New Treatment Strategy for RA: Combo Therapy Lite

Last week's articles on rheumatology topics in the major non-rheumatology journals.

Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trialLancet, October 26, 2013

Biological treatment in rheumatoid arthritis: when to stop?Lancet, October 26, 2013

For patients with early rheumatoid arthritis (RA), a reasonable strategy might be to induce stable, low disease activity for six months with adalimumab (Humira) plus methotrexate, then withdraw adalimumab and continue with methotrexate monotherapy.

The OPTIMA trial was a two-stage study in which 1,032 patients were randomized to methotrexate monotherapy or adalimumab plus methotrexate combination therapy.

Patients treated initially with combination therapy were nearly twice as likely to achieve the target low disease activity than patients treated with methotrexate monotherapy.

At the end of 26 weeks, those patients who achieved stable low disease activity on combination therapy were again randomized into methotrexate monotherapy or combination therapy. After adalimumab withdrawal, the methotrexate monotherapy group did about as well as the group that continued combination therapy, by the end of 78 weeks.

This result was noteworthy because withdrawal of tumor necrosis factor inhibitor results in reactivation of the disease in patients with established RA.

Also at the end of 26 weeks, those patients who had started on methotrexate monotherapy without stable low disease activity were switched to combination therapy. Their results were about the same as those for patients who were originally assigned to combination therapy.

A commentary observed that the OPTIMA trial was not a pure test of methotrexate monotherapy; more than 40% of patients had been treated with glucocorticoids, which were continued during the trial.

The commentators recommend their own practice of methotrexate plus glucocorticoids, with biological modifiers only when needed, and only until stable low disease activity is reached.The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: propensity score matched landmark analysisBMJ, October 30, 2013

Patients with moderate to severe hip or knee osteoarthritis (OA) who had total joint arthroplasty had a lower risk of cardiovascular disease than a matched set of patients who did not have arthroplasty, with a hazard ratio of 0.56.

In a seven-year followup, the absolute risk reduction was 12%.

The entire population of two areas of Ontario, Canada was screened to identify those with hip or knee problems.

A total of 2,200 patients had confirmed hip or knee OA and of these, 173 had hip or knee arthroplasty while 153 were matched by propensity score.


Immune-Mediated Pore-Forming Pathways Induce Cellular Hypercitrullination and Generate Citrullinated Autoantigens in Rheumatoid ArthritisSci Transl Med, October 30, 2013

Poking Holes in Rheumatoid JointsSci Transl Med, October 30, 2013

Researchers have found a second, more widespread mechanism of citrullination in rheumatoid arthritis (RA).

The calcium-dependent enzyme peptidyl arginine deiminase (PAD) converts the amino acid arginine to citrulline. RA patients have autoantibodies to PAD which activate PAD by lowering its calcium threshold.

Researchers have found another mechanism, termed hypercitrullination,  that is active in the neutrophils, monocytes, and macrophages of the RA joint.

In a cell-death process, lymphokine-activated killer cells secrete the pore-forming protein perforin, which inserts itself into the membranes of dying neutrophils and creates pores that allow the influx of calcium.

This calcium activates PAD to citrullinate even more proteins than are created by the autoantibody mechanism. The researchers found that the complement membrane attack complex, which also generates pores, similarly allows the influx of calcium and activates PAD.

These citrullinated autoantigens were characteristic of RA.