Sustained benefit from early RA treatment with multiple DMARDs

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Sustained benefit from early RA treatment with multiple DMARDs

Jul 29, 2004 Janis

Tampere, Finland - " Early, aggressive treatment with a 3-drug DMARD regimen

significantly retards joint damage (vs a single DMARD), and this advantage

persists even when many of the original single-drug patients switch to

combination DMARDs after 2 years, " Dr Markku Korpela tells rheumawire.

Korpela and colleagues in the Finnish Rheumatoid Arthritis Combination

Therapy (FIN-RACo) study report 5-year follow-up data in the July 2004 issue

of Arthritis & Rheumatism [1].

Starting combo DMARDs early provides lasting joint protection

Early, aggressive treatment with a 3-drug DMARD regimen significantly

retards joint damage . . . and this advantage persists even when many of the

original single-drug patients switch to combination DMARDs after 2 years.

" The results of the FIN-RACo trial showed that radiologic progression during

the first 2 years as significantly reduced not only in peripheral joints but

also in the cervical spine of patients treated according to the combination

[DMARD] strategy compared with those treated according to the single [DMARD]

strategy. The results of the present follow-up study demonstrate

convincingly that radiologic progression continued to be significantly

retarded (actually by 33%) at 5 years in RA patients originally allocated to

the combination strategy, compared with those treated according to the

single strategy, despite the lifting of restrictions on DMARD treatment

after 2 years, " Korpela et al write.

The FIN-RACo study is a prospective, randomized trial comparing the efficacy

and tolerability of a combination of 3 DMARDs with that of DMARD monotherapy

in patients with early active RA. The 2-year follow-up study comprised 178

patients. " The main purpose of this study was to determine whether the

relatively high frequency of remissions and slower deterioration of joint

damage obtained by the combination therapy at 2 years were sustained despite

the unrestricted choice of drug therapy thereafter, " Korpela writes.

The trial enrolled DMARD-naïve patients with RA symptom duration of less

than 2 years (median 6 months). Patients were randomized to a single DMARD

(initially, sulfasalazine with or without prednisolone) or to simultaneous

sulfasalazine, methotrexate, and hydroxychloroquine, with prednisolone. None

of the patients in this study were taking biologicals such as

tumor-necrosis-factor (TNF) inhibitors.

" In Finland, we use biologicals like infliximab when combination DMARDs

[such as those used in FIN-RACo study] are ineffective and polyarthritis is

active [there are at least 6 tender and swollen joints, and acute-phase

reactants are elevated], " Korpela explains.

Patients continued treatment as assigned in these 2 parallel groups for 2

years, after which choice of treatment was unrestricted. Treatment was

allowed to be tapered for patients in remission. Clinical activity was

determined by the Disease Activity Score in 28 joints (DAS28). Hands and

feet were radiographed yearly and scored according to the Larsen method.

Remission was defined according to American College of Rheumatology (ACR)

criteria, excluding the criteria for fatigue. All 5 of the remaining ACR

criteria had to be fulfilled to meet the standard for remission.

Those starting combo DMARDs later never catch up

At 5 years, 9 of 87 patients who completed 2 years of treatment in the

" combined-DMARD " group and 9 of 91 patients in the " single-DMARD " group were

lost to follow-up, and Korpela presented data for 160 patients (78 in the

combination group and 82 in the single group).

As might be expected, after the 2 years of required treatment, most patients

in the combined-DMARD group continued combined treatments, but most of the

patients in the single group switched to a DMARD combination. " DMARD

treatment was free (unrestricted) after 2 years, ie, rheumatologists were

allowed to adjust medications to achieve remission. Of the original

combination group, 70 (90%) continued to receive combinations after 2 years,

and 51 of the 82 patients in the original single group (62%) received

combinations after 2 years, " Korpela says.

This did not, however, enable those who began with single-agent treatment to

make up for lost time. The increase in median Larsen score was significantly

slower during the first 2 years in the combination-DMARD patients and

remained " consistently lower " in those patients up to 5 years, despite the

fact that many of the patients in the comparison group switched to triple

DMARD regimens after year 2. According to Korpela, the expected rate of

spontaneous remission in untreated RA is about 14%, and the rate of

remission with conventional single-DMARD therapy is about 18%.

Radiologic damage in early RA (Larsen scores)

Time period Initial combined DMARDs Initial single DMARD p

Baseline 0 2 0.05

2 y 4 12 0.005

5 y 11 24 0.001

To download the table as a slide, click on slide logo at the bottom of this

page.

" In the present FIN-RACo study, the rate of remissions at 2 years was 40% in

DMARD-naïve patients with early RA treated with combinations of 3 DMARDs for

the first 2 years. However, the lifting of treatment restrictions after 2

years resulted in a decrease in the rate of remissions (28% at 5 years. . .

.. The results imply that the revocation of therapy with combinations of

DMARDs after 2 years was not prudent, since the high remission rate was

partly lost, " Korpela writes. " [T]he 'late' institution of DMARD

combinations (after 2 years from the time of diagnosis) does not increase

the rate of remissions in patients who are initially treated with a single

DMARDthat is, the therapeutic 'window of opportunity' appears to be lost in

most of these patients. "

Ordered logistic regression analyses showed that the extent of joint damage

in the hands and feet at 5 years was predicted most strongly by the presence

of serum rheumatoid factor at baseline (odds ratio 2.75) and by single-DMARD

treatment for the first 2 years (OR 2.53). " Despite aggressive treatment of

RA, rheumatoid factor still remained a very significant predictor of

radiologic progression at 5 years, " Korpela says.

Despite aggressive treatment of RA, rheumatoid factor still remained a

very significant predictor of radiologic progression at 5 years.

Korpela comments that the use of " new, very expensive " biologic

antirheumatic drugs has become routine over the past few years. " Prospective

studies comparing the effects, including the cost-effectiveness, of

combinations of traditional DMARDs with the effects of biologic drugs in

patients with early RA are urgently needed, " Korpela says.

Other unanswered questions include whether combination DMARDs should be

continued in patients in clinical remission and for how long and whether

there is a subgroup of patients who will need biologicals in addition to the

FIN-RACo DMARD combination in the early phases of RA.

" Our results suggest that 3-drug treatment should be started in most

patients with early RA at the time of diagnosis. However, if the DMARD

therapy can be started within 4 months from the first symptoms of RA, a high

proportion of remissions can be achieved also by single-DMARD therapy. If

the delay in the institution of DMARDs was more than 4 months, the high

proportion of remissions is achieved only by combination treatment

strategy, " Korpela tells rheumawire.