Inflammatory markers, urate and baseline investigations in rheumatic disease

At a glance

• Most rheumatology blood tests answer one of four questions: is there inflammation, which organs are involved, is something else mimicking it, and is it safe to start treatment.
• CRP tracks the IL-6 signal within a day. ESR lags by days to weeks and is pushed up by immunoglobulins, anaemia, age and renal failure. The physiology and confounders are in Acute phase response and inflammatory markers.
• Serum urate confirms hyperuricaemia but doesn't diagnose gout. It can be normal during a flare.
• Autoantibodies have their own notes: ANA, ENA and anti-dsDNA, RF and anti-CCP, ANCA, complement and antiphospholipid antibodies in Antiphospholipid syndrome.
• Pitfall: no blood test rules inflammatory arthritis in or out. Synovitis on examination outranks a normal CRP.

Inflammatory markers in practice

Test	Typical reference	Useful for	Misleads when
CRP	Under 5 mg/L (lab dependent)	RA, PMR, GCA, Still disease, sepsis, monitoring response	On tocilizumab, sarilumab or JAK inhibitors (suppressed); SLE flares (often normal)
ESR	Men age/2, women (age + 10)/2 mm/h	SLE activity, GCA, PBS biologic criteria (over 25 mm/h)	Anaemia, paraprotein, CKD, pregnancy, old age, obesity

Read them together. Concordant rises suggest active inflammation. A high ESR with a normal CRP points to immunoglobulins (SLE, Sjögren syndrome, myeloma, chronic liver disease) or anaemia. A high CRP in known SLE means infection, serositis or synovitis until proven otherwise.

When markers change management:

• DAS28-CRP or DAS28-ESR for treat-to-target in rheumatoid arthritis, and PBS biologic applications. Initial applications generally need ESR over 25 mm/h or CRP over 15 mg/L (RA, PsA) or over 10 mg/L (AS). If this can't be met, the application must state why.
• CRP or ESR is raised in over 90% of GCA. A normal value lowers the probability but never stops urgent assessment of visual symptoms.
• Pitfall: do not use CRP to judge relapse or infection in a patient on IL-6 blockade. Use symptoms, examination and imaging.

Urate

• Reference upper limit is about 0.42 mmol/L in men and about 0.35 to 0.36 mmol/L in women (lab dependent). Urate saturates at about 0.40 mmol/L.
• Diagnosis: crystals on aspiration are the gold standard. Urate during a flare is often normal, because the acute phase response increases renal urate excretion. Recheck 2 to 4 weeks after it settles. In the 2015 ACR/EULAR criteria, urate under 0.24 mmol/L scores negatively.
• Monitoring: treat to below 0.36 mmol/L, or below 0.30 mmol/L with tophi. Check monthly while titrating allopurinol, then 6 to 12 monthly. Details in Gout and CPPD.
• Most people with hyperuricaemia never get gout. Don't treat a number.

FBC, renal and liver tests, urinalysis

Test	Patterns that matter
FBC	Normocytic anaemia of inflammation and thrombocytosis in active RA; leucopenia, lymphopenia and thrombocytopenia in SLE; eosinophils 1 × 10^9/L or more in EGPA (2022 ACR/EULAR criteria), often much higher; cytopenias from methotrexate, azathioprine or leflunomide; neutrophilia from prednisolone
Creatinine and eGFR	Vasculitis and lupus nephritis; dose methotrexate by eGFR (reduce under 60, generally avoid under 30); NSAID safety
LFTs	Baseline and monitoring for methotrexate and leflunomide; mild ALP rise in PMR and GCA; raised AST and ALT from myositis
CK	Myositis, statin and hypothyroid myopathy
Urinalysis	Dipstick blood and protein, then microscopy for dysmorphic red cells and red cell casts; urine protein:creatinine ratio

• Urinalysis is mandatory in every new case of SLE, vasculitis or unexplained systemic illness. A UPCR over 50 mg/mmol (about 0.5 g/day) with active sediment in lupus usually means a renal biopsy.
• Pitfall: methotrexate toxicity is blamed for raised transaminases that come from muscle. Check CK.

ACE and viral serology

• Serum ACE is made by granuloma epithelioid cells. Raised in about 60% of active sarcoidosis, and also in TB, berylliosis, silicosis, leprosy, primary biliary cholangitis, hyperthyroidism and Gaucher disease. ACE inhibitors lower it. It can support a diagnosis but doesn't make one, and tracking it adds little.
• Viral arthritis serology in acute polyarthritis under 6 weeks: parvovirus B19 IgM, Ross River and Barmah Forest virus serology with mosquito exposure, HBsAg, hepatitis C antibody and HIV. Single positive alphavirus IgM is weak evidence. See Viral arthritis.

Baseline before DMARDs and biologics

Before	Check
Any conventional DMARD	FBC, creatinine, LFTs, HBsAg, anti-HBc, anti-HBs, hepatitis C antibody, HIV; pregnancy test and contraception plan; chest X-ray (within the previous year) before methotrexate, as a baseline for later pneumonitis (3E 2009)
Biologic or JAK inhibitor	Add IGRA and chest X-ray for latent TB; varicella IgG; lipids (JAK inhibitors, tocilizumab)
Azathioprine	TPMT (and NUDT15 where available) activity or genotype
Rituximab	Immunoglobulins (low IgG predicts infection), hepatitis B status
From endemic regions	Strongyloides serology before high-dose steroids, including many Aboriginal communities in northern Australia and migrants from South-East Asia

• HBsAg positive: antiviral therapy before immunosuppression. Isolated anti-HBc positive with rituximab: prophylaxis with entecavir or tenofovir. With other DMARDs: monitor HBV DNA and ALT, or give prophylaxis per hepatology advice. See Complications of immunosuppression.
• Vaccination review belongs in the same visit: live vaccines such as MMR and yellow fever must be given at least 4 weeks before biologics; Shingrix (non-live, 2 doses) is recommended before or early in biologic or JAK inhibitor therapy. NIP funding covers people aged 65 and over, First Nations people aged 50 and over, and adults with the moderate or severe immunocompromising conditions and therapies listed in the Handbook eligibility table (for example HSCT, solid organ transplant, haematological malignancy or advanced HIV). Check that table for the patient's therapy; if it isn't listed, Shingrix is a private prescription.

Worked examples

A 72-year-old woman with fatigue and back pain has ESR 88 mm/h, CRP 4 mg/L, Hb 104 g/L, total protein 92 g/L and albumin 34 g/L. The globulin gap is 58 g/L. The ESR rise is out of proportion to the CRP and globulins are high: request serum protein electrophoresis, free light chains and calcium, not a temporal artery biopsy. See Immunoglobulins and protein electrophoresis.

A 48-year-old man has a hot first MTP. Urate is 0.33 mmol/L, CRP 96 mg/L. The normal urate doesn't exclude gout; aspirate if possible and repeat the urate a month later. A result of 0.52 mmol/L then confirms hyperuricaemia.

A 35-year-old woman with SLE has a fever. CRP is 140 mg/L, C3 and anti-dsDNA are unchanged. A CRP this high in lupus means infection or serositis, not a typical flare. Take cultures before increasing steroids.

Pitfalls

• Pitfall: ordering a broad "arthritis screen" (ANA, RF, ESR, urate) for widespread pain without synovitis. Positive results in healthy people outnumber true disease.
• Pitfall: repeating RF, anti-CCP or ANA to monitor disease. They don't track activity.
• Pitfall: normal CRP on tocilizumab reassuring the team in a febrile patient.
• Pitfall: treating asymptomatic hyperuricaemia found on a routine panel.
• Pitfall: starting rituximab without checking anti-HBc, or a TNF inhibitor before an IGRA.