Probable RA Treated With Methotrexate or Placebo
The PROMPT study, a randomised clinical trial in patients with UA, was set up to establish whether very early treatment with MTX could induce drug-free remission or prevent progression to RA (1987). Early study results showed that MTX can postpone progression from UA to RA and suppresses radiological damage progression, in particular in ACPA-positive patients. In this study we have found that after 5 years there is little lasting benefit of early MTX treatment. Overall, patients with UA treated with MTX did not achieve more DFR, did not progress less often to RA (1987) and had comparable damage progression compared with patients with UA who initially were treated with placebo. Only in ACPA-positive patients did initial MTX postpone progression to RA (1987). These results indicate that early treatment with MTX is ineffective in altering the disease course of UA. This may be owing to inefficacy of the drug, duration of treatment, characteristics of the targeted illness, inadequate timing of treatment, or all of the above.
MTX may be seen as the cornerstone of antirheumatic treatment, yet MTX monotherapy as initial treatment in patients with RA is often inferior to initial combination treatment with corticosteroids or biological DMARDs. It may be that such initial combination treatment in our population would have been more successful in altering the disease course than MTX monotherapy. It is also possible that discontinuation of MTX after 1 year was too soon, but longer treatment cannot be seen as induction therapy, which was the target of the PROMPT study.
The finding that initial treatment with MTX delayed progression to 1987 classifiable RA only in ACPA-positive patients suggests that the effect of treatment may depend on the type of illness presenting as UA. We found that ACPA and RF are independent predictors for disease progression to RA (1987) after 60 months. Time to progress to RA (1987) was significantly shorter in ACPA-positive patients than in the ACPA-negative patients. Absence of ACPA was the only independent predictor of drug-free remission after 5 years. ACPA-positive patients showed more radiographic progression, despite the fact that having progressed to classifiable RA many started treatment with open-label MTX, after which damage progression was suppressed. Overall, we found no difference in radiographic progression between the MTX- or placebo-treated groups. These results suggest that ACPA-positive and ACPA-negative early arthritis are different disease entities, which may require different treatments. In addition, the persistence of remission in the majority of ACPA-negative patients (also those treated with placebo) suggests that these had a temporary disease, which could not be identified at presentation, by symptom duration or characteristics other than ACPA status.
It might be that we started initial treatment with MTX too late. We included and treated patients who were at the time considered to have UA, but who now would be classified as RA, based on the 2010 classification criteria for RA. In retrospect, 43 patients (39%) of the patients included as UA fulfilled the 2010 ACR/EULAR criteria at baseline, 23 of whom were ACPA positive. It is possible that for these patients the opportunity to achieve a change in the disease course by whatever treatment, might already have been lost. On the other hand, the new criteria may also misclassify some patients as having RA, and lead to overtreatment. Twenty-four of the 43 patients fulfilling the 2010 criteria were randomised to initial placebo treatment, and six of those 24 achieved clinical remission. This means that, had we started MTX in all patients who fulfilled the 2010 criteria, we would have overtreated these six patients (25%). We also started MTX treatment in 36 patients who in retrospect did not fulfil the 2010 classification criteria, which may also qualify as overtreatment. Of these patients, 13 did progress to RA (1987), which more effective treatment might have prevented.
In summary, in this randomised clinical trial comparing the outcomes after 5 years of initial MTX treatment and placebo in patients with UA, there is no lasting effect of MTX treatment given in the first year. A positive ACPA status and radiological damage at baseline are independent predictors for progression to RA and a negative ACPA status is a predictor for DFR. The observed rate of spontaneous remission, particularly in the ACPA-negative patients, demonstrates that initiation of MTX treatment in all patients who fulfil the 2010 ACR/EULAR criteria would constitute overtreatment in 25% of patients. On the other hand, mostly in ACPA-positive patients, initial MTX monotherapy is insufficient to prevent disease progression. Further research should focus on early and correct recognition of RA, as well as identifying a treatment that might truly alter the disease process.
Discussion
The PROMPT study, a randomised clinical trial in patients with UA, was set up to establish whether very early treatment with MTX could induce drug-free remission or prevent progression to RA (1987). Early study results showed that MTX can postpone progression from UA to RA and suppresses radiological damage progression, in particular in ACPA-positive patients. In this study we have found that after 5 years there is little lasting benefit of early MTX treatment. Overall, patients with UA treated with MTX did not achieve more DFR, did not progress less often to RA (1987) and had comparable damage progression compared with patients with UA who initially were treated with placebo. Only in ACPA-positive patients did initial MTX postpone progression to RA (1987). These results indicate that early treatment with MTX is ineffective in altering the disease course of UA. This may be owing to inefficacy of the drug, duration of treatment, characteristics of the targeted illness, inadequate timing of treatment, or all of the above.
MTX may be seen as the cornerstone of antirheumatic treatment, yet MTX monotherapy as initial treatment in patients with RA is often inferior to initial combination treatment with corticosteroids or biological DMARDs. It may be that such initial combination treatment in our population would have been more successful in altering the disease course than MTX monotherapy. It is also possible that discontinuation of MTX after 1 year was too soon, but longer treatment cannot be seen as induction therapy, which was the target of the PROMPT study.
The finding that initial treatment with MTX delayed progression to 1987 classifiable RA only in ACPA-positive patients suggests that the effect of treatment may depend on the type of illness presenting as UA. We found that ACPA and RF are independent predictors for disease progression to RA (1987) after 60 months. Time to progress to RA (1987) was significantly shorter in ACPA-positive patients than in the ACPA-negative patients. Absence of ACPA was the only independent predictor of drug-free remission after 5 years. ACPA-positive patients showed more radiographic progression, despite the fact that having progressed to classifiable RA many started treatment with open-label MTX, after which damage progression was suppressed. Overall, we found no difference in radiographic progression between the MTX- or placebo-treated groups. These results suggest that ACPA-positive and ACPA-negative early arthritis are different disease entities, which may require different treatments. In addition, the persistence of remission in the majority of ACPA-negative patients (also those treated with placebo) suggests that these had a temporary disease, which could not be identified at presentation, by symptom duration or characteristics other than ACPA status.
It might be that we started initial treatment with MTX too late. We included and treated patients who were at the time considered to have UA, but who now would be classified as RA, based on the 2010 classification criteria for RA. In retrospect, 43 patients (39%) of the patients included as UA fulfilled the 2010 ACR/EULAR criteria at baseline, 23 of whom were ACPA positive. It is possible that for these patients the opportunity to achieve a change in the disease course by whatever treatment, might already have been lost. On the other hand, the new criteria may also misclassify some patients as having RA, and lead to overtreatment. Twenty-four of the 43 patients fulfilling the 2010 criteria were randomised to initial placebo treatment, and six of those 24 achieved clinical remission. This means that, had we started MTX in all patients who fulfilled the 2010 criteria, we would have overtreated these six patients (25%). We also started MTX treatment in 36 patients who in retrospect did not fulfil the 2010 classification criteria, which may also qualify as overtreatment. Of these patients, 13 did progress to RA (1987), which more effective treatment might have prevented.
In summary, in this randomised clinical trial comparing the outcomes after 5 years of initial MTX treatment and placebo in patients with UA, there is no lasting effect of MTX treatment given in the first year. A positive ACPA status and radiological damage at baseline are independent predictors for progression to RA and a negative ACPA status is a predictor for DFR. The observed rate of spontaneous remission, particularly in the ACPA-negative patients, demonstrates that initiation of MTX treatment in all patients who fulfil the 2010 ACR/EULAR criteria would constitute overtreatment in 25% of patients. On the other hand, mostly in ACPA-positive patients, initial MTX monotherapy is insufficient to prevent disease progression. Further research should focus on early and correct recognition of RA, as well as identifying a treatment that might truly alter the disease process.