Consider this disease as a cause of fever, weight loss and pain.
My aim is to present a common case and work through the reasoning of why I order each test, what questions are most useful to help diagnose this condition and a simple approach to management. The approach is practical and based upon experience and evidence (where it exists). I hope you will find it useful in your day-to-day practice.
A 64-year-old Middle Eastern man was referred with a generalised non-specific illness. His health had been deteriorating over the last three months with unintentional weight loss of 8kg, widespread pain, poor appetite, low mood and dizziness. His illness had started gradually but was progressive. There is a strong family history of solid organ malignancy.
On examination, he was pale and looked unwell. He had tenderness at a number of joints without appreciable synovitis. There was conjunctival pallor and small sub-centimetre non-tender palpable lymph nodes in his neck and axilla. The spleen tip was just palpable. Respiratory and cardiac examination was normal.
The differential is broad with a non-specific illness, but falls into three broad categories: 1) Malignancy (haematological or solid organ); 2) Chronic infective illness (such as tuberculosis, HIV, hepatitis B and C, or endocarditis); or 3) Autoimmune (systemic vasculitis or connective tissue disease would be the most common).
Investigations are thus directed towards these and are likely to be crucial given the non-specific illness and examination findings.
Initial investigations showed borderline microcytic anaemia with Hb 112, but 6 months earlier the Hb was 140. Iron studies showed raised ferritin and reduced transferrin saturation, consistent with a chronic inflammatory process. ESR was markedly raised at 116mm/hr (normal <20) and CRP was raised at 59 (normal <5). A range of other initial pathology tests were performed, with normal results for ANA, ENA, dsDNA, C3, C4, RF, CCP antibody, CK and ANCA. Urinalysis is normal.
The initial findings of anaemia prompted colonoscopy and endoscopy, but no malignant process or bleeding source was identified. A CT chest, abdomen and pelvis showed borderline enlarged cervical, axillary, mediastinal and iliac lymph nodes with splenomegaly measuring 16cm. These findings prompted haematological review with concern over lymphoma.
A PET-CT scan was ordered as part of the investigations for possible lymphoma. It confirmed mildly enlarged lymph nodes with only borderline uptake. Splenomegaly was confirmed. The findings were consistent with a low-grade indolent lymphoproliferative disorder. However, the most surprising finding was diffuse active uptake in the subclavian, brachiocephalic, thoracic aorta and femoral arteries. There were no appreciable atherosclerotic changes and the findings were in keeping with a large vessel vasculitis.
He had no headache, jaw claudication or scalp dysesthesias to point to the classic symptoms of giant cell arteritis (GCA). He does not describe claudicant leg pain and there was no blood pressure differential between arms. No bruits were appreciated.
GCA is the most common large vessel vasculitis over the age of 50 years, but it is typically diagnosed in patients >60 years. GCA has traditionally been diagnosed on temporal artery biopsy in patients presenting with headaches or other suggestive symptoms such as jaw claudication. A temporal artery biopsy is an invasive test and lacks a degree of sensitivity given potential “skip lesions” leading to false negative results. Obtaining a longer segment of the temporal artery (ideally 20-30mm) can help mitigate this.
Recently there has been interest in utilising PET-CT scan to diagnosis large vessel vasculitis. PET is not sensitive in detecting medium vessel vasculitis and is not used for small vessel vasculitis as it does not have the resolution to accurately detect small vessel inflammation.
While GCA was originally thought to mainly affect the extracranial vessels, PET-CT imaging has shown a much greater extent of disease. Subclavian arteries are the most commonly affected area, occurring in 74% of individuals, however, thoracic aorta involvement occurs in 51% and femoral artery involvement occurs in 37%.
His clinical presentation is most suggestive of GCA. The haematological abnormalities were further defined, and he was diagnosed with small lymphocytic lymphoma with genetic abnormality del 13q. This is an indolent disease and unlikely to account for his symptoms. Fortuitously, the PET-CT led to the correct diagnosis!
He was started on high dose prednisone 50mg daily and an application to the PBS for approval for tocilizumab was made. Tocilizumab is an IL-6 inhibitor and has good results as a steroid sparing agent in GCA, allowing a rapid taper of prednisone over 6 months. It has good data in prevention of visual loss and is usually well tolerated. The main contraindications for tocilizumab include high infection risk and diverticular disease.
The high corticosteroid doses that have traditionally been required to treat GCA result in high rates of side effects in a typically comorbid older individual. It is great to have a truly effective steroid sparing agent to treat this difficult disease.
Other issues to consider here are infection prophylaxis and bone protection, given prednisone will still be required for a number of months. I typically use PJP prophylaxis until prednisone dose is below 20mg daily, prescribing Bactrim DS 4 tablets per week, although there are other regimens. I also use calcium supplementation and aim for a vitamin D level greater than 60. A bisphosphonate is recommended if there is osteopenia or osteoporosis on DEXA scan. A PPI is used for gastric protection on higher doses of prednisone.
He responded very well to prednisone and tocilizumab, with rapid improvement of symptoms and improvement of anaemia. It should be noted that inflammatory markers are usually normal when taking tocilizumab, due to the reduction of IL-6. This can make it difficult to monitor disease activity as these markers are not reliable in detecting disease flares.
The prednisone was tapered and then ceased after 6 months. He continued tocilizumab monotherapy with good control of disease. GCA is a long-term condition, and it remains to be seen whether he will be able to stop therapy completely. A challenge in the long-term management is that the PBS only approves one-year lifetime treatment with tocilizumab for GCA. I typically transfer patients to methotrexate or leflunomide after one year of tocilizumab, as there are extremely high rates of disease relapse for many years after diagnosis.
This case illustrates a systemic presentation of GCA, rather than the typical cranial presentation. Systemic vasculitis can present in a multitude of ways, and it is important to consider as part of your differential in a patient with high-inflammatory markers and non-specific illness. PET-CT is increasingly being used to diagnose large vessel vasculitis.
Dr Andrew Jordan is a rheumatologist based in Parramatta, Sydney, with a special interest in inflammatory arthritis, gout and PRP injections.
