyperferritinemia. The 2016 classification criteria for MAS in systemic JIA include fever with ferritin >684 ng/mL plus at least 2 of: platelets ≤181,000/µL, AST >48 U/L, triglycerides >156 mg/dL, or fibrinogen ≤360 mg/dL. Ferritin may be in the thousands.

Diagnosis and Disease Activity

JIA is a clinical diagnosis of exclusion. Important mimics include septic arthritis, osteomyelitis, leukemia, trauma, postinfectious arthritis, Lyme arthritis, inflammatory bowel disease-associated arthritis, and systemic lupus erythematosus. Labs help classify and assess inflammation but are not diagnostic by themselves. ESR is commonly elevated; a typical normal ESR is <20 mm/hr, and CRP is often considered normal at <10 mg/L, though reference ranges vary. ANA predicts uveitis risk, RF/anti-CCP identify RA-like polyarticular disease, and HLA-B27 supports enthesitis-related disease.

Disease activity may be quantified with the Juvenile Arthritis Disease Activity Score (JADAS), which combines physician global assessment, parent/patient global assessment, active joint count, and ESR or CRP. For JADAS10, inactive disease is often defined as ≤1; high disease activity is approximately >4.2 for oligoarticular disease and >10.5 for polyarticular disease.

Pharmacology and Treatment Principles

Therapy targets inflammation early to prevent disability, growth disturbance, and ocular damage. Current American College of Rheumatology guidance emphasizes subtype- and severity-based escalation rather than prolonged symptomatic therapy alone.

Drug/Class	Typical Pediatric Dose	Mechanism and High-Yield Toxicities
NSAIDs, e.g., naproxen	10–20 mg/kg/day divided twice daily	Reversible COX inhibition → decreased prostaglandins; GI irritation, renal vasoconstriction
Intra-articular triamcinolone hexacetonide	Often 1 mg/kg for large joints, maximum about 40 mg	Glucocorticoid receptor agonist; local anti-inflammatory effect; avoid repeated systemic steroid exposure when possible
Methotrexate	10–15 mg/m² once weekly orally or subcutaneously with folic acid	Inhibits dihydrofolate reductase and increases adenosine-mediated anti-inflammatory signaling; hepatotoxicity, marrow suppression, mucositis, teratogenicity
TNF-α inhibitors, e.g., etanercept	0.8 mg/kg weekly, maximum 50 mg/week	Blocks TNF signaling; infection risk, TB reactivation screening before use
IL-6 receptor inhibitor, tocilizumab	Weight-based IV or SC regimens; used especially in systemic/polyarticular JIA	Blocks IL-6 receptor; neutropenia, transaminitis, lipid elevation
IL-1 blockade, anakinra/canakinumab	Anakinra often 1–2 mg/kg/day SC	Targets IL-1-driven systemic JIA; infection risk, injection-site reactions

High-yield therapeutic logic: oligoarticular JIA often responds to NSAIDs and intra-articular glucocorticoids; polyarticular JIA often requires methotrexate and, if inadequate, biologic DMARDs; systemic JIA with prominent systemic inflammation is particularly responsive to IL-1 or IL-6 inhibition. Before biologics, students should remember screening for latent tuberculosis and hepatitis where appropriate because cytokine blockade impairs host defense.

Ankylosing Spondylitis

Definition, Epidemiology, and Core Pathology

Ankylosing spondylitis is a chronic, immune-mediated inflammatory arthritis primarily affecting the axial skeleton, especially the sacroiliac joints and spine. It belongs to the seronegative spondyloarthropathies: “seronegative” means rheumatoid factor and anti-CCP antibodies are typically absent. The disease usually begins before age 45 years, often in late adolescence or early adulthood, and is classically more common in males.

The fundamental lesion is enthesitis, inflammation at sites where tendons, ligaments, or joint capsules insert into bone. In the spine, inflammation at the annulus fibrosus–vertebral body interface promotes erosions followed by repair with new bone formation. This produces syndesmophytes, vertically oriented bony bridges between vertebral bodies, eventually causing spinal fusion and the classic radiographic “bamboo spine.”

Immunogenetics and Mechanism

The strongest genetic association is HLA-B27, a class I MHC molecule. Approximately 90%–95% of White patients with ankylosing spondylitis are HLA-B27 positive, but most HLA-B27-positive individuals never develop disease; thus, HLA-B27 is sensitive in appropriate populations but not diagnostic by itself. Proposed mechanisms include abnormal peptide presentation, misfolding of HLA-B27 with endoplasmic reticulum stress, and altered gut/mucosal immunity. Key inflammatory pathways include TNF-α and the IL-23/IL-17 axis, explaining the efficacy of TNF inhibitors and IL-17 inhibitors.

Clinical Features

The classic presentation is inflammatory back pain: insidious onset before age 45, duration greater than 3 months, morning stiffness, improvement with exercise, and poor improvement with rest. Pain often begins in the buttocks due to sacroiliitis and may alternate sides. Progressive disease reduces spinal mobility and chest expansion due to costovertebral involvement.

• Axial findings: sacroiliac pain, lumbar stiffness, reduced forward flexion, kyphosis in advanced disease.
• Peripheral findings: asymmetric oligoarthritis, especially hips and shoulders; enthesitis at the Achilles tendon or plantar fascia.
• Extra-articular associations: acute anterior uveitis, inflammatory bowel disease, psoriasis, aortitis with aortic regurgitation, apical pulmonary fibrosis, and rarely cauda equina syndrome.

Diagnosis, Classification, and Scoring

Diagnosis integrates clinical pattern, imaging, and HLA-B27 status. Inflammatory markers such as ESR and CRP may be elevated, but normal values do not exclude disease. Rheumatoid factor and anti-CCP are usually negative.

Framework	High-Yield Criteria
Modified New York criteria	Definite ankylosing spondylitis requires radiographic sacroiliitis plus clinical features such as low back pain >3 months improved by exercise, limited lumbar motion, or reduced chest expansion.
Radiographic sacroiliitis threshold	Bilateral grade ≥2 sacroiliitis or unilateral grade ≥3 sacroiliitis on plain radiograph.
ASAS axial spondyloarthritis criteria	Back pain ≥3 months and age at onset <45 years plus sacroiliitis on imaging with ≥1 SpA feature, or HLA-B27 positivity with ≥2 SpA features.
BASDAI	Bath Ankylosing Spondylitis Disease Activity Index; 0–10 patient-reported scale. A score ≥4 often indicates active disease in trials and treatment algorithms.
ASDAS	Ankylosing Spondylitis Disease Activity Score incorporates back pain, stiffness, peripheral pain/swelling, patient global assessment, and CRP or ESR; ASDAS ≥2.1 indicates high disease activity.

Radiographs may be normal early. MRI is more sensitive for early sacroiliitis, showing bone marrow edema on STIR sequences before structural fusion develops. Classic late findings include sacroiliac joint erosion and sclerosis, squaring of vertebral bodies, syndesmophytes, and bamboo spine.

Pharmacology and Treatment Principles

Step 1 emphasizes mechanism-based therapy. Exercise and physical therapy preserve posture, spinal extension, and chest expansion. NSAIDs are first-line because prostaglandin inhibition reduces inflammatory pain and stiffness. Examples include naproxen 500 mg orally twice daily or indomethacin 25–50 mg orally two or three times daily. Monitor for gastrointestinal ulceration, renal vasoconstriction, hypertension, and platelet effects depending on the agent.

Drug Class	Examples and Doses	Mechanism / High-Yield Toxicities
TNF-α inhibitors	Etanercept 50 mg weekly; adalimumab 40 mg every 2 weeks; infliximab 5 mg/kg IV at weeks 0, 2, 6, then every 6–8 weeks	Block TNF-mediated macrophage and endothelial activation. Screen for latent tuberculosis and hepatitis B; risks include serious infection and demyelinating disease. Approximate half-lives: etanercept 3–5 days, adalimumab about 2 weeks.
IL-17 inhibitors	Secukinumab 150 mg subcutaneously weekly for 5 doses, then every 4 weeks; half-life about 27 days	Blocks IL-17A-driven neutrophilic and stromal inflammation. Can worsen or unmask inflammatory bowel disease; risk of mucocutaneous Candida.
Conventional DMARDs	Sulfasalazine may help peripheral arthritis	Methotrexate and sulfasalazine have limited benefit for purely axial disease, unlike in rheumatoid arthritis.

Landmark biologic trials support these pathways: the ATLAS trial of adalimumab showed ASAS20 responses at week 12 of approximately 58% versus 21% with placebo, and MEASURE trials of secukinumab showed week 16 ASAS20 responses around 61% versus 28% with placebo. Current ACR/SAA/SPARTAN guidance recommends NSAIDs initially and biologic therapy, usually a TNF inhibitor or IL-17 inhibitor, for persistently active axial disease despite NSAID therapy.

Classic USMLE Associations

• Young man + chronic inflammatory low back pain + HLA-B27 + sacroiliitis strongly suggests ankylosing spondylitis.
• Anterior uveitis presents with painful red eye, photophobia, and blurred vision.
• Aortic root inflammation can cause aortic regurgitation and conduction abnormalities.
• Bamboo spine reflects syndesmophyte-mediated vertebral fusion, not osteophytes from degenerative disease.

Psoriatic Arthritis

Psoriatic arthritis (PsA) is a chronic, seronegative inflammatory arthritis associated with psoriasis. It belongs to the spondyloarthropathy family because it commonly involves the axial skeleton, entheses, and digits, and is typically negative for rheumatoid factor. Psoriasis affects approximately 2–3% of the population; among patients with psoriasis, about 20–30% develop PsA. Skin disease precedes arthritis in 75–85% of cases, arthritis precedes psoriasis in about 10–15%, and both appear simultaneously in a minority.

Pathogenesis and Immunology

PsA is driven by immune activation at the skin–joint–enthesis axis. The enthesis is the site where tendon, ligament, or joint capsule inserts into bone; inflammation here is called enthesitis, a key concept for spondyloarthropathies. Mechanical stress at entheses may activate innate immune cells and dendritic cells, promoting cytokine release.

• IL-23/Th17 pathway: dendritic cell-derived IL-23 promotes differentiation and maintenance of Th17 cells, which produce IL-17A, IL-17F, and IL-22. These cytokines stimulate keratinocyte proliferation, neutrophil recruitment, synovial inflammation, and bone remodeling.
• TNF-α: promotes endothelial activation, macrophage recruitment, synoviocyte activation, and osteoclastogenesis.
• Bone effects: PsA characteristically combines erosion with new bone formation. Inflammatory cytokines increase RANKL-mediated osteoclast activation while also promoting aberrant osteoblast activity at periosteal and entheseal sites.
• Genetics: associations include HLA-Cw6 with psoriasis, HLA-B27 with axial disease, and HLA-B38/B39 with peripheral arthritis.

Clinical Patterns

PsA is heterogeneous. The classic exam clues are DIP joint arthritis, dactylitis (“sausage digit”), enthesitis, nail pitting or onycholysis, and asymmetric oligoarthritis in a patient with psoriasis.

Pattern	Typical Features	High-Yield Clue
Asymmetric oligoarthritis	Few joints, often lower extremity	Most common presentation
Symmetric polyarthritis	RA-like involvement of small joints	Usually RF and anti-CCP negative
DIP-predominant arthritis	Distal interphalangeal joints of hands/feet	Strong association with nail disease
Axial disease	Sacroiliitis, inflammatory back pain	Associated with HLA-B27
Arthritis mutilans	Severe osteolysis and deformity	“Telescoping” digits; uncommon but classic

Inflammatory back pain is suggested by onset before age 40, insidious onset, improvement with exercise, no improvement with rest, and nocturnal pain. Peripheral joints may be swollen and tender, but morning stiffness is usually inflammatory, often lasting >30–60 minutes.

Diagnosis, Classification, and Scoring

No single laboratory test diagnoses PsA. ESR and CRP may be elevated, but can be normal; typical reference ranges are approximately ESR <20 mm/hr and CRP <10 mg/L, depending on laboratory standards. Rheumatoid factor and anti-CCP antibodies are usually absent; anti-CCP positivity occurs in a minority, roughly 5–10%, and can complicate distinction from rheumatoid arthritis.

The CASPAR criteria are commonly used for classification: inflammatory articular disease plus at least 3 points from psoriasis, nail dystrophy, negative RF, dactylitis, or radiographic juxta-articular new bone formation. Reported performance is approximately 91.4% sensitivity and 98.7% specificity.

• Radiographs: marginal erosions with adjacent bone proliferation, asymmetric sacroiliitis, periostitis, ankylosis, and the classic “pencil-in-cup” deformity.
• Nail findings: pitting, oil-drop discoloration, subungual hyperkeratosis, and onycholysis.
• Activity measures: PASI scores skin psoriasis from 0–72; DAPSA incorporates tender/swollen joint counts, patient pain/global assessment, and CRP; minimal disease activity requires meeting 5 of 7 target criteria.

Pharmacology and Treatment Principles

Step 1 emphasis is on mechanism-based therapy. Treatment is selected by disease domains: peripheral arthritis, axial disease, enthesitis, dactylitis, skin/nail disease, and erosive severity. Current ACR/NPF and GRAPPA approaches are increasingly domain-based; TNF inhibitors, IL-17 inhibitors, and IL-23 pathway agents are central for moderate-to-severe disease.

Drug/Class	Typical Adult Dose	Mechanism and Key Toxicities
NSAIDs	Example: naproxen 250–500 mg orally twice daily	COX inhibition; symptomatic relief. Toxicities: gastritis, renal vasoconstriction, platelet dysfunction.
Methotrexate	7.5–25 mg orally or subcutaneously once weekly plus folic acid 1 mg/day	Inhibits dihydrofolate reductase and increases adenosine; useful for peripheral arthritis and skin. Toxicities: hepatotoxicity, myelosuppression, pulmonary fibrosis, teratogenicity.
Leflunomide	20 mg orally daily	Inhibits dihydroorotate dehydrogenase, blocking pyrimidine synthesis. Half-life about 2 weeks; teratogenic.
Adalimumab	40 mg subcutaneously every 2 weeks	Anti-TNF monoclonal antibody; screen for latent TB and hepatitis B. Half-life about 10–20 days.
Secukinumab	150–300 mg subcutaneously weekly at weeks 0–4, then every 4 weeks	Anti-IL-17A; effective for skin and joints. May worsen inflammatory bowel disease and increase mucocutaneous candidiasis risk.
Apremilast	30 mg orally twice daily after titration	PDE-4 inhibitor increasing intracellular cAMP; adverse effects include diarrhea, nausea, weight loss, depression.

Landmark biologic trials established cytokine targeting: the ADEPT trial showed adalimumab achieved ACR20 responses in about 58% versus 14% with placebo at week 12; IMPACT showed infliximab ACR20 response around 65% versus 10% at week 16; FUTURE studies supported secukinumab, with ACR20 responses near 50–55% versus about 15% with placebo. For exams, remember: PsA is seronegative, DIP/nail-associated, enthesitis- and dactylitis-prone, and radiographically erosive with new bone formation.

Reactive Arthritis

Definition and Classification

Reactive arthritis is a sterile inflammatory arthritis that occurs after an infection at a distant mucosal site, classically the genitourinary or gastrointestinal tract. It belongs to the seronegative spondyloarthropathies: rheumatoid factor and anti-CCP antibodies are typically negative, and disease may involve the axial skeleton, entheses, and extra-articular tissues. The classic Step 1 mnemonic is “can’t see, can’t pee, can’t climb a tree”, referring to conjunctivitis/uveitis, urethritis/cervicitis, and arthritis.

Classification	Typical Trigger	Important Organisms	Timing
Postvenereal	Urethritis/cervicitis	Chlamydia trachomatis most classic; also Ureaplasma	Usually 1–4 weeks after infection
Postenteric	Inflammatory diarrhea	Salmonella, Shigella, Campylobacter, Yersinia, sometimes Clostridioides difficile	Usually 1–4 weeks after infection
Acute vs chronic	Duration-based	Any trigger	Acute <6 months; chronic/recurrent >6 months

Pathogenesis

The joint inflammation is immune-mediated rather than due to direct septic invasion. Synovial fluid cultures are typically negative, hence “reactive.” Microbial antigens or nucleic acids may persist in synovial tissue, especially after Chlamydia, stimulating innate and adaptive immune responses. Key mechanisms include CD8+ T-cell activation, cytokine release, and inflammation at entheses and synovium. Cytokines implicated in the spondyloarthritis family include TNF-α, IL-17, and IL-23.

HLA-B27 is strongly associated but not diagnostic. It is present in approximately 30–50% of patients with reactive arthritis, compared with about 6–8% of the general U.S. population. HLA-B27 positivity increases risk of more severe disease, sacroiliitis, uveitis, and recurrence. Proposed mechanisms include abnormal antigen presentation, molecular mimicry, and endoplasmic reticulum stress leading to cytokine activation.

Clinical Manifestations

The arthritis is classically an asymmetric oligoarthritis affecting the lower extremities, especially knees, ankles, and feet. Enthesitis, particularly at the Achilles tendon or plantar fascia, is high-yield because entheses are a major target in spondyloarthropathies. Dactylitis, or “sausage digit,” may occur.

• Articular: asymmetric oligoarthritis, enthesitis, dactylitis, inflammatory back pain, sacroiliitis.
• Ocular: conjunctivitis is common and often mild; anterior uveitis causes painful red eye, photophobia, and blurred vision.
• Genitourinary: urethritis, dysuria, cervicitis, prostatitis; symptoms may be mild or absent in chlamydial infection.
• Mucocutaneous: keratoderma blennorrhagicum, a hyperkeratotic rash on soles or palms; circinate balanitis, painless shallow erosions on the glans penis; oral ulcers.

Diagnosis

Diagnosis is clinical: inflammatory arthritis plus a recent compatible infection. A commonly used classification concept requires asymmetric lower-limb oligoarthritis plus preceding urethritis/cervicitis or diarrhea within approximately 3 days to 6 weeks. No single laboratory test confirms the disease.

Test	Expected Finding	Step 1 Significance
ESR/CRP	Often elevated	Nonspecific evidence of inflammation
RF and anti-CCP	Negative	Distinguishes from rheumatoid arthritis
Synovial fluid	Inflammatory, often 2,000–50,000 WBC/µL, neutrophil-predominant; Gram stain/culture negative	Helps exclude septic arthritis and crystal arthritis
NAAT for C. trachomatis	Positive in active infection; sensitivity and specificity generally >90–95%	Use first-catch urine, vaginal, cervical, rectal, or pharyngeal samples depending on exposure
HLA-B27	May be positive	Risk/severity marker; not a screening or diagnostic test

Imaging is often normal early. Chronic disease may show asymmetric sacroiliitis, enthesophytes, periostitis, or erosive changes, especially in the feet.

Treatment Principles and Pharmacology

For Step 1, understand the mechanism-based approach: reduce inflammation, eradicate active triggering infection when appropriate, and suppress chronic immune disease if persistent.

Therapy	Typical Adult Dose	Mechanism/Notes
NSAIDs	Naproxen 500 mg PO twice daily or indomethacin 25–50 mg PO three times daily	First-line; inhibit COX enzymes → decreased prostaglandins. Naproxen half-life ~12–17 hours.
Glucocorticoids	Intra-articular triamcinolone commonly 10–40 mg depending on joint size	Bind cytosolic glucocorticoid receptor → decreased NF-κB/AP-1 inflammatory transcription.
Chlamydia treatment	Doxycycline 100 mg PO twice daily for 7 days; alternative azithromycin 1 g PO once	CDC-recommended for uncomplicated chlamydia; treat partners. Doxycycline half-life ~18–22 hours; azithromycin terminal half-life ~68 hours.
DMARDs for chronic peripheral arthritis	Sulfasalazine 1–3 g/day or methotrexate 15–25 mg weekly with folic acid	Used when symptoms persist >3–6 months; methotrexate inhibits dihydrofolate reductase and AICAR transformylase, increasing anti-inflammatory adenosine.
TNF-α inhibitors	Examples: etanercept, adalimumab	Reserved for refractory spondyloarthritis-type disease; screen for latent TB before use.

Antibiotics are important for active chlamydial infection, but they generally do not shorten established postenteric reactive arthritis once the inciting diarrheal illness has resolved. Most cases improve within 3–12 months, but 15–30% may develop chronic or recurrent arthritis, especially with HLA-B27 positivity.