Options for treating persistent rheumatoid arthritis

We look at a common rheumatological case and works through the reasoning for ordering each test, what questions are most useful to help diagnose this condition and a simple approach to management

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A 63-year-old female presents with a one-month history of right knee pain and swelling. There was no preceding trauma and the pain started gradually. She has prolonged morning stiffness, lasting at least two hours. She is having difficulty walking at times and has missed work due to pain and immobility. 

Examination shows a large right knee effusion and range of movement is 0 to 90 degrees. Examination of the other joints is unremarkable. There is no psoriasis.

A knee X-ray is normal, with no signs of chondrocalcinosis. A MRI scan of the knee is ordered and it shows minor cartilage wearing in the medial compartment, a small medial meniscal tear, a large joint effusion and prominent synovitis.  There are no erosions.

What are the possible diagnoses for a monoarthritis in this case?

The main considerations would be new onset inflammatory arthritis, crystal arthritis (gout or pseudogout), infection or haemarthrosis.

Haemarthrosis is unlikely as she is not taking antiplatelets or anticoagulation, there is no history of trauma and no fracture is seen on the MRI scan. Crystal arthritis typically presents as sudden onset swelling, with severe pain and swelling often occurring within 24 hours.  Gout or pseudogout is always a possibility for a knee monoarthritis in her age group.  Inflammatory arthritis (RA, spondyloarthritis) will often develop over days, however sudden onset swelling can occur. Infection is always a possibility; however she is afebrile.

What are the best investigations to order in this case?

A joint aspirate is performed, and it is highly inflammatory – 24,600 x 10⁶/L white cell count, 79% neutrophils. Crystal analysis is negative and culture results are negative. Serum uric acid is 0.24 mmol/L.  CRP is raised at 47 (N<5) and ESR raised at 72 (N<20).  CCP antibody 184 (N<5) and RF is 92 (N<20).

The strongly positive RF and CCP antibodies suggest this is rheumatoid arthritis, especially as the alternative diagnoses have been excluded with the joint aspirate.

A knee joint corticosteroid injection is given to reduce the right knee pain and swelling. She is commenced on methotrexate.

Methotrexate is regarded as the first-line option to treat rheumatoid arthritis as it has the strongest evidence of efficacy of the conventional DMARD medications. While awaiting the effect of methotrexate (onset of action is typically six to eight weeks), she develops left knee swelling, bilateral wrist synovitis and right shoulder pain. Treatment is escalated to include low-dose prednisone (10mg daily) and hydroxychloroquine 200mg daily.

Her rheumatoid arthritis never really settles and eight months after starting DMARD therapy, consideration is given to starting a biologic medication.

There are now 10 PBS listed biologic DMARDs/targeted synthetic DMARDs for rheumatoid arthritis.

So which is the “best” biologic agent for her?

There are very few head-to-head trials comparing the different biologic DMARDs.  The highest response rates are generally seen with the first biologic, regardless of which one is used. The response rates for a second line agent is much lower if there has been an inadequate response to the first biologic.

Rheumatologists vary widely in their choice and rationale on which biologic agent they use.  Familiarity, habit, interest in trying new agents and interpretation of clinical trial results and safety may affect the decision. There is no “right answer” for this question. I take patient concerns and preferences into account and make a collaborative decision with the patient.

These are my considerations for the different groups of medications.

TNF inhibitors

These were the first biologic medications approved and have an excellent long-term safety record and proven efficacy.  Tuberculosis reactivation is a concern and this needs to be screened prior to commencing.  There are five different products approved – etanercept (weekly injection), adalimumab (fortnightly injection), certolizumab (fortnightly injection, although can also be given monthly), golimumab (monthly injection) and infliximab (intravenous infusion in a hospital setting).

Tocilizumab (IL-6 inhibitor) is given as a once weekly injection and less frequently as a monthly IV infusion.  It has excellent efficacy data for use in monotherapy (ie. without methotrexate) and thus can be a good choice if a patient is intolerant to methotrexate.  Tocilizumab usually suppresses both CRP and ESR to the normal range and these markers are not reliable ways to monitor disease activity or to detect infection.

Rituximab (CD-20 inhibitor) is given as two infusions spaced a fortnight apart and can be repeated at a minimum of every six months. It can only be administered in a hospital due to the risk of infusion reactions. Methotrexate must also be used and rituximab has good evidence in seropositive disease (RF and CCP positive).

Abatacept inhibits co-stimulatory activation of T cells.  It is usually given as a weekly injection.  There is better data in seropositive disease and it has excellent safety record and appears to have a low risk of infection. This may be useful is patients who have high infection risk, such as recurrent urinary tract infection or bronchiectasis

JAK-inhibitors 

These are the “new kids on the block” and are targeted synthetic DMARDs rather than “biologics” as they are not monoclonal antibodies.  There are three licensed products in Australia – tofacitinib, baricitinib and upadacitinib.

At the time of writing, only the first two are PBS subsidised. These medications are oral tablets and are generally well tolerated. Oral medication may suit those who are needle phobic or those who travel a lot as the logistics of carrying injections pens can be avoided.

There is a higher rate of shingles, which may be of concern in the older age groups.  Tuberculosis reactivation can also occur. This group can be used without methotrexate.

There are multiple other JAK inhibitors in the pipeline and this group looks set to be a significant part of RA management in the future.

Dr Andrew Jordan is a rheumatologist based in Paramatta, Sydney, with a special interest in inflammatory arthritis, gout and osteoporosis