Drug Therapy in Undifferentiated Arthritis
Drug Therapy in Undifferentiated Arthritis
This systematic literature review shows that to date, few placebo-controlled RCTs have been done to answer the question if early treatment in patients with UA is beneficial and which treatment might be the best. To compare results is difficult because of inconsistent outcome measures. Five clinical trials, two open-label studies and four observational studies suggest that starting treatment early may provide symptom relief, improve functional ability and suppress radiological progression. It may also postpone progression to classifiable RA or the need for other therapies. The strongest evidence of a potential benefit is present on early treatment with MTX, possibly in combination with other DMARDs or corticosteroids. Observational studies, which by using propensity scoring and minimal structural models try to partially compensate for indication bias, suggest that other DMARDs than MTX may be used. Data from these cohorts also suggest that starting treatment in UA may be a case of 'the earlier the better'. The benefit of earlier treatment has been previously demonstrated for patients with RA. But contrary to what is recognised and recommended for patients with classifiable RA, one study suggests that patients with UA may not gain additional benefit from tight controlled targeted treatment.
The ultimate goals in the treatment of UA would be to prevent progression to destructive RA or even induce permanent remission. Achieving these goals would mean that the so-called 'window of opportunity', in which appropriate treatment can alter the disease course, does exist. The closest evidence for the presence of the window of opportunity possibly comes from a study in 253 patients with UA where after a 3 week course of IM corticosteroid injections more patients achieved remission (20% vs 10%), fewer required initiation of DMARDs (61% vs 76%) and possibly fewer progressed to classifiable RA than in the placebo group (49% vs 60%). Also 6 months abatacept appears to suppress progression to RA, at least over 1 year follow-up, although no statistically significant difference was found possibly due to small numbers. Similarly, a 1 year course of MTX suppressed progression to RA and radiological progression, but after discontinuation of MTX the disease appeared to rerun its course. None of the articles included data on sustained drug-free remission.
Overdiagnosis as 'early RA' followed by overtreatment is a serious concern when treating patients with UA, or even patients who according to the new 2010 criteria would now be classified as RA. Patients may have another illness that may go into spontaneous remission. The solution may lay in predicting disease outcome, such as persistent arthritis or radiological progression, or response to treatment. Prediction models for disease outcome have been developed. However, to predict disease outcome and response to treatment in individual patients is not yet possible.
In conclusion, there are limited trials and observational studies exploring the possibility of inducing remission and/or permanently altering the disease course in patients with UA. Long-term follow-up data are mostly not available. During treatment with MTX monotherapy, combination therapy with multiple DMARDs or corticosteroids, biological agents and IM corticosteroid injections, active inflammation and ensuing radiographic damage may be suppressed. Early initiation of treatment may be better than delayed initiation, in particular if disease activity appears to be high. Thus, we should optimise strategies for early referral and early identification of patients with arthritis. In addition, any new randomised clinical trials in patients with UA should include a short-term placebo arm to investigate if early treatment can induce (drug-free) remission and a long-term follow-up period to demonstrate if early treatment can alter the disease course.
Discussion
This systematic literature review shows that to date, few placebo-controlled RCTs have been done to answer the question if early treatment in patients with UA is beneficial and which treatment might be the best. To compare results is difficult because of inconsistent outcome measures. Five clinical trials, two open-label studies and four observational studies suggest that starting treatment early may provide symptom relief, improve functional ability and suppress radiological progression. It may also postpone progression to classifiable RA or the need for other therapies. The strongest evidence of a potential benefit is present on early treatment with MTX, possibly in combination with other DMARDs or corticosteroids. Observational studies, which by using propensity scoring and minimal structural models try to partially compensate for indication bias, suggest that other DMARDs than MTX may be used. Data from these cohorts also suggest that starting treatment in UA may be a case of 'the earlier the better'. The benefit of earlier treatment has been previously demonstrated for patients with RA. But contrary to what is recognised and recommended for patients with classifiable RA, one study suggests that patients with UA may not gain additional benefit from tight controlled targeted treatment.
The ultimate goals in the treatment of UA would be to prevent progression to destructive RA or even induce permanent remission. Achieving these goals would mean that the so-called 'window of opportunity', in which appropriate treatment can alter the disease course, does exist. The closest evidence for the presence of the window of opportunity possibly comes from a study in 253 patients with UA where after a 3 week course of IM corticosteroid injections more patients achieved remission (20% vs 10%), fewer required initiation of DMARDs (61% vs 76%) and possibly fewer progressed to classifiable RA than in the placebo group (49% vs 60%). Also 6 months abatacept appears to suppress progression to RA, at least over 1 year follow-up, although no statistically significant difference was found possibly due to small numbers. Similarly, a 1 year course of MTX suppressed progression to RA and radiological progression, but after discontinuation of MTX the disease appeared to rerun its course. None of the articles included data on sustained drug-free remission.
Overdiagnosis as 'early RA' followed by overtreatment is a serious concern when treating patients with UA, or even patients who according to the new 2010 criteria would now be classified as RA. Patients may have another illness that may go into spontaneous remission. The solution may lay in predicting disease outcome, such as persistent arthritis or radiological progression, or response to treatment. Prediction models for disease outcome have been developed. However, to predict disease outcome and response to treatment in individual patients is not yet possible.
In conclusion, there are limited trials and observational studies exploring the possibility of inducing remission and/or permanently altering the disease course in patients with UA. Long-term follow-up data are mostly not available. During treatment with MTX monotherapy, combination therapy with multiple DMARDs or corticosteroids, biological agents and IM corticosteroid injections, active inflammation and ensuing radiographic damage may be suppressed. Early initiation of treatment may be better than delayed initiation, in particular if disease activity appears to be high. Thus, we should optimise strategies for early referral and early identification of patients with arthritis. In addition, any new randomised clinical trials in patients with UA should include a short-term placebo arm to investigate if early treatment can induce (drug-free) remission and a long-term follow-up period to demonstrate if early treatment can alter the disease course.
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