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Infliximab efficiency and failure
  1. A P Rozin1
  1. 1Bat Galim, Rambam Medical Centre, Post Box 9602 Haifa, Israel 31096
  1. Correspondence to:
    Dr A P Rozin
    a_rozinrambam.health.gov.il
  1. A P Andonopoulos2,
  2. N Meimaris2,
  3. D Daoussis2,
  4. A Bounas2,
  5. G Giannopoulos2
  1. 2Department of Medicine – Division of Rheumatology, University of Patras School of Medicine, Patras, Greece

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I would like to comment on an interesting letter in the Annals about anti-tumour necrosis factor (TNF) monotherapy for giant cell arteritis (GCA).1 The suggestion that vasculitis may be cured by anti-TNF treatment may seem to be reasonable. The factors sustaining autoimmune inflammation may include new target antigen production, immune system activation, and a vicious cycle of lymphocyte cascade activation. This mechanism has been recently suggested2 after a report of long term remission (6–24 months) of Wegener’s granulomatosis as a result of infliximab treatment,3 but unfortunately, it is not relevant in this case.

The authors considered overcoming infliximab failure with an increased dose and frequency,1 but “such an approach is by no means cost effective and should not be attempted”. There is another way of dealing with a loss of infliximab efficiency, which may be explained by examining the generation of human antichimeric antibodies (HACA). The following information should be considered:

  • Second line treatment should be added at the start of infliximab treatment to prevent HACA production.

  • HACA may be related to a shortened duration of response after repeated infliximab doses as was first described in patients with rheumatoid arthritis (RA).4

  • The assay used to determine HACA is affected by the presence of infliximab itself,5 and HACA levels have to be measured after the drug has been stopped. In the ATTRACT study, 27 patients who discontinued infliximab treatment were tested for the presence of HACA: three (11%) were positive, two with a titre of 1/10 and one with a titre of 1/40.6

  • Formation of HACA may be inversely related to the infliximab dose. HACA were found in 53, 21, and 7% of patients with RA receiving infliximab 1, 3, or 10 mg/kg, respectively, 12 weeks after the last of five infusions of the drug.7 It has been suggested that higher doses may be associated with immunological tolerance.5,7

  • HACA appeared to be associated with lower serum infliximab concentrations.8

Concomitant administration of methotrexate (MTX) appears to reduce HACA formation. While infliximab maximal concentration values are similar when infliximab is given, with or without MTX, serum concentrations of infliximab decline more slowly when MTX is present. Eight weeks after the last of 5×3 mg/kg doses, serum concentrations of infliximab were 2 and <0.1 mg/l in those receiving concomitant MTX and those not.7 Clinical response declines rapidly after serum infliximab concentrations drop below 1 mg/l.9 The mean serum concentration in patients receiving the recommended dosage regimen of infliximab 3 mg/kg at weeks 0, 2, and 6 and every 8 weeks thereafter was 1.5 mg/l at week 30 (that is, 8 weeks after the last dose).6 Moreover, the rates of formation of HACA were 15, 7, and 0% with the 1, 3, and 10 mg/kg doses in those receiving concurrent MTX.7 Possibly, MTX, by decreasing the immunogenic potential of infliximab, may slow its rate of clearance from the blood. The clinical response rate achieved with infliximab 1–10 mg/kg in combination with MTX was consistently greater than that achieved with infliximab alone.7

An HACA-reactive discontinuous epitope has recently been developed in order to create a functional mutant which has significantly reduced reactivity with the sera of patients with HACA after treatment.10 The technique is a valuable tool for identifying and adapting undesirable immunogenic sites on protein therapeutic agents.

In contrast with HACA, antibodies to another anti-TNF drug etanercept (Enbrel) are rarely found (2–4%) and, as they are non-neutralising they do not interfere with the efficiency of etanercept as monotherapy for at least 1 year. The reason for these differences is still unclear. Lower immunogenicity of the receptor-fusion protein may be implied.

Finally, it seems to me that one cannot define GCA as a self limiting disease, unlike polymyalgia rheumatica, as it may have an occult and long term course with a risk of progressive vessel and target organ damage. I also think that relapse of the disease may be dramatic (blindness, cerebrovascular accident) and should be considered before the first administration of infliximab as monotherapy, with its unknown duration of action and possibility of exposing the patient to serious complications. However, the problem of relapsing and “disease escaping” mechanisms should be further investigated.

References

Authors’ reply

We thank Dr Rozin for his interest in our report,1 describing our experience with anti-tumour necrosis factor α (infliximab) administration as monotherapy for giant cell arteritis (GCA), because this provides us with the opportunity to express some further thoughts on this approach.

It appears that Dr Rozin’s initial concern about the loss of response to infliximab of our two patients with GCA, has to do with the possibility of development of human antichimeric antibodies (HACA) in their sera. The development of such antibodies in our patients, who did not receive concomitant methotrexate (MTX) and were treated with relatively low dose infliximab, is quite likely, as this occurrence is well established as Dr Rozin indicates. However, we would like to make the following points on this matter.

Firstly, the design of our trial precluded the use of MTX because our purpose was to investigate the effectiveness of infliximab alone in GCA, and MTX has been used, albeit with questionable results, in the treatment of this disease, mainly as a steroid sparing agent.2

Secondly, we employed the usual therapeutic regimen with 3 mg/kg body weight of infliximab empirically, and after the initial impressive response of our patients to that dose we continued with it.

Thirdly, although the development of HACA in our patients is quite likely, we cannot be at all sure that this influenced the clinical response of the patients to infliximab. Our point is mainly based on the results of a recent report by Wagner et al,3 in rheumatoid patients of the ATTRACT study. These showed that HACA were developed in 25 of 295 patients (8.5%), but their presence did not affect the proportion of patients with an American College of Rheumatology (ACR)20 or ACR50 response, after long term infliximab treatment.

Fourthly, we indicated that infliximab administration, probably in higher doses and more frequently, should be kept for refractory cases, otherwise we considered that such an approach was not cost effective. Thus we suggested that for a disease easily controlled with corticosteroids, an expensive treatment such as one employing infliximab is only justified if it proves effective in “curing” GCA in a relatively short time—that is, five infusions at the most. In this way, the long term undesirable side effects of chronic corticosteroid administration would be avoided. Returning now to that point, after having shown that infliximab is effective in GCA (and this is, we think, the most important finding of our trial), we cannot preclude its use, in combination with MTX, in the usual 3 mg/kg body weight or higher dosage, in refractory cases of the disease or where chronic corticosteroid administration is contraindicated or is not tolerated. However, appropriately designed studies using this agent in “routine” cases of GCA, probably including serum interleukin 6 in their evaluation of disease remission,4 are needed to answer the question whether short term infliximab treatment (five infusions), combined with MTX and even corticosteroids, is “curative”.

Finally, we agree with Dr Rozin that “self limiting disease” was not the most appropriate characterisation for GCA. This term was used because most studies have suggested that treatment with steroids is usually stopped within 2 years in most patients, although there is no evidence that such treatment reduces the duration of the disease,4 and a great deal of controversy exists.4,5 It has been further argued from clinical experience that partial suppression of the inflammatory process of the disease is sufficient to prevent most vascular complications and justifies the currently used corticosteroid regimens.4 Dr Rozin is concerned about the possibility of a dramatic relapse of the disease, with blindness or cerebrovascular accident, which should have been considered before the first administration (by us) of infliximab as monotherapy. We would not have given a second infusion, if the first one had not impressively encouraged us to continue. Furthermore, we should emphasise that we followed up our patients closely, with a complete physical and ophthalmological evaluation and appropriate laboratory work every 2 weeks, and this should have enabled us to detect in time any undesirable occurrence.

References

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