LEIDEN, The Netherlands—After the failure of initial methotrexate (MTX) in patients with recent-onset rheumatoid arthritis (RA), adding or substituting conventional DMARDs is unlikely to produce remission or to arrest joint damage in most patients, according to a post-hoc analysis of data from the BeSt study. Reporting in Annals of the Rheumatic Diseases, Sjoerd M. van der Kooij, MD, and colleagues suggest that adding or switching to a TNFα blocker would be a better second-line strategy.¹

"The most important finding of our study was that if patients do not respond to MTX 25 mg/week after 6 months, switching to or adding different traditional DMARDs [according to the protocol in the BeSt study] does not result in a DAS <e;2.4 in the vast majority [75% to 80%] of the patients. Other effective therapies should provide earlier and better responses in patients not responding to MTX," Dr. van der Kooij told CIAOMed.

Dr. van der Kooij is at Leiden University Medical in The Netherlands. The BeSt study was supported by the Dutch College for Health Insurance Companies, Schering-Plough Corp, and Centocor Inc.

32% have sustained remission with MTX alone…

This analysis included two of the four BeSt study groups. These patients began treatment with MTX 7.5 mg/week and increased to 15 mg/week after 4 weeks. Those who had DAS >2.4 after 3 months had MTX increased to 25 mg/week or to the highest tolerated dose. Those who continued to have DAS >2.4 were then switched either to sulfasalazine (2000 to 3000 mg/day) or to MTX plus sulfasalazine. Those switched to sulfasalazine monotherapy (Group 1) were then switched to leflunomide (Arava®, sanofi-aventis) 20 mg/day if DAS >2.4 was maintained; then to MTX plus infliximab (Remicade®, Centocor) 3 mg/kg to 10 mg/kg; to sodium aurothiomalate 50 mg/week plus depomedrol; to MTX, cyclosporine, plus prednisone; and finally to azathioprine plus prednisone. Group 2 had second-line MTX plus sulfasalazine; were then switched to MTX, sulfasalazine plus hydroxychloroquine; to MTX, sulfasalazine, hydroxychloroquine, plus prednisone; to MTX plus infliximab; to MTX, cyclosporine, plus prednisone; to leflunomide monotherapy; to sodium aurothiomalate plus depomedrol; and finally to azathioprine plus prednisone.

Twenty-one percent of patients achieved remission on MTX 15 mg/week after 3 months, and 44% achieved remission on MTX 15 mg/week to 25 mg/week after 6 months. At 2 years, 32% of patients were "MTX successes" with DAS <e;2.4 on MTX monotherapy. Mean doses for patients on MTX monotherapy dropped from 21.4 mg/week at 6 months to 11.2 mg/week at 24 months.

...but the other two-thirds need something other than conventional DMARDs

After 2 years, 66% of patients had discontinued MTX due to insufficient response or to toxicity. For most of these patients neither the Group 1 nor the Group 2 approach to subsequent therapy led to DAS <2.4. Disease activity remained at unacceptably high levels in 78% of those switched to sulfasalazine (either alone or added to MTX), in 87% switched to leflunomide, and in 64% switched to MTX, sulfasalazine, plus hydroxychloroquine. Seventy-one percent (34 of 48 patients) achieved DAS <e;2.4 when treated with MTX plus infliximab.

After 2 years, those who had not achieved remission on MTX monotherapy had significantly worse total Sharp/van der Heijde score (TSS) progression than those still on MTX monotherapy, regardless of what DMARD regimen they had been switched to (median TSS progression 3 units versus 1 unit, P = .007).
 
"In our opinion, patients who fail to respond to MTX need effective therapies as soon as possible. TNF blockers like infliximab have shown quick and sustained responses in MTX failures in various trials, and this treatment also proved more effective in patients who failed on multiple DMARDs in the BeSt trial, so our choice would be to add a TNF blocker to MTX. Possibly switching to a combination of DMARDs with corticosteroids might also give a quick good response, but this approach was not tested in our study," Dr. van der Kooij said.
 
The investigators had not expected that after 2 years, only 32% of patients would be successfully treated with MTX, or that the response to different traditional DMARDs after MTX failure would be only 20% to 25%.

"Observational studies have described higher retention rates of use of these DMARDs than what we found. We believe that such observations rest on the fact that the DMARDs are relatively well tolerated, and provided the expectations towards response are not high, they appear to have a reasonable effect. Our data suggest that after MTX failure, trying consecutive conventional DMARDs to achieve a good response is a waste of time [irrespective of the strategy chosen]. MTX failures need effective treatment quickly like the addition of TNF blockers, so first trying different traditional DMARDs is not the best choice for these patients," Dr. van der Kooij added.

For physicians whose national health insurance plans permit TNFα blockers only after trials of several DMARDs, Dr. van der Kooij does recommend a short course of combined DMARDs as second-line treatment "not because together they are more effective, but to save time in complying with ‘more than 1 DMARD tried' requirements."

Further support for first-line MTX?

"Our findings that significantly earlier and more clinical improvement with less joint damage progression can be achieved with initial combination strategies, have raised the question of whether MTX monotherapy is obsolete as initial treatment of patients with recent onset, active RA unless we are able to identify who will respond to MTX and won't need initial combination therapy," Dr. van der Kooij concluded.

Lee S. Simon, MD, disagreed. Dr. Simon is associate clinical professor of medicine at Harvard Medical School in Boston, Massachusetts, and is former director of the FDA's division of anti-inflammatory, analgesic, and ophthalmologic drug products.

"These data further solidify the importance of beginning with MTX, especially in these days of cost containment. Many patients get a good response to MTX as a first choice drug, in fact upwards of 30% get a DAS <2.4 suggestive of a clinical remission. This is very good," Dr. Simon commented. "But not good enough. The clinician needs to set up a system to allow for this type of aggressive monitoring. If the patient has not achieved a DAS <2.4 or so by 3 months, consider adding another drug. In the US that would most likely be today a TNFα inhibitor or abatacept [Orencia®, Bristol-Myers Squibb Co]. This is not true in Europe, where sulfasalazine is still often used in combination with MTX because cost is still such an important issue. And step-up is still considered okay, for cost reasons [in Europe] but not in the US."

However, Dr. Simon emphasized that if the patient has not achieved adequate disease control after 3 months with MTX alone, additive therapy is critical. "There are not enough data within this database about combining leflunomide with MTX in those patients, and in the US there are issues with liver function test monitoring in those patients, so again a biologic addition would be appropriate," Dr. Simon surmised. He might extend MTX alone beyond 3 months "if the patient seems to be improving" but would then switch to a TNFα inhibitor or abatacept. 


Table 1: BeSt Study Protocol for Patients With Persisting DAS >2.4

Group 1	Group 2
MTX ↓ Sulfasalazine ↓ Leflunomide ↓ MTX + infliximab ↓ Sodium aurothiomalate + depomedrol ↓ MTX + cyclosporine + prednisone ↓ Azathioprine + prednisone	MTX ↓ MTX + Sulfasalazine ↓ MTX + sulfasalazine + hydroxychloroquine ↓ MTX + sulfasalazine + hydroxychloroquine + prednisone ↓ MTX + infliximab ↓ MTX + cyclosporine + prednisone ↓ Leflunomide ↓ Sodium aurothiomalate + depomedrol ↓ Azathioprine + prednisone

Source: van der Kooij et al.¹

Table 2: Results at 24 Months

	MTX "success" (DAS <e;2.4)	MTX "failure" (DAS >2.4)	P
Patients	32% (n = 73)	66% (n = 140)
Median TSS progression	1	3	.007
Mean TSS progression	3	9	.007

*Patients switched to other DMARD regimens if DAS >2.4 after 3 months of MTX.

Source: van der Kooij et al.¹

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