Methotrexate and TNF Combo May Be Worthwhile for Biologic-Naïve RA Patients

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Adding methotrexate to a tumour necrosis factor inhibitor benefits patients with rheumatoid arthritis who have not received biologic treatment previously, but makes little difference to outcomes in patients who have previously used a biologic, a study published by the online journal Medicine in May suggests.

Combining methotrexate with a tumour necrosis factor inhibitor has been shown to have both short and long term benefits for patients with early rheumatoid arthritis, including reduced radiographic progression, and The American College of Rheumatology 2015 guidelines on rheumatoid arthritis recommend biologic therapy is combined with methotrexate because the combination has superior efficacy to monotherapy. 

However, Marc Schmalzing of the department of rheumatology/clinical Immunology at University Hospital Würzburg, Würzburg, Germany points out that randomized trials on the benefit of concomitant methotrexate  over TNF inhibitor monotherapy have focused on patients with early rheumatoid arthritis and that the benefits of the combination have been less well studied in patients with long-standing disease.

Schmalzing and colleaguescombined data from two large studies conducted in Germany in which a total of 2654 patients were given the TNF inhibitor adalimumab with or without methotrexate to treat rheumatoid arthritis during routine clinical practice between 2003 and 2013. Mean doses of methotrexate given in the study ranged from 11.3 to 15.6mg per week.

Just over a quarter of the patients (28%) had been treated with biologic therapy previously, and 72% were biologic naïve. The most common previous biologic therapies were etanercept (68%) and infliximab (40%), and some patients had received more than one.

Patient outcomes were assessed using the Disease Activity Score-28 joints (DAS28) and patient-reported outcomes – the patient global assessment of health (PGA) and a pain scale.

Improvements in patient outcomes were seen in all patient groups following initiation of adalimumab, but improvements were far greater the group where adalimumab was combined with methotrexate in patients who had received no previous biologic treatment. In biologic naïve patients, adding methotrexate to continuous adalimumab was associated with significantly greater improvements in DAS28, PGA, and pain at month 12 compared to continuous adalimumab alone (P= 0.0006, 0.0031, and 0.0032, respectively).

In patients previously treated with a biologic, the addition of methotrexate was associated with statistically significant benefits only for reducing pain.

To further assess whether the addition of methotrexate was associated with benefit in patients with no prior exposure to biologics compared to those with previous exposure, the researchers performed subgroup analyses to look at the outcomes at 12 months in patients in whom methotrexate had been added or stopped at 6 months.  In these analyses patients served as their own controls, thus eliminating confounding factors.  Although the subgroups were small the analyses supported the overall finding that adding methotrexate was beneficial; biologic-naïve patients started on adalimumab alone showed improvement in DAS28 if methotrexate was added at six months, whereas removal of methotrexate was associated with significant worsening of DAS28.

The researchers conclude that their study strongly supports the use of continuous methotrexate alongside adalimumab in patients who have not received previous biologic therapy.

“Although initial administration of combination therapy is optimal, the addition of methotrexate at a later time point results in statistically significant improvements in outcomes in biologic-naive patients,” writes Schmalzing. “On the contrary, if these patients stop methotrexate comedication, it is important to be aware that they may lose some disease control.”

The study found no significant improvement in DAS28 or PGA when concomitant methotrexate was given adalimumab in patients who had received prior biologic therapy. “There were some benefits on pain and modest improvement in other parameters that may have had clinical significance to individual patients,” Schmalzing says, so the findings “should be used to help inform the patient/provider decision” on whether to add methotrexate.

“The data from this observational study support an interesting hypothesis concerning reduced methotrexate activity in patients treated with prior biologics, but randomized trials will be required to confirm this finding,” he emphasises.  He points out that, as the study was not randomized, the decision on whether to add concomitant methotrexate was likely to be influenced by patient characteristics as well as physician and patient preferences, reflecting real-world clinical care.

It was “likely” that their findings on the use of methotrexate with adalimumab could be extrapolated to its use with other TNF inhibitors, but again studies will be required to confirm this, he says.

SOURCES

Schmalzing M, Behrens F, Schwaneck EC, Koehm M, Greger G, Gnann H, Burkhardt H, Tony HP. Does concomitant methotrexate confer clinical benefits in patients treated with prior biologic therapy? Analysis of data from a noninterventional study of rheumatoid arthritis patients initiating treatment with adalimumab. Medicine 2020;99:19(e20201).

American College of Rheumatology guidelines for the treatment of rheumatoid arthritis. 2015