Over the past two decades, the emergence of targeted therapies has revolutionized the management of rheumatoid arthritis (RA). Tumor necrosis factor inhibitors (etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol), anti-CD20 monoclonal antibodies (rituximab), T-cell costimulation inhibitors (abatacept) and anti-interleukin-6 receptor antibodies (tocilizumab and sarilumab) have all shown efficacy in the management of RA.
However, despite this success, around 30–40% of patients fail to respond adequately to their first line of targeted therapy, with the chance of an adequate response to subsequent targeted therapies declining sequentially when compared with treatment naïve patients.
An observational longitudinal cohort study of RA patients treated with biologic DMARDs (bDMARDs) showed a 1-year retention rate of 68%, with only 9% of patients remaining on a single biologic drug for 10 years. Furthermore, a literature review has stated that of those patients who did respond to a bDMARD therapy, around 20% lost their response to treatment within 2 years of beginning therapy.
As a result there is now a growing cohort of patients who have failed multiple targeted therapies. Refractory, or difficult to treat, RA is therefore emerging as an area of unmet need in the targeted therapy era. At present there is no agreed definition for refractory RA, but failure to respond to two conventional synthetic (cs) DMARDs and two or more targeted therapies or failure to respond to both an anti-cytokine treatment and a cell-targeted treatment have been postulated.
Recently the RA treatment armamentarium has been augmented by the introduction of the Janus kinase (JAK) inhibitors tofacitinib and baricitinib. Both have shown efficacy in phase III clinical trials as first line targeted therapies in patients with RA. Both tofacitinib and baricitinib have also shown efficacy in patients who have previously had an inadequate response to bDMARDs.
Below, we present the case of a patient with biologic refractory RA who has responded to treatment with tofacitinib as her sixth line targeted therapy.
We present the case of a 75-year-old female who was originally diagnosed with seropositive RA aged 46 years. Her relevant past medical history includes a thyroidectomy for hyperthyroidism in 1967, and a history of peptic ulcer disease. She was diagnosed with monoclonal gammopathy of unknown significance in 2006.
Her RA was initially managed with steroids and gold injections, but gold was stopped due to the development of a rash. She subsequently failed a number of conventional synthetic (cs)DMARDs including methotrexate, cyclosporine, azathioprine, and sulfasalazine due to a combination of nausea, anorexia, and malaise. As a result, she had been managed with maintenance prednisolone at doses varying between 5 mg and 15 mg per day. In 2001 she was treated with leflunomide, with an initial good response, but by 2003 she developed severely active disease despite 20 mg leflunomide and 15 mg oral prednisolone daily. Her DAS28-CRP score at this time was 5.4.
Due to her high disease activity and resistance to csDMARDs, she was commenced on etanercept 25 mg twice weekly in September 2004. She had an initial improvement in DAS28 to 3.13, but developed secondary loss of response within 1 year. In 2006 she had a primary non-response to treatment with adalimumab. She was treated with rituximab in combination with leflunomide as part of a clinical trial in 2006, but lost response and developed hypogammaglobulinemia after 3 cycles.
She subsequently commenced treatment with intravenous tocilizumab 8 mg/kg every 4 weeks. She responded well to tocilizumab and maintained a response for a number of years before developing a secondary failure in early 2017. She was subsequently treated with abatacept but had no improvement in her inflammatory arthritis and developed cellulitis and mouth ulcers, so this was stopped.
In late 2017 she presented once again with severe active RA. She had significant pain and swelling in both hands, both wrists and both elbows. She felt fatigued and systemically unwell.
Clinical examination revealed synovitis across all of the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of both hands, both wrists, both elbows, and an effusion in her left knee. She was pale, but her systemic examination was otherwise unremarkable. Disease activity assessment revealed a tender joint count (TJC) of 26, a swollen joint count (SJC) of 25, and a VAS of 100/100. Her inflammatory markers were elevated, with a C-reactive protein (CRP) level of 56 mg/L . This gave her a DAS28 score of 8.07 suggesting severe RA disease activity. Her other blood tests were unremarkable, other than a hemoglobin level of 92 g/L.
The patient commenced treatment with tofacitinib 5 mg twice daily in combination with 10 mg prednisolone. She had a rapid improvement over the course of the next few weeks. She suffered from side effects of nausea for the first 4 weeks, but this subsided without intervention. After 8 weeks of treatment she developed a lower respiratory tract infection and required a course of oral antibiotics, and a 2 week pause in treatment. She was able to restart tofacitinib after 2 weeks without further complications.
Outcome and follow-up
After 3 months of treatment the patient’s arthritis had improved significantly. She felt systemically well. Steroids had successfully been weaned down to 5 mg daily. There was continued evidence of synovitis in the MCP and PIP joints, but this was much improved. Her CRP had reduced to 19 mg/L and her DAS28 score had improved to 5.54 (TJC: 9; SJC: 9; VAS: 70; CRP: 19). At 6 months, her DAS28 was 3.83 (TJC: 3; SJC: 2; VAS: 40; CRP: 12.6).
She had another brief pause in her treatment in order to undergo an orthopedic procedure on the extensor tendons on her right hand.
Her last clinic appointment was after 14 months of treatment with tofacitinib. On this occasion, she had no tender or swollen joints and her CRP was normal. Her DAS28 score was 1.77, meeting the criterion for clinical remission.
We have presented the case of a patient with longstanding RA, who had been exposed to, and ultimately failed, multiple csDMARDs and bDMARDs. Despite this she responded well to treatment with the JAK inhibitor tofacitinib, as her sixth line targeted therapy.
This case highlights a number of issues in the management of patients with refractory RA. It suggests that treatment with JAK inhibition has the potential to be efficacious in patients who have tried and failed a number of previous bDMARDs.
JAK inhibitors have a downstream effect on multiple cytokines in all cell types, rather than on one single cytokine, and therefore may have the potential to avoid some of the effects of cytokine redundancy, where several cytokines perform similar roles in inflammatory disease. This could give them a unique role in management of complex, advanced RA.
Furthermore, despite that fact that it is well established that early intervention with aggressive treat-to-target strategies is the best way to achieve remission, patients with longstanding RA still have the potential to achieve good results on targeted therapy.
Written informed consent was obtained from the patient for publication of this case report
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