Clinicians often question whether the measured differences in radiographic progression between treatment arms are clinically relevant. To answer this question, long-term follow-up of other outcomes such as functional disability and loss of work is required. However, collection of these long-term data takes several years; therefore, it is useful to look for circumstantial evidence. Structural joint damage in clinical trials is assessed in small joints. However, there is a good correlation between the damage in small joints with the damage in large joints [24
]. Therefore, an observed reduction in disease progression in small joints is likely a reflection of the disease course in large joints. Moreover, there is an association between structural joint damage and physical function that is stronger with increasing disease duration [25
]. Lastly, it is important to consider that RA is a chronic disease, and it can be expected that without treatment, patients will continue to show progression of structural damage.
As an example, the interpretation of the radiographic results of the ATTRACT trial are presented here. Are the findings clinically relevant? All films were scored by the Sharp/van der Heijde method (range 0 to 440), by two independent observers, and without knowledge of the radiograph sequence. The average score of two observers was used. The median increase in the modified Sharp score in all patients treated with infliximab plus MTX was 0.5 (IQR -2.0, 2.5), versus 4.3 (IQR 0.5, 10) in patients treated with MTX alone [26
]. These data imply that at least 50% of patients treated with infliximab achieved a progression score of 0.5 or less and that 75% of patients progressed to a maximum value of 2.5. In patients treated with MTX alone, 50% of patients showed an increase of 4.3 and 75% progressed to a maximum value of 10.
At first glance, when considering the median increase in joint damage observed in patients treated with MTX alone in the context of the total range of the scoring system (0 to 440), a median increase of 4 appears clinically insignificant. In practice, however, it is extremely rare for patients to have complete destruction of all joints in both hands and feet and thereby receive a maximum score. Scores around 100 already represent major destruction. Usually, the progression score of 4 represents an increase in erosion and joint space narrowing in several joints. However, it is difficult to envision how this will affect the patient. As the maximum erosion score per hand joint is 5, one could imagine that an increase of 4 would represent an almost completely eroded hand joint. Thus, a median increase of 4 is actually a substantial finding. Furthermore, this especially makes sense if the long duration of the disease, resulting in an increase of 40 over 10 years, is taken into account. Assuming a continuation of what was observed in the trial, 50% of patients receiving MTX alone will develop eight completely eroded hand joints in the following 10 years and 25% of these patients will reach a score exceeding 100 (if they started with normal films), which represents marked joint destruction. In contrast, 50% of patients treated with infliximab will have no progression of joint destruction in the following 10 years, and 25% of patients will reach a score of 25 points, which represents five completely eroded hand joints. Furthermore, recent research has shown that clinical experts consider an increase of 5 Sharp/van der Heijde points a clinically meaningful change [23
]. Therefore, on the basis of this expert opinion, 50% of patients treated with MTX alone had clinically meaningful disease progression, whereas 75% of patients treated with infliximab did not [23
The ATTRACT trial also analyzed radiographic progression in individual patients by using the SDD as a cutoff level. This value (8.6) represented the progression of disease that was distinguishable from measurement error. Measurements >8.6 represented significant radiographic progression. From these results, the number of patients needed to be treated (NNT) to prevent major progression can be calculated, where NNT = 1/(% of MTX-only-treated patients with progression above the SDD [31%] - % of infliximab-treated patients with progression above the SDD [6%]) × 100, which yields an NNT of 4. Therefore, four patients need to be treated with infliximab to prevent major radiographic progression in one patient. The NNT value associated with infliximab treatment compares favorably with that of many treatments used to prevent fractures due to osteoporosis, which have an NNT value of 100 to 200.