AMSTERDAM, The Netherlands— The 30% of rheumatoid arthritis (RA) patients who do not respond to infliximab treatment may be clearing the drug very quickly due to formation of infliximab/anti-infliximab immune complexes with human antichimeric antibodies (HACA), according to Conny J. van der Laken, MD, of the Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands. Dr. van der Laken and colleagues report in Annals of the Rheumatic Diseases an analysis of two responding and two nonresponding RA patients.¹

"Nonresponders had much higher anti-infliximab levels (=HACA) than responders. In fact, HACA was not found in one responder, and a very low level was found in the other responder. A low amount of small complexes was found in the responder with the low HACA level, without clinical significance. Apparently, the HACA level must rise above a critical level to have clinical consequences," Dr. van der Laken told CIAOMed. "Our hypothesis that HACA and antibody complex formation is one of the causes of nonresponding to infliximab was confirmed by our findings. These findings will help us to develop successful anti-TNF treatment strategies for RA patients in the future. As has also been proposed by others, shortening of the interval between infliximab infusions and/or increasing the dose of infliximab per infusion may help to prevent/decrease the formation of HACA."

Patients were treated with at least 5 infliximab (3 mg/kg) infusions, given once every 8 weeks. Two responders (defined by EULAR criteria) and two nonresponders were then infused with 10 mg 740 MBq ^99mTc-infliximab and simultaneously with 3 mg/kg (minus 10 mg) of unlabeled infliximab via the same infusion needles. Blood samples were analyzed prior to infusion, during infusion, and 118 and 24 hours after infusion. Imaging was done directly after infusion and 24 hours later. Imaging included both whole body images and spot views of joints.

One of the nonresponder patients went into shock after 45 minutes of administration of  ^99mTc-infliximab and discontinued the study. The other nonresponder  "developed a light transient pressure in the chest" but was able to continue the infusion.

At the 24-hour imaging, 98%–100% of the ^99mTc-infliximab was still present in the whole body imaging of the responders. The nonresponder who continued the study had relatively faster clearance, with 76% whole-body retention at 24 hours. At 2 hours after infusion, liver and uptake in the nonresponder were higher than in the responders. Spleen and liver uptake at 24 hours were not significantly between responders and nonresponders. Uptake of ^99mTc-infliximab was also apparent in clinically inflamed joints.

The levels of infliximab in patients' sera varied according to levels of anti-infliximab antibodies. Patient A had no anti-infliximab and had infliximab of about 45 μg/mL. Patient B had 82 AU/mL of anti-infliximab before the radiolabelled infusion, and infliximab levels rose to 35 μg/mL. Nonresponder patient C had much higher anti-infliximab (1008 U/mL), and nonresponder patient D had 1641 U/mL anti-infliximab. In both those patients, all infused infliximab bound to circulating anti-infliximab in the first half-hour of infusion, and infliximab concentrations began to rise only after 30 to 60 minutes of infusion.

Patient A also had no infliximab/anti-infliximab complexes. Patient B had minor amounts of small complexes, which apparently disappeared later. Both of the nonresponders had higher levels of infliximab/anti-infliximab immune complexes. Patient C had high amounts of small complexes, and patient D (who had the infusion reaction) had complexes of various sizes, including large complexes with molecular weight >1,000,000.

"We think that both the very high level of HACA and the formation of large antibody complexes contributed to the severe infusion reaction in patient D. We assume that complement activation is involved," Dr. van der Laken said. "Interestingly, prior to the study, we collected the following information about this patient. After the third clinical infliximab infusion, the following infusion had to be postponed because of a severe airway infection. Thereafter, clinical response to infliximab disappeared. Most likely, HACA was formed in the period of discontinuation of infliximab."

"For the first time, this study demonstrated formation of infliximab/anti-infliximab complexes during infliximab infusion in RA non-responders. Due to antibody complex formation, low infliximab levels were observed within the first hour of infusion. Images suggested a faster clearance of infliximab in the nonresponding patient, possibly by removal of antibody complexes by liver and spleen. The quantity of HACA appeared to be important for responsiveness to therapy....Our results showed that formation of antibody complexes, due to presence of HACA, may be responsible for nonresponding and are most likely responsible for infusion reactions," the authors write.

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