Australian study fills evidence gap for MTX as steroid-sparing agent in PMR

The case for prescribing methotrexate (MTX) as a steroid-sparing agent in established Polymyalgia Rheumatica (PMR) has been bolstered with new Australian evidence showing it improves inflammatory markers and reduces prednisolone dose in some patients who were unable to wean corticosteroids.

A retrospective observational study looked at 70 patients attending two outpatient clinics in South Australia. Of these patients, 22 (31%) were prescribed MTX because of disease relapse (34%) or inability to wean prednisolone dose (66%) –  the mean disease duration at MTX initiation was 2.5 years. In some patients it was as long as seven years exposing patients to a host of harmful effects associated with long-term steroid use. At MTX initiation, median ESR was 33 (13-60 mm/hr) and CRP 19 (8-42 mg/L).

At six months after MTX initiation, investigators reported a significant reduction in ESR (p=0.012), CRP (p=0.0003) and prednisolone dose (p<0.0001). Meanwhile, 50% of patients were found to have stopped MTX – five due to controlled PMR, and six due to adverse effects.

Rheumatologist and study investigator Professor Catherine Hill from the University of Adelaide told the limbic that there is desperate need for alternatives to prolonged steroid use in PMR but  the condition has remained under-researched for decades.

Current European guidelines, which Australian practitioners follow, recommend methotrexate as a glucocorticoid-sparing agent in patients who relapse or suffer glucocorticoid adverse effects despite acknowledging there is no Level 1 evidence to support the recommendation. Evidence for the use of MTX in PMR comes from four existing RCTs that recruited patients with newly diagnosed PMR, explains Professor Hill.

But evidence from those studies is of limited use, she says, because MTX is not widely used in newly-diagnosed PMR.

Given the lag-period till onset of maximal MTX benefit – around three months – most clinicians are willing to try initial steroid monotherapy. It has been reported that around 30-45% of PMR patients can be managed successfully on glucocorticoids without relapse for the first year, so use of MTX in new onset PMR would expose some patients to unnecessary potential adverse effects and the inconvenience of MTX, she adds.

Furthermore, PMR is predominantly managed by GPs who don’t routinely refer patients with PMR to a rheumatologist unless there are atypical features or inability to wean glucocorticoids.

“The reality in Australia is that rheumatologists only really see PMR if patients don’t have an appropriate response to steroids or if they recurrently relapse and have been referred from a GP,” Professor Hill told the limbic.

As for when patients who can’t wean glucocorticoids should be started on MTX, Professor Hill says there no real evidence base for determining the optimum time.

“It’s really going to be related to the patient’s characteristics – if someone’s got diabetes and poor sugar control on their steroids or if someone’s got poorly controlled hypertension for instance and you want to get their steroids down I think those are the patients you’re going to start on steroid sparing agent earlier. Patients who continuously have two or more relapses are people you’re also going to think about trialling methotrexate.”

Commenting on the study findings Professor Hill concluded that: “combined with the data from existing randomised controlled trials I think our study, with all the caveats that with an observational study, does demonstrate benefit for methotrexate in this subset of patients who have established PMR and either can’t get off their steroids or relapse but we need a clinical trial in this setting.”

Such a trial would answer questions about optimal dosing, tailoring the therapy and understanding the risk-benefit profile, she added.

Rheumatologist and clinical pharmacologist at Austin Health in Victoria, Dr David Liew, who was not involved in the study, agrees there is a ‘massive gap’ in the evidence around MTX for PMR and describes the findings from the current study as ‘encouraging’.

“Most of us do this in practice and it’s encouraging to see this kind of data. At the same time we are all conscious that not everyone seems to respond to methotrexate in the same way and right now it’s hard for us to make a solid evidence-based case for steroid-sparing agents. It’s something that we really need to see tested in this disease relapsing population with a randomised trial.”

Guidelines recommend an initial dose of 15mg for three weeks, although some patients may require 25mg to alleviate symptoms, And while tapering regimens can vary greatly, most schedules involve a minimum of 46 weeks of prednisolone therapy, notes Dr Liew.

But for a lot of patients the clinical reality plays out very differently to those recommended schedules.

“We used to live with a fallacy that PMR was a self limiting condition, that everyone would get off steroids. We now know that’s not true,” says Dr Liew, who argues that at least a third of patients get stuck on steroids after several years.

“I think we’re going from a paradigm where we used to be happy maintaining patients on prednisolone indefinitely and I think that’s becoming increasingly unacceptable,” argues Dr Liew pointing to the increasing awareness of the dangers long-term steroid use even at low doses.

“I think that has been easy for us to ignore in the past – perhaps we’re still getting used to a world where we don’t give high dose steroids a lot of the time because in amongst that we’ve been slightly callous about giving low dose steroids and its’ only recently that we have started to understand that that’s not benign.

If you’re at the point where a patient is weaning off steroids and keeps flaring then that’s a clear sign that the status quo is unsustainable and those are the patients for which we really have to think about using methotrexate.”

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