Natalizumab Treatment in a Patient With Chronic Inflammatory Demyelinating Polyneuropathy FREE

Natalizumab is a humanized monoclonal antibody against the α₄ integrin approved for treating relapsing forms of multiple sclerosis.¹ Experimental evidence in an animal model suggests that targeting α₄ integrins in the inflamed peripheral nervous system may translate into clinical efficacy.^2- 3 Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated disease in which an aberrant immune response, often T cell driven, is mounted against a yet unknown target antigen within the peripheral nerve.⁴ A number of immunomodulatory and suppressive treatment strategies, though generally not approved by regulatory authorities, are currently used for treating CIDP. However, clinical efficacy of these therapeutic approaches varies in the clinical subtypes of this disease, requiring different strategies, including individualized regimens of drug administration.⁵ Theoretically, there is a good rationale that natalizumab should be clinically effective in CIDP as well, yet clinical experience has not been reported so far.

We report on the case of a 61-year-old woman with CIDP diagnosed 28 months before presentation. Clinical and paraclinical evidence for a paraneoplastic disorder was not given; a monoclonal gammopathy was excluded. The patient failed to respond to established treatment strategies, including steroids, azathioprine (discontinued after 8 months because of loss of hair), intravenous immunoglobulins, mycophenolate mofetil, and cyclophosphamide (Figure 1). Plasma exchange (PE) was the only therapeutic approach that resulted in transient clinical improvement. After a course of 5 cycles of PE within 10 consecutive days, mild tetraparesis remained. However, within 3 weeks the patient's condition deteriorated dramatically clinically and paraclinically (Table 1 and Table 2). She became paraplegic and required a new course of PE; she recovered with the remaining sequelae just described. The patient was referred to our center to explore alternative treatment options.

Given the need for PE at high frequency and the lack of established alternative treatment choices, we considered natalizumab to be a therapeutic option. After discussing the experimental nature of this treatment and its potential adverse effects, informed consent was obtained and the patient was given a new course of PE followed by 300 mg of natalizumab intravenously. We were anticipating to stabilize the clinical course of the disease and to prolong the time to the next PE required. However, she did not respond clinically to natalizumab and showed measurable disease progression on the Inflammatory Neuropathy Cause and Treatment scale⁶ 3 weeks after the infusion, requiring a new course of PE. Our clinical observation was shown on magnetic resonance imaging (Figure 2), where strong gadolinium enhancement of the roots was visible prior to PE, reduced enhancement was visible after PE and prior to the infusion of natalizumab, and reappearance of strong gadolinium uptake of the roots was visible 3 weeks after natalizumab. The patient progressed clinically and currently requires weekly PE.

We describe a case of highly active CIDP that further deteriorated despite initiation of anti–α₄ integrin therapy with natalizumab. By labeling natalizumab with biotin and applying this antibody for immunohistochemistry on a sural nerve biopsy from a patient with CIDP, we were able to stain the α₄ integrin on perivascular T cells, which indicated that the target antigen of natalizumab is expressed in the peripheral nerve, underlining the rationale for our therapeutic attempt (Figure 3). Furthermore, we studied the saturation of the α₄ integrin on peripheral venous T lymphocytes from our patient before and after treatment with natalizumab by flow cytometry analysis (Figure 4) as described before.⁷ This analysis revealed clear evidence that natalizumab sufficiently bound to its target antigen on T cells and as such could have been effective in blocking inflammatory egress out of the blood vessels into the peripheral nervous system.

The role of α₄ integrin in the inflamed peripheral nerve is not fully understood. Experimental studies in an animal model suggest that blocking this molecule translates into clinical disease amelioration and induction of apoptosis in invading T lymphocytes within the peripheral nervous system.³ Our patient, however, did not show any clinical or paraclinical indications that natalizumab was effective. The antibody has a high affinity to its target antigen and already a single infusion translates into measurable efficacy, as seen on magnetic resonance imaging in patients with multiple sclerosis.⁸ Thus, despite the short treatment we could probably have expected some degree of effectiveness of the drug already after a single infusion. In addition, long-term therapy with natalizumab obviously exerts some long-lasting immunomodulatory changes that clearly exceed the immediate effects on transmigration over a short period.

Given the clinical and immunopathologic heterogeneity of CIDP, this case report clearly does not exclude natalizumab from being effective in patients with another subform of this immune-mediated disease. At present, however, given its safety profile,⁹ the application of natalizumab cannot be recommended in CIDP and should only be explored in controlled clinical trials.

Correspondence: Bernd C. Kieseier, MD, Department of Neurology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany (bernd.kieseier@uni-duesseldorf.de).

Accepted for Publication: September 22, 2009.

Author Contributions:Study concept and design: Menge, Meyer zu Hörste, and Kieseier. Acquisition of data: Wolf, Menge, Stenner, Saleh, Hartung, Wiendl, and Kieseier. Analysis and interpretation of data: Wolf, Menge, Stenner, Meyer zu Hörste, Saleh, Wiendl, and Kieseier. Drafting of the manuscript: Wolf, Menge, Stenner, Meyer zu Hörste, Wiendl, and Kieseier. Critical revision of the manuscript for important intellectual content: Menge, Stenner, Meyer zu Hörste, Saleh, Hartung, Wiendl, and Kieseier. Statistical analysis: Meyer zu Hörste. Obtained funding: Kieseier. Administrative, technical, and material support: Menge, Stenner, Meyer zu Hörste, Saleh, Wiendl, and Kieseier. Study supervision: Kieseier.

Financial Disclosure: Drs Hartung, Wiendl, and Kieseier have received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Health Care, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, and TEVA.