Biologic refractory disease affects about 6% of patients with rheumatoid arthritis – with patients increasingly cycling through the available biologic disease-modifying antirheumatic drugs (bDMARDs).
Defining refractory disease from when patients commenced on a third class of bDMARD, the UK biologics registry study found 6% of 13,502 patients were refractory over 111,034 patient years of follow-up.
The study comprised patients starting on their first TNF inhibitor (TNFi) between 2001 and 2014.
Most were women with a median disease duration of 10 years and indicators of high disease activity and severity when they commenced their TNFi.
The study found, overall, patients with bDMARD refractory disease remained on their first TNFi for a median of 3.9 years, then shorter periods of time – 1.5 years – for their second and third class of bDMARDs.
The most common class-switching pathways were from TNFi to B-cell-targeted agents (almost exclusively rituximab) and then either to IL-6-targeted agent tocilizumab or T-cell costimulation blocker abatacept – ‘largely reflecting the order in which these drugs became available’.
Most bDMARD refractory patients (38%) reported use of four different agents, 20% had used five agents and 8% used at least six different bDMARDs.
Patients recruited more recently (2011-2014) were 15 times more likely to have refractory disease than those recruited earlier (2001-2008).
Smoking and BMI were identified as potentially modifiable risk factors for refractory disease.
Commenting on the study, Sydney rheumatologist Associate Professor Peter Youssef said the heterogeneity of rheumatoid arthritis and the lack of biomarkers explained the many drugs some patients were exposed to.
“Rheumatoid arthritis is probably not a single disease – so some patients need to try different drugs. Sometimes we cycle through these biologics in order to find the drug that attacks the correct driver in patients – and we may not get that first off.”
He said some patients also had persistent pain, which further encouraged trialling different drugs to find something that would help.
“Patients, particularly those with a lot of soft tissue rheumatism and fibromyalgia, are often very distressed with their pain.
“As a rheumatologist, we always have to keep in mind whether their ongoing pain is due to inflammation or not. Because it is very rare that these drugs don’t control the inflammation.”
“And sometimes those patients will do well with physical therapies, replacing joints or simple analgesics that may help with pain rather than actually increasing the anti-inflammatory therapy or immunosuppression.”
He added that psychological support and antidepressant therapy may also play a role when a pain syndrome rather than active inflammation was at play.
Associate Professor Youssef agreed with the study authors that other basic strategies such as smoking cessation were important.
“We do know our drugs work less in patients who are smokers. And I’ve had several patients who have failed biological therapy and when they have stopped smoking they have responded, because it affects the metabolism of the drugs.”
The UK study authors said that quantifying the frequency of multiple bDMARD class failure was crucial, “particularly in an environment where bDMARD choice is largely based on custom and experience rather than by individual biomarkers.”
“As response to subsequent bDMARDs is known to reduce, targeted personalised pathways are important to identify. This knowledge can therefore drive clinical guideline development as well as inform cost-effectiveness analyses,” they wrote.