Increasing infliximab doses may not restore previous response in RA

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Apr 15, 2004

Increasing infliximab doses may not restore previous response in RA

Stockholm, Sweden - Increased infliximab dosing in rheumatoid arthritis (RA)

patients whose response has waned may have less clinical benefit than

expected. Moreover, much of the perceived benefit may actually be a

regression effectnot a recapturing of the previous response, Swedish

researchers report in the April 2004 issue of ls of the Rheumatic

Diseases [1].

" The appearance of an improvement when a subset of patients is analyzed,

starting at a time of worsened disease, causes an error in interpretation

known in statistics as 'regression to the mean.' "

" The improvement seen in our patients following a period of worsening

disease activity, irrespective of treatment, is typical of the waxing and

waning course of rheumatoid arthritis and many other chronic diseases. The

appearance of an improvement when a subset of patients is analyzed, starting

at a time of worsened disease, causes an error in interpretation known in

statistics as 'regression to the mean,' " write Dr F van Vollenhoven

(Karolinska Hospital, Stockholm, Sweden) and colleagues.

" Improvement " no different with higher-dose infliximab than in control group

without dose increase

The investigators used structured longitudinal follow-up studies to compare

outcomes when infliximab doses were increased above 3 mg/kg per infusion to

outcomes in infliximab patients whose doses were not increased and to

patients treated with etanercept. Van Vollenhoven noted that physicians

often increase the dose of infliximab when a patient either has an

inadequate response to infliximab or has a response that does not persist

through the usual 8-week dosing interval. According to the new study, this

practice may not be wise, as improvement is not a given, the cost increases

exponentially with increased doses, and higher infliximab doses may be

associated with greater cardiovascular risk.

" We recommend that formal studies of infliximab-dose escalation be

undertaken and that the individual physicians wishing to increase infliximab

dosage do so under very clearly prescribed conditions of follow-up, " they

conclude.

STURE data analyzed

Using data from the Stockholm TNF- follow-up registry (STURE), van

Vollenhoven and colleagues compared clinical outcomes in 44 patients with RA

whose infliximab doses were increased to 5 to 7 mg/kg per infusion, 44

patients treated with infliximab without dose increases, and 36 patients

treated with etanercept. The point at which the average disease activity

score (DAS28) value showed any increase (despite infliximab/etanercept

treatment) was used as the reference time point for study controls.

Researchers compared best outcome achieved before the dose increase or

before the reference time point; outcomes at this point; and best outcomes

after this point.

The DAS28, swollen joint count, and numerical American College of

Rheumatology responses did significantly improve after dose increase, but

the degree of improvement was modest. Moreover, the values after dose

increase were similar to the best results obtained previous to dose

increase.

The improvement achieved after dosage escalation was equal to but not better

than the best values before dose escalation. Van Vollenhoven says that

although the improvements after infliximab dose increase might be

interpreted as " showing that a previous response to infliximab treatment

that had been diminished over time could be 'recaptured' by dose increase, "

a more likely explanation is that this is a regressionlike effect, as

similar improvements were seen in both control groups. The same pattern of

worsening and subsequent improvement was seen with or without the infliximab

dose increase, the researchers report. The key to the effect is that

infliximab dose increase typically happens after a period of worsening

disease activity. The improvement that follows is then mistakenly attributed

to treatment rather than to the natural history of the disease.

" When informally reviewing the cases in this study we found, rather

soberingly, that the treating physicians tended to assess the results as

more favorable than was warranted by the actual outcomes, and that even when

the results were assessed as being no better than before, the dose increases

were rarely reversed, " the investigators write.

" Clinical improvement with increased infliximab dose, and the impression

that a previous response can be 'recaptured' with higher doses, cannot be

taken at face value, as similar improvements occurred in 2 control groups, "

van Vollenhoven and colleagues write. " The use of infliximab at doses higher

than 3 mg/kg needs to be evaluated further. "

Mann

Source

1. van Vollenhoven RF, Brannemark S, Klareskog L. Dose escalation of

infliximab in clinical practice: improvements seen may be explained by a

regression-like effect. Ann Rheum Dis 2004 Apr; 63(4):426-30.