What causes septic arthritis, particularly in individuals with compromised immune systems, such as those with diabetes, rheumatoid arthritis (RA), or taking immunosuppressive medications?

What Causes Septic Arthritis

Septic arthritis occurs when bacteria, viruses, or fungi directly invade the joint space, most commonly through hematogenous spread (bloodborne seeding), direct inoculation from trauma or surgery, or contiguous spread from adjacent infected tissues. 1

Primary Mechanisms of Joint Infection

Hematogenous Seeding (Most Common Route)

• Bacteria travel through the bloodstream and seed the highly vascular synovial membrane, which lacks a protective basement membrane, making joints particularly vulnerable to infection during bacteremia 1
• This mechanism predominantly affects the metaphyses of long bones in children and can simultaneously involve adjacent joints 1
• Accounts for the majority of septic arthritis cases, particularly in patients without obvious trauma or recent procedures 2

Direct Inoculation

• Occurs following joint surgery, intra-articular injections, arthrocentesis, or penetrating trauma 3, 4
• Prosthetic joints are especially vulnerable, with infection rates around 5% following orthopedic hardware placement 1

Contiguous Spread

• Infection extends from adjacent osteomyelitis or soft tissue infections into the joint space 1
• Particularly relevant in pediatric cases where 30-58% of septic arthritis cases have concurrent osteomyelitis 5, 6

Risk Factors in Immunocompromised Patients

Diabetes Mellitus

• Diabetes is identified as one of four major comorbidities significantly increasing infection risk in septic arthritis 1, 3
• Impairs neutrophil function, phagocytosis, and overall immune response 1
• Creates an environment conducive to atypical infections, including fungal pathogens like Candida albicans 7

Rheumatoid Arthritis (RA)

• RA patients face elevated risk through two mechanisms: the underlying disease itself damages joint architecture, and the immunosuppressive treatments further compromise immune defenses 1, 3
• Pre-existing joint damage in RA creates favorable conditions for bacterial seeding during transient bacteremia 4
• The chronic inflammation and altered joint anatomy provide less resistance to infection 2

Immunosuppressive Medications

Anti-TNF Therapy:

• Anti-TNF agents increase rates of serious bacterial infections, opportunistic infections, and specifically septic arthritis in RA patients, with highest risk in the first 6 months of treatment 1
• The CORRONA, RABBIT, and British Society biologics registries all documented increased septic arthritis rates in anti-TNF treated RA patients 1
• In IBD, anti-TNF therapy carries a 2-fold increased risk of opportunistic infections 1

Corticosteroids:

• Prednisolone doses ≥20 mg daily for ≥2 weeks significantly increase infection risk 1
• Dose-dependent relationship exists, with relative risk increasing at ≥10 mg/day 1
• Corticosteroids were associated with higher hazard ratio (1.57) for serious infections compared to anti-TNF therapy (1.47) in the TREAT registry 1

Combination Immunosuppression:

• The use of two or more immunomodulators concomitantly dramatically increases opportunistic infection risk (OR 14.5,95% CI 4.9-43) compared to monotherapy (3-fold risk) 1
• This includes combinations of thiopurines, methotrexate, calcineurin inhibitors, and biologics 1

Additional Risk Factors

• Age >80 years represents an independent risk factor, with 90-day mortality rates reaching 22-69% in this population 3, 4
• Age >50 years carries OR 3.0 (95% CI 1.2-7.2) for opportunistic infections 1
• Chronic lung disease, alcoholism, organic brain disease all identified as significant comorbidities 1
• Skin infections provide a portal of entry for bacteria 3, 4
• Recent joint surgery or prosthetic joints 3, 4

Common Causative Organisms

Bacterial Pathogens:

• Staphylococcus aureus is the most common pathogen overall, accounting for the majority of cases across all age groups 5, 6, 3
• MRSA prevalence is increasing, particularly in immunocompromised patients 5, 6
• Streptococcal species are the second most common bacterial cause 8
• Gram-negative bacilli occur less frequently but should be considered in specific populations 8

Age-Specific Pathogens:

• Neonates: Group B streptococcus predominates 6
• Children <4 years: Kingella kingae is common 5, 6
• Patients with sickle cell disease: Salmonella species 5

Atypical Organisms in Immunocompromised Hosts:

• Fungal infections, particularly Candida species, occur more frequently in patients with diabetes and on immunosuppressive therapy 1, 7
• Mycobacterial infections should be considered with anti-TNF therapy 1
• Viral and parasitic infections can occur with any immunomodulator 1

Critical Clinical Pitfalls

• Malnutrition compounds immunosuppression by depriving the immune system of components needed for effective response, impairing cell-mediated immunity, phagocyte function, and complement system 1
• No strict correlation exists between specific immunomodulator drugs and certain infection types—any immunosuppressive agent can lead to any type of infection 1
• Elderly patients (>65 years) on TNF inhibitors have higher rates of severe infections and mortality compared to younger patients 1
• The mortality rate of septic arthritis ranges from 2-15% overall, emphasizing the urgency of prevention in high-risk populations 8