What conditions can cause an elevated erythrocyte sedimentation rate (ESR) with a normal C‑reactive protein (CRP)?

High ESR with Normal CRP: Causes and Clinical Significance

An elevated ESR with normal CRP most commonly indicates chronic inflammatory conditions (especially polymyalgia rheumatica, giant cell arteritis, or multiple myeloma), chronic infections (particularly osteomyelitis), or conditions where ESR remains elevated after acute inflammation has resolved, since CRP normalizes within days while ESR remains elevated for weeks.

Primary Mechanisms of ESR/CRP Discordance

The discordance between ESR and CRP occurs through three distinct mechanisms 1:

• Different kinetics of inflammatory markers: CRP rises within 12-24 hours and peaks at 48 hours with a half-life of 19 hours, while ESR remains elevated longer with a half-life of 4-7 days after inflammation resolves 2, 1
• ESR elevation from plasma proteins: ESR reflects chronic inflammation through fibrinogen and immunoglobulins (IgG, IgA, IgM), which persist longer than acute-phase reactants 3
• Technical factors: Anemia and azotemia artificially elevate ESR independent of inflammation but do not affect CRP 4, 2

Most Common Disease Associations

Chronic Inflammatory Conditions (Most Likely)

Polymyalgia Rheumatica (PMR):

• Bilateral shoulder and hip girdle pain with morning stiffness >45 minutes in patients >50 years 4
• ESR >40 mm/h is associated with higher relapse rates 4
• Responds dramatically to prednisone 12.5-25 mg daily 4

Giant Cell Arteritis (GCA):

• ESR >40 mm/h has 93.2% sensitivity for GCA 4
• New-onset localized headache, jaw claudication, or visual symptoms require urgent same-day evaluation 4
• ESR >100 mm/h has 92.2% specificity with positive likelihood ratio of 3.11 4

Multiple Myeloma and Plasma Cell Disorders:

• Monoclonal or polyclonal increases in IgG, IgA, or IgM elevate ESR through increased plasma viscosity 3
• Significant correlations exist between ESR and monoclonal protein concentrations 3
• Check serum protein electrophoresis and free light chains if suspected 4

Chronic Infections

Osteomyelitis:

• ESR ≥70 mm/h has 81% sensitivity and 80% specificity for osteomyelitis in diabetic foot infections 4
• Persistent high ESR/normal CRP pattern was documented in chronic osteomyelitis cases 1
• Consider in patients with back pain, diabetes, IV drug use, or immunosuppression 4

Subacute Bacterial Infections:

• Infection was the leading diagnosis (40%) in patients with extremely elevated ESR 5
• Chronic infections can produce elevated ESR with normal WBC counts 6

Autoimmune Conditions with Specific Patterns

Lupus Nephritis:

• Demonstrates persistent high ESR/normal CRP disagreement 1
• Renal insufficiency independently increases risk of elevated ESR/low CRP discordance (p=0.003) 7

Adult-Onset Still's Disease:

• ESR elevation occurs in 95-98% of cases 4
• Markedly elevated serum ferritin is characteristic 4
• Presents with fever, rash, and arthralgia 6

Diagnostic Algorithm

Initial Laboratory Assessment

Confirm true discordance:

• Repeat CRP measurement to confirm it is truly normal, as CRP normalizes faster than ESR during inflammation resolution 4
• Obtain measurements 2-4 weeks apart if initial discordance is found 1

Essential first-line tests:

• Complete blood count with differential to assess for anemia (artificially elevates ESR) 4
• Comprehensive metabolic panel including creatinine (azotemia elevates ESR) 4
• Serum protein electrophoresis if ESR >100 mm/h to evaluate for monoclonal gammopathy 3

Age and Symptom-Directed Evaluation

For patients >50 years with musculoskeletal symptoms:

• Rheumatoid factor and anti-CCP antibodies if joint involvement 4
• Consider PMR if bilateral shoulder/hip pain with morning stiffness >45 minutes 4
• Urgent GCA evaluation if headache, jaw claudication, or visual symptoms 4

For patients with localized bone/joint pain:

• ESR ≥70 mm/h strongly suggests osteomyelitis in diabetic foot infections 4
• Consider MRI for suspected spine infection or chronic osteomyelitis 4

For unexplained ESR elevation:

• Serum ferritin (elevated in Still's disease, malignancy, infection) 4
• ANA panel only if clinical signs suggest specific autoimmune disease 4
• Chest radiography to exclude pulmonary malignancy or infection 4

Critical Clinical Caveats

Factors that artificially elevate ESR without affecting CRP:

• Anemia (most common confounding factor) 4, 7
• Renal insufficiency/azotemia 4, 7
• Low serum albumin (associated with both types of discordance) 7
• Female sex and advanced age (higher baseline ESR) 4

When discordance is transient and clinically insignificant:

• Slight fluctuations around upper limits of normal for both tests 1
• Resolution phase of acute inflammation (ESR lags behind CRP normalization) 2, 1
• Only 4 of 14 patients (29%) with initial CRP/ESR disagreements had stable discordance on repeat testing 1

Red flags requiring urgent evaluation:

• ESR >100 mm/h is an independent prognostic factor for mortality 4
• New visual symptoms with elevated ESR (GCA emergency) 4
• Fever with extremely elevated ESR (infection most common cause at 40%) 5

Monitoring Strategy

• Repeat ESR and CRP in 2-4 weeks to determine if elevation is persistent or transitory 4
• For confirmed chronic inflammatory conditions, monitor ESR every 1-3 months during active disease, then every 3-6 months in remission 4
• ESR is superior to CRP for monitoring chronic conditions like PMR and GCA 4