Investigating joint pain using a rational testing approach

Continuing our series, rheumatologists Dr Alastair Hepburn and Dr Ho Juen Ko outline a rational approach to testing when investigating joint pains in a young adult woman

The case: A 24-year-old woman attends with painful joints. This has been going on for a few months and seems to be getting worse. She notices that her finger joints are affected in both hands, and possibly her wrists, too – and in recent weeks she has noticed similar issues in her feet. The symptoms are worse in the morning, when the joints also feel very stiff and seem swollen. She feels vaguely out of sorts but has noticed that over-the-counter anti-inflammatories help. Apparently, there is a history of arthritis in an aunt – she’s not clear what sort but thinks it started when her aunt was young.

What are the causes of joint pains in a young female?

The differentials can be wide in a young female who present with joint pain. Inflammatory arthritis (rheumatoid arthritis, seronegative inflammatory arthropathies such as psoriatic arthritis), connective tissue disease (systemic lupus erythematosus, Sjogren’s syndrome, systemic sclerosis, idiopathic inflammatory myositis), fibromyalgia and hypermobility are important differentials to consider.

Degenerative causes such as osteoarthritis and crystal arthropathies would be less likely in this age group.

What other information would be useful to ask in the history?

Ascertaining features of an inflammatory joint pain would be important. This would include joint swelling, morning stiffness lasting >30 minutes, pain that is worse with rest and improves with mobility and improvement with anti-inflammatory medications such as NSAIDs. In patients with inflammatory polyarthritis, fatigue, general malaise and weight loss are not uncommon.

Asking about their past medical and family history, in particular any autoimmune conditions such as T1DM, thyroid disease and coeliac disease would be important to ascertain their risks of developing an autoimmune condition.

A detailed systems review would be important too to ascertain any extra-articular features associated with the inflammatory or connective tissue disease (CTD). Ascertaining their general flexibility, previous joint subluxations or dislocations, bruising and skin extensibility will help point towards a heritable collagen disorder, such as Ehlers Danlos syndrome.

The key features of the different causes of joint pain in a young adult woman are shown in Table 1.

Table 1. Potential causes of joint pain in young adult female

Relevant first-line tests

We will only focus here on the role of laboratory testing in the investigation of a patient presenting with pain in multiple joints (polyarthralgia). The important role of imaging is beyond the scope of this article. Further, there is some overlap with the laboratory tests recommended for the investigation of muscle pain (myalgia), which may coexist, and the reader is directed to the recent article in this series on this topic.

Full blood count – anaemia of chronic disease can be seen in all forms of inflammatory polyarthritis, as can a reactive thrombocytosis; leucopoenia and thrombocytopenia can be features of SLE.

Renal profile, liver function tests – to identify any organ involvement in CTD (i.e., low albumin, high creatinine) and useful to have as baseline to inform treatment options.

C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) – inflammatory markers will be raised in inflammatory arthropathies, although a less pronounced acute phase response is usually seen in seronegative inflammatory polyarthritides. However, these tests are non-specific and may be elevated for other reasons such as the presence of infection. Some local health economies may restrict testing to one or the other, most commonly CRP rather than ESR. It should also be noted that the latter can rise with age and is generally higher in females than males. The CRP can also be mildly raised in individuals who are obese.

Anti-CCP antibodies are highly specific for rheumatoid arthritis so should be included in any patient presenting with symptoms and signs of inflammatory polyarthritis. However, rheumatoid factor (RF) is less specific and is only detected in up to 85% of patients with RA. Therefore, screening with anti-CCP antibodies is preferred and in some areas of the UK testing for RF may not be available in primary care for this reason. Rheumatologists may still test for RF in secondary care for classification purposes and to guide biologic treatment.

Hypothyroidism may present with non-specific joint and muscle pain, so screening for this with a TSH measurement as a minimum would be appropriate. Furthermore, autoimmune hypothyroidism may coexist with rheumatoid arthritis and other systemic autoimmune rheumatic diseases.

CK levels are often worth measuring as patients may confuse joint and muscle pain, or they may coexist. The latter might occur, for example, in patients with ‘overlap’ autoimmune CTD when inflammatory myositis coexists with other systemic diseases such as RA or scleroderma. Raised CK levels may be drug-induced, most commonly with statins, but it should be noted that these drugs can also cause joint pain specifically, albeit less commonly. Joint pain is also very common with aromatase inhibitors such as letrozole and anastrozole.

Potential second-line tests

As with investigation of myalgia, malignancy and paraneoplastic syndromes are also possible causes to consider in patients with polyarthralgia. Multiple myeloma may present with non-specific musculoskeletal pain, so screening for this with protein electrophoresis should be considered. The latter can show ‘acute’ or ‘chronic inflammatory patterns’ in patients with inflammatory polyarthritis or autoimmune connective tissue disease (CTD) but measurement of ESR and/or CRP is still preferred. Autoimmune CTDs, particularly Sjogren’s syndrome, may also show polyclonal increases in immunoglobulin levels, notably IgG.

In patients with polyarthralgia, only request a CTD screen or antinuclear antibodies (ANA) when there are clear clinical features of an autoimmune CTD such as systemic lupus erythematosus, systemic sclerosis or Sjogren’s syndrome. These diseases are all associated with presence of ANA. When the latter is positive, the laboratory will go on to measure extractable nuclear antibodies (ENA) and double stranded DNA (dsDNA). Approximately 20-30% of the normal population have weakly positive ANA and to further complicate matters, patients can have seronegative autoimmune disease, although this is rare.

Coeliac disease can present with polyarthralgia and, very rarely, a true inflammatory polyarthritis. Therefore, consider measuring anti-TTG antibodies, particularly if relevant gastrointestinal symptoms are present or there are other clues to malabsorption in the remainder of the blood screen, such as deficiencies of iron, folate and vitamin B12.

Typing for HLA B27 should only really be considered where the clinical picture is very suggestive of an axial spondyloarthropathy (i.e., in a patient with a history of inflammatory back pain). Though possible, it is unusual for the latter to present with a predominant peripheral joint inflammatory polyarthritis. However, rheumatologists may request this in secondary care to aid disease classification in a small proportion of patients. It can also be positive in patients with a true reactive arthritis (Reiter’s syndrome) or those with psoriatic arthritis. It’s important to note that HLA B27 shouldn’t be used as a diagnostic test as it is present in approximately 9% of the normal healthy population. Further, as it’s a genetic test, it shouldn’t be repeated.

Parvovirus B19 is most commonly associated with ‘slapped cheek syndrome’ is children, but in adults can present with a clinical picture similar to early rheumatoid arthritis. Therefore, requesting parvovirus B19 serology to look for evidence of recent infection (IgM as opposed to IgG antibodies) might be worthwhile.

Sexually transmitted infection (STI) screen – if suspicion of reactive arthritis is high, then tests to look for STIs can be done. These would include a blood-borne virus screen (HIV, Hepatitis B, Hepatitis C) and urinary nuclear acid amplification tests (NAATs) for chlamydia and gonorrhoea.

Complement components – low C3 and C4 levels are indicators of active SLE disease.

Specific myositis/scleroderma panels – these can be sent in a specialist setting once the diagnosis of connective tissue disease has been confirmed to determine phenotype and prognosis of disease.

Gout may present with a polyarticular involvement, but this diagnosis would be unusual in a woman of this age. Gout is more common in men and the incidence increased with age. Therefore, only measure serum urate levels in patients with significant risk factors for gout or where the clinical picture is more suggestive (i.e., in a patient presenting with an acute hot joint).

Tests to avoid

Measurement of vitamin D levels should be avoided routinely as a significant proportion of the UK population will have insufficiency or deficiency on testing but not have osteomalacia.

Do not request serology for Lyme disease unless there’s a clear history of tick bite and an associated rash prior to the development of the rheumatic symptoms, in a patient who has been in an environment where the disease is endemic.

Do not request anti-neutrophil cytoplasmic antibodies (ANCA) unless the clinical suspicion of a small vessel vasculitis is high. These serious multisystem conditions often involve the lungs, kidneys and skin, and ENT involvement is also common. There were no features to suggest systemic vasculitis in this case, and it would be unusual for vasculitis to present primarily with an inflammatory polyarthritis.

Genetic screen – genetic screening for potential hypermobility syndromes (such as Ehlers Danlos Syndrome or Marfan syndrome) should be done in a secondary or tertiary setting, if clinically indicated.

Key points

• Joint pain is a common presentation across all ages.
• An autoimmune/inflammatory cause would be more likely in a young patient.
• A detailed history ascertaining the distribution and features of inflammation is important to help determine a potential cause.
• A thorough systems review is also important to ascertain any extra-articular features which will help guide the investigations you would order going forward.
• Further advice on appropriate laboratory testing can be sought from a Rheumatologist. As this patient’s presentation is very suggestive of an early inflammatory polyarthritis, prompt referral to secondary care for further management would be appropriate.

Dr Alastair Hepburn is consultant rheumatologist and Dr Ho Juen Ko is rheumatology registrar at University Hospitals Sussex NHS Foundation Trust