Manchester — Two-thirds of patients with rheumatoid arthritis (RA) who previously reached sustained disease control on tumour necrosis factor inhibitors (TNFi) maintain disease control for 1 year after tapering of dosage, and one-third maintain control for 3 years, according to the longest-term data available to date.
Tapering was more successful among patients concurrently taking methotrexate, who had a 40% reduction in the likelihood of tapering failure, according to researchers presenting their results to the British Society of Rheumatology conference in Manchester Monday.
However, the researchers, led by Dr May Nwe Lwin from University Hospital Southampton NHS Foundation Trust, noted that around one third of those who fail TNFi tapering do not return to remission or low disease activity when the full dose of TNFi is restarted, according to the 1-year follow up.
Tapering TNF Inhibitors is 'Well Accepted' by 20% of Patients
Co-researcher, Christopher Edwards, consultant rheumatologist at the University Hospital Southampton NHS Foundation Trust, told Medscape News UK: "There is good reason to try to reduce therapies to the lowest effective dose if possible. However, the trade-off might be a higher risk of flare."
"In the real-world setting, tapering of TNF inhibitors is well accepted and occurred in around 20% of individuals, with one third still maintaining remission at 3 years," Dr Lwin pointed out.
Tapering when patients have sustained disease control is supported by international recommendations, and there are economic and safety benefits, noted Dr Lwin. However she added that it ran the risk of loss of disease control, with subsequent damage to the patient.
She said that longer-term studies – lasting over 2 years – were needed to understand more about tapering strategies because most trials to date have only lasted for 12 or 18 months.
Consequently, Dr Lwin and her colleagues aimed to explore the longer-term use of tapering strategies.
Tapering Failed in 74% Patients
Drawing on the University of Southampton biologics database that comprises information since 2005, Dr Lwin sourced data on a total of 1180 patients on biological therapies, 668 of whom received a TNFi (adalimumab, infliximab, etanercept, golimumab, certolizumab, or other). Of these, 18% had undergone dose tapering by one-third and then 30% of these had their dose tapered to 50% once sustained remission was demonstrated (DAS28<2.6 on two occasions over 6 months apart, without corticosteroids). If a flare occurred (DAS28>2.6, power doppler synovitis, or patient reported flare), then patients returned to full dose.
A failure of tapering was defined as a flare resulting in return to full dose TNFi, stopping the TNFi, or changing to another advanced therapy. Dr Lwin explored the associations between the time spent on dose reduction therapies and individual characteristics.
Tapering failed in 74% of patients at a median time of 2.2 years.
"Around one third of patients failed tapering within the first year and around two-thirds by 3 years, before a slower decline," she reported. "Unfortunately, there are no parameters to predict tapering success or failure yet."
Association with Use of Methotrexate
No significant effect was seen between tapering success and age, sex, time between diagnosis and TNFi start, seropositivity, smoking and DAS28 score.
"However, we did find a significant association between the concomitant use of methotrexate and reduced likelihood of tapering failure, with a hazard ratio of 0.60 [95% CI: 0.39 to 0.94; P=0.03]."
Dr Lwin and her co-researchers also wanted to know what happened after tapering ended, so monitored the DAS28 score in patients at 3, 6, and 12 months after tapering was finished, when data from 68 patients (of a total of 88 who failed tapering) were available for analysis.
"There were no patients with severe disease activity after 1-year of follow up. Around 50% were in complete remission, but there was a downward trend with increasing time [after end of tapering], with 57% in remission at 3 months after tapering ended, 51% at 6 months, and 47% at 12 months," she said.
"Around 30% had moderate disease activity after 3-12 months, and they did not return to remission or low disease activity after tapering failure," she added.
Which Therapies Should be Tapered First?
Moderator, Dr Kenneth Baker, honorary consultant rheumatologist at Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust, asked Dr Lwin about the order of tapering – whether it was preferable to taper the TNFi or the DMARD first? "Previous EULAR guidance says we should taper biologics first then follow with conventional synthetic drugs, but this has changed recently to allow the physician and patient to make their own joint decision. What does your evidence suggest is best for the patient, given that it appears to be beneficial to have some methotrexate in the background during tapering?"
Dr Lwin replied: "We try to dose taper the anti-TNF inhibitor first because of the safety profile and because of the cost-effectiveness too." Professor Edwards added: "The most common approach in Europe has been to taper the biological therapy first. Interestingly, the ACR [American College of Rheumatology] suggests reducing the csDMARD such as methotrexate first. Our approach was to taper the biological therapy first."
Dr Baker also raised the point about communicating the risk associated with tapering failure to the patient. "The conversation about how, after tapering failure, there is an unquantifiable risk of not retaining the remission and not going back to the treatment success achieved previously, must be difficult because we don’t have biomarkers that predict who will have high risk of flare after tapering. It's hard to say to a patient we don't know what their risk of flare and impact of flare actually is."
"We have a thorough discussion about whether to increase the dose, but we always follow up our tapered patients closely to check their disease activity, and restart TNFi therapy quickly if needed," said Dr Lwin.
Stephanie Butler, lead specialist rheumatology pharmacist, University Hospitals Sussex NHS Foundation Trust, said that there are lots of benefits in tapering TNFi for patients. "There are fewer injections, lower immunosuppressive burden, comfort and convenience, but there is some risk, especially in a well-controlled patient," she remarked.
"Particularly with adalimumab there's a risk of making antibodies to the drug if patients stop and restart, so we always tell patients it's a long-term treatment, and if it goes well we might lengthen the interval between injections, but might not stop the drug. From experience we know patients who stop can flare, and disease returns, and when they restart they don't do so well."
Dr Lwin has no relevant conflicts to declare. Prof Edwards declares: Member of speakers’ bureau; Abbvie, Astra Zeneca, BMS Celltrion Chugai, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sandoz, Samsung. Grants/research support; Abbvie, Astra Zeneca, BMS Celltrion Chugai, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sandoz, Samsung. Other; Advisory boards: Abbvie, Astra Zeneca, BMS Celltrion Chugai, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sandoz, Samsung. Dr Baker has a research consultancy agreement with Modern Biosciences, KB has received clinical improvement grant funding from Pfizer, and research support from Genentech, inventor on drug-free remission biomarker International Patent Application by Newcastle University. Ms Butler declares financial conflicts with Lilly, Galapagos, and Janssen.