Treatment responses to RA pharmacotherapeutics can lag initiation by weeks to months. While therapeutic responses to biologic immunomodulators are generally more rapid compared to non-biologic DMARDs, maximal benefit is usually not evident until 3 months of therapy, at the earliest. In some patients, maximal benefit is not achieved until 12 months of continuous therapy have elapsed. There are currently no reliable clinical or serologic measures to accurately predict therapeutic response to any DMARD in advance. Considering the expense of biologic immunomodulators, and the potential for articular and extraarticular damage associated with a delay in disease control, the ability to predict treatment response early in the course of therapy would be a valuable addition to clinical practice. Here, Buch et al (Arthritis Rheum 52(1):42, 2005) examine the predictive value of early CRP reduction after initiation of infliximab on future response to therapy.
Consecutive patients beginning infliximab therapy (3mg/kg dosage) for active RA (DAS28 > 5.1) despite prior therapeutic trials of at least 2 DMARDs were identified from a prospectively collected database of patients receiving biologic immunomodulating therapy for RA. Patients receiving at least 12 weeks of infliximab therapy were categorized as either ACR20 responders or ACR20 non-responders (ACR20 NR). All patients were further characterized according to observed suppression of serum CRP level after the first infusion of infliximab (week 2) and at week 12. ACR20 NR at week 12 with <20% reduction in CRP at week 2 were designated Type A NR. ACR20 NR at week 12 with an initial >20% reduction in CRP that was not sustained to 12 weeks were designated Type B NR. ACR20 NR at week 12 with an initial >20% reduction in CRP that was sustained to 12 weeks were designated Type C NR. Baseline and therapeutic response characteristics were compared between responder and NR groups.
199 patients received at least 12 weeks of infliximab therapy. Median baseline CRP levels (approx 40 mg/L) and mean baseline DAS28 scores (approx 6.5) reflected very active disease, in general. 107 patients (54%) achieved an ACR20 or better response by week 12 and in all of these an ACR20 response was preceded by a > 20% reduction in CRP at week 2. Of the 92 ACR20 NR, 12 (13%) were designated Type A NR, 22 (24%) were designated Type B NR, and 58 (63%) were designated Type C NR. No significant differences in baseline characteristics (gender, mean age, seropositivity for RF, median CRP, or mean DAS28) were noted between ACR20 responders and the 3 groups of NR (though ACR20 responders were predominantly RF positive at 92%). Type A NR demonstrated increasing CRP levels after initiation of infliximab therapy (median week 12 CRP 225% of baseline). Stratification for response based on baseline CRP level did not reveal any differences between patients with higher vs. lower baseline CRP levels.
Based on the above observations, the positive and negative predictive values of utilizing a 20% reduction in CRP at 2 weeks post-initiation of infliximab to predict ACR20 response at 12 weeks were determined:
|Positive predictive value||57%|
|Negative predictive value||86%|
At 12 weeks, 10 Type A NR (80%) and 15 Type B NR (70%) were switched to therapy with etanercept. 71% of these achieved an ACR20 or greater response after 12 weeks of etanercept (57% ACR50, 14% ACR70). Marked CRP reduction was observed in those with responses to etanercept (median CRP reduction 71% in Type A NR, 57% in Type B NR). All 58 Type C NR continued to receive infliximab. By week 24, 34 (59%) of these had achieved an ACR20 or better response (35% ACR50, 6% ACR50).
A lack of CRP reduction of at least 20% after 2 weeks of infliximab therapy is potentially useful in predicting poor overall therapeutic response at 12 weeks. Early non-responders who demonstrate early and sustained CRP reductions may benefit from continuation of therapy past 12 weeks. Lack of response to infliximab did not predict subsequent response to etanercept.
These results are interesting but will require confirmation in much larger cohorts in order to be readily applied to general clinical practice, particularly in light of recent reports identifying a slowing of radiographic progression in patients treated with TNF inhibitors even in whom a subjective clinical response was not observed. A negative predictive value of 86% is good; however, a strict application of this system would mean that a substantial number of patients would have an effective therapy abandoned prior to assessing its true efficacy.
In addition, rather than discontinuing treatment with infliximab at 12 weeks, a currently accepted clinical practice response to insufficient efficacy of infliximab at the starting dose of 3mg/kg is to increase the dose to 5mg/kg (and/or reduce the dosing interval). Thus, it would have been as interesting and clinically useful to compare whether an increased dose of infliximab vs. initiation of an alternative TNF inhibitor would have generated similar results. In this way, lack of CRP suppression could potentially be applied to predict patients who will require higher doses of infliximab to achieve optimal control of their disease. Also, it is not clear whether methotrexate was used in al patients. Though not seminal to the authors hypothesis, one wonders whether the addition of methotrexate to a patient not responding to infliximab monotherapy might also present alternatives to discontinuation of infliximab.