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Decreased clinical response to adalimumab in ankylosing spondylitis is associated with antibody formation
  1. M K de Vries1,
  2. E Brouwer5,
  3. I E van der Horst-Bruinsma1,
  4. A Spoorenberg6,
  5. J C van Denderen3,
  6. A Jamnitski3,
  7. M T Nurmohamed1,3,
  8. B A C Dijkmans1,3,
  9. L A Aarden2,4,
  10. G J Wolbink2,3
  1. 1
    VU University Medical Centre, Amsterdam, The Netherlands
  2. 2
    Sanquin Research, Amsterdam, The Netherlands
  3. 3
    Jan van Breemen Institute, Amsterdam, The Netherlands
  4. 4
    Landsteiner Laboratory Academic Medical Centre, Amsterdam, The Netherlands
  5. 5
    University Medical Center, Groningen, The Netherlands
  6. 6
    Medical Center, Leeuwarden, The Netherlands
  1. Correspondence to Dr I E van der Horst-Bruinsma, VU University Medical Centre, Rheumatology Department, room 3A-64, P O Box 7057, 1007 MB Amsterdam, The Netherlands; ie.vanderhorst{at}

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Treatment with anti-tumour necrosis factor (TNF) is very effective in most patients with ankylosing spondylitis (AS), but inefficacy occurs in about 40% of cases.1 Antibody formation against TNF blocking agents is an increasingly recognised problem;2 however, no data have yet been reported on antibody formation against adalimumab (anti-adalimumab) in AS. Lack of response can be explained in two ways: (1) TNF might not be important for disease activity in certain patients; and (2) TNF inhibition might be insufficient. The latter could be caused by excessive production of TNF, low compliance of the patient, insufficient dosing or an enhanced clearance of adalimumab due to antibody formation. Adalimumab is a fully human monoclonal antibody against TNF but, despite this fact, an immune response still can be provoked by the antigen binding site also known as the idiotype. In previous studies we have described the problem of immunogenicity of TNF blocking drugs in patients with rheumatoid arthritis (RA),3 in patients with AS treated with infliximab4 and in patients with RA treated with adalimumab,5 and concluded that the presence of antibodies against infliximab or adalimumab was associated with low or undetectable serum levels of infliximab or adalimumab and clinical non-response.

The objective of the present study was to investigate the relation between the formation of anti-adalimumab, serum adalimumab levels and clinical response in AS.

Patients with AS6 were treated with adalimumab, 40 mg every other week, according to the international ASAS consensus statement.7 8 Clinical response was defined as a 50% improvement or an absolute improvement of 2 points on the BASDAI scale (0–10). Serum samples were collected at baseline and after 3 and 6 months of treatment. Serum adalimumab levels were determined with an ELISA and anti-adalimumab was measured with a validated antigen binding test. The assays used were similar to those described previously for the detection of infliximab levels and antibodies against infliximab.4 5

Thirty-five patients were included. After 6 months of treatment, 18 were ASAS responders (table 1). Within 6 months of treatment, 11 patients developed anti-adalimumab with low or undetectable adalimumab levels, 9 were ASAS non-responders (p = 0.012) and 1 had an allergic reaction with flushing, dyspnoea and undetectable serum adalimumab levels (fig 1).

Figure 1

Relation between the presence of anti-adalimumab and response of ankylosing spondylitis to treatment with adalimumab.

Table 1

Baseline characteristics and clinical variables

Thus, anti-adalimumab was detected in 31% of the patients after 6 months of treatment and this corresponded with diminished or undetectable serum adalimumab levels in these patients. These preliminary observations will need confirmation in a larger study. In contrast with the treatment of RA, adalimumab is given without methotrexate in the treatment of AS. This might be an explanation for the higher incidence of anti-adalimumab formation in AS. In Crohn’s disease and in RA, the concomitant use of immunosuppressive drugs or corticosteroids has been proved to decrease antibody formation against infliximab.9 10

To date, no other papers have reported on immunogenicity in the treatment of AS with adalimumab and no systemic allergic reactions have been described. The detection of antibodies might predict the inefficacy of adalimumab and should be explored further for use in daily clinical practice.


The authors thank Mrs Abrahams and Mrs Bulstra, research nurses, for their support; Mrs van Houten and Mr de Vrieze for determining adalimumab levels and anti-adalimumab; and Mrs Vesters for proof reading this manuscript.



  • Funding The clinical part of this study was partially financed by Abbott. This investigation was also facilitated by the Clinical Research Bureau of the Jan van Breemen Institute and received financial support from the Dutch Arthritis Foundation.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.