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December 01, 1996; 47 (6) Article

Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2

B. W. van Oosten, F. Barkhof, L. Truyen, J. B. Boringa, F. W. Bertelsmann, B.M.E. von Blomberg, J. N. Woody, H.-P. Hartung, C. H. Polman
First published December 1, 1996, DOI: https://doi.org/10.1212/WNL.47.6.1531
B. W. van Oosten
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F. Barkhof
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L. Truyen
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J. B. Boringa
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F. W. Bertelsmann
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B.M.E. von Blomberg
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J. N. Woody
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H.-P. Hartung
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C. H. Polman
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Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2
B. W. van Oosten, F. Barkhof, L. Truyen, J. B. Boringa, F. W. Bertelsmann, B.M.E. von Blomberg, J. N. Woody, H.-P. Hartung, C. H. Polman
Neurology Dec 1996, 47 (6) 1531-1534; DOI: 10.1212/WNL.47.6.1531

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Abstract

There is evidence that treatment with an antibody to tumor necrosis factor alpha (TNF alpha) improves an animal model of multiple sclerosis (MS) and is beneficial in two systemic inflammatory diseases in humans, but there are no reports about anti-TNF treatment of MS. Therefore, we treated two rapidly progressive MS patients with intravenous infusions of a humanized mouse monoclonal anti-TNF antibody (cA2) in an open-label phase I safety trial and monitored their clinical status, gadolinium-enhanced brain magnetic resonance imaging (MRI), and peripheral blood and cerebrospinal fluid (CSF) immunologic status.

We did not notice any clinically significant neurologic changes in either patient.The number of gadolinium-enhancing lesions increased transiently after each treatment in both patients. CSF leukocyte counts and IgG index increased after each treatment.

The transient increase in the number of gadolinium-enhancing lesions that followed each infusion of cA2 together with the increase in cells and immunoglobulin in the CSF of each patient suggest that the treatment caused immune activation and an increase in disease activity. These results suggest that further use of cA2 in MS is not warranted and that studies of other agents that antagonize TNF alpha should be carried out with frequent monitoring of gadolinium-enhanced MRIs.

NEUROLOGY 1996;47: 1531-1534

Although the etiology of multiple sclerosis (MS) is not c lear, there is evidence for an important role of immunologic mechanisms in the pathogenesis of this disease. Mononuclear cells from the peripheral circulation of MS patients, when examined in a whole-blood mitogen stimulation assay, show an increased production of tumor necrosis factor (TNF) and interferon (IFN) gamma preceding clinical exacerbations. [1] In MS patients with active disease, peripheral blood mononuclear cells express higher levels of TNF alpha and TNF beta mRNA compared to those with stable disease and to normal controls. [2,3] Along with other cytokines and adhesion molecules, TNF alpha and TNF beta are present in MS plaques. [4,5] There is evidence, derived from in vitro studies, that TNF alpha is able to damage oligodendrocytes. [6,7]

In animals suffering from experimental allergic encephalomyelitis (EAE), the animal model of MS, the symptoms can be aggravated by injection of TNF alpha. [8] In animals treated with drugs that are known to inhibit the production or effects of TNF alpha, such as pentoxifylline, [9,10] phosphatidylserine, [11] anti-TNF antibodies, [12-14] or rolipram, [15] EAE does not develop or is less severe than in controls.

In other human immune-mediated diseases where high levels of TNF alpha can be found in affected organs, such as Crohn's disease (CD) and rheumatoid arthritis (RA), intravenous treatment with the humanized monoclonal anti-TNF antibody cA2 resulted in significant improvement lasting for 2 to 4 months after a single infusion, without causing severe adverse events. [16-19]

In our opinion the results of treatment of EAE with anti-TNF antibodies and of treatment of CD and RA with cA2 justified an open-label phase I safety trial of intravenous monoclonal anti-TNF antibodies (cA2) in two patients who were suffering from an aggressive form of MS that had not responded to standard treatment with intravenous methylprednisolone.

Methods.

Patients.

In patient A, a 26-year-old woman, we diagnosed MS after several episodes of fatigue and sensory disturbances in both legs. Magnetic resonance imaging (MRI) revealed multiple cerebral white matter lesions, and examination of the cerebrospinal fluid (CSF) revealed an IgG index of 1.68 (normal: <0.60). In the 4 years following diagnosis we treated a number of relapses which remitted without significant residual disability, with short courses of corticosteroids. Three months after giving birth to a healthy son, patient A experienced an episode of sensory and motor disturbances in the left arm and leg, followed by an acute left-sided optic neuritis and gait instability. Intravenous methylprednisolone (500 mg per day for 5 days) at best resulted in a temporary stabilization, but after some weeks she further deteriorated. Gadolinium-enhanced MRI performed 3 weeks after intravenous steroids revealed many enhancing lesions. In the next few months there was a gradual development of brainstem signs, which resulted in significant disability. Because of this devastating disease course, with an increase in the Expanded Disability Status Scale (EDSS) [20] from 2.0 to 5.5 in 6 months, the possibility of cA2 treatment was discussed with the patient and her partner, and informed consent was obtained.

Patient B was a woman aged 25 years when we diagnosed MS after several episodes of gait disturbance, dysarthria, and disturbances of eye movements. MRI revealed several cerebral white matter lesions. At CSF examination the IgG index was 0.87 (normal: <0.60). In the next 5 years the disease followed a relapsing-remitting course. Relapses were treated with short courses of intravenous corticosteroids. However, after these 5 years the disease started to follow a relapsing progressive course. Over 2 years patient B developed ataxia and sensory and pyramidal disturbances of the legs, leading to a change of the EDSS from 3.0 to 6.0, despite several courses of intravenous corticosteroids. In the next year the progression accelerated: her mobility was impaired by a progressive paraparesis and ataxia, and she started to suffer from dysarthria and dysphagia, resulting in an EDSS of 8.0. Because of this aggressive disease course, which did not react to standard corticosteroid treatment, the possibility of cA2 treatment was discussed with the patient and her partner, and informed consent was obtained.

Treatment with cA2 and safety procedures.

The cA2 antibody was supplied by Centocor, Inc. (Malvern, PA) as a sterile, vialed product. Each vial contained 20 ml of a solution of 10.0 mg/ml cA2 in 0.15 M sodium chloride, 0.01 M sodium phosphate, 0.01% polysorbate 80, pH 7.2. This murine-human chimeric monoclonal anti-TNF antibody was constructed by joining the antigen-binding variable regions of a murine monoclonal IgG antibody (A2), which is secreted by the murine hybridoma cell line C134A and binds with high affinity to natural and recombinant human TNF alpha, to the constant regions of a human IgG1 kappa immunoglobulin. This was done in order to lessen a potential human anti-mouse response. Also, the chimeric antibody might be expected to have better effector function and a longer serum half-life.

Both patients received two infusions of 10 mg/kg cA2 with an interval of 2 weeks. Neither patient had been treated with any corticosteroids within 3 months preceding the cA2 infusions. Before administration, the appropriate amount of cA2 was diluted to 300 ml in sterile saline. During intravenous infusion over 2 hours, this solution was filtered through an 0.2 micro l in-line filter (Pall Set Saver, Pall Biomedical Inc., Fajardo, PR, USA). This treatment regimen was the same as that used in the studies that demonstrated the efficacy of cA2 in the treatment of CD and RA. [16-19]

Serum levels of the administered cA2 were measured regularly on both treatment days and at least until 2 days after cA2 infusions. In both patients, CSF levels of cA2 were measured on each occasion that lumbar puncture was performed.

Blood pressure, temperature, respiratory rate, and heart rate were constantly monitored during and for at least 2 hours after both infusions. Before the second infusion, an intravenous test dose of 0.1 mg of cA2 was given over 5 minutes, after which the patients were observed for 15 minutes for signs of a hypersensitivity reaction. In the absence of any hypersensitivity reaction the full dose was given.

Standard hematologic and biochemical blood tests were performed during and after the infusions (up to 6 months after the second infusion).

Measures of efficacy.

One day before each infusion, T2-and gadolinium-enhanced T1-weighted MRI was performed using a standardized protocol. [21] The same MRI protocol was repeated 1 day and also 1 week after each infusion. After the second infusion, additional MRI investigations according to the same protocol were performed after 2 and after 7 weeks. All scans were evaluated by an experienced investigator (F.B.), who was blinded for the relation of each scan to the time of the infusions.

As a clinical measure of efficacy, Kurtzke's EDSS was documented on the days that MRI examinations were performed.

In both patients we obtained CSF by lumbar puncture and assessed cell counts, IgG index, and oligoclonal bands the day before and 24 hours after the first infusion; in patient B these figures were also obtained the day before and 48 hours after the second infusion.

To assess possible changes in CSF and serum levels of TNF alpha, intercellular adhesion molecule (ICAM)-1, ICAM-3, vascular cell adhesion molecule (VCAM)-1, L-selectin, and TNF receptor (60 kD), we employed a battery of ELISAs, as described previously. [22] We measured the production of TNF alpha, IFN gamma and interleukin (IL)-6 by stimulated peripheral white blood cells before and for several weeks after the two infusions, using methods described elsewhere. [23]

Results.

cA2 levels and safety.

Peak levels of cA2 of approximately 500 micro g/ml were reached shortly after infusion, followed by a decline to levels around 200 micro g/ml after 72 hours. However, we did not detect cA2 in the CSF of either patient. The assay used is able to detect levels of cA2 exceeding 64 ng/ml.

The infusion of the cA2 antibodies was tolerated well. Patient A's blood pressure dropped temporarily from 127/68 to 95/51 mm Hg during the first infusion, and from 110/59 to 94/62 mm Hg during the second infusion, without clinical signs of vasovagal collapse or anaphylactic reactions. We did not see any clinically evident adverse event in patient B. Standard hematologic and biochemical assessments remained normal in both patients.

Measures of efficacy.

The number of gadolinium-enhancing lesions on T1-weighted scans increased in both patients after the first infusion. With longer follow-up both patients returned to their (high) pretreatment levels of activity (Figure 1).

Figure1
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Figure 1. Number of gadolinium-enhancing lesions in patients A and B.

On the EDSS patient A improved from 5.5 to 5.0 after the first infusion and was stable afterwards; patient B improved from 8.0 to 7.5 after the first infusion but returned to 8.0 after 6 weeks.

Both lymphocyte counts and IgG index were higher post-treatment compared to the patients' already abnormal pretreatment values (Table 1).

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Table 1. IgG index and CSF lymphocytes per 3 micro l

In both patients we did not find any TNF alpha, ICAM-1, or L-selectin in the CSF (detection limits of the assays were 40 pg/ml, 30 ng/ml, and 80 ng/ml, respectively), whereas we found VCAM-1 levels of 100 ng/ml in patient A only after the first infusion and in patient B only after the second infusion. There were no striking changes in serum levels of adhesion molecules, but there was a trend toward lower serum levels of the soluble form of the adhesion molecules VCAM-1 and ICAM-1 in both patients (data not shown). The production of TNF alpha by stimulated peripheral white blood cells was reduced after treatment, but there was no effect on production of IFN gamma and IL-6 (data not shown).

Discussion.

Recent evidence suggests that TNF alpha is of major importance in the pathogenesis of several autoimmune disorders, such as RA, CD, and MS. Treatment of CD [16,17] and RA [18,19] with the TNF alpha antibody cA2 yielded encouraging results. However, treatment of MS with TNF alpha antibodies has not been reported before. Here we describe the results of a phase I open-label study of treatment of two MS patients with cA2.

Unexpectedly, we saw a rise in the number of gadolinium-enhancing lesions compared to baseline after each infusion in both patients, which was most obvious after the first infusion. We would have preferred to compare these MRI data with a series of monthly pretreatment scans (e.g., 6 or 12 months), because this would have allowed a statistical interpretation of our results. [24] However, since this was an open-label phase I study in patients who were deteriorating rapidly, this was not a realistic option in our view.

We also saw a rise in the IgG index and in the number of CSF lymphocytes after each infusion of cA2 (see Table 1), reinforcing the MRI findings and suggesting that intravenous administration of cA2 triggers an intrathecal immune activation in MS patients.

The occurrence of VCAM-1 in the CSF after the cA2 infusions is consistent with an intrathecal immune activation as suggested by MRI and other CSF data. The lower levels of ICAM-1 and VCAM-1, and the decrease in TNF alpha production by stimulated white blood cells, seem to suggest that the observed immune activation was limited to the intrathecal compartment. However, little is known about the day-to-day variability of these measurements in MS patients, which makes it hard to judge their significance.

Taking into account the MRI and CSF (IgG index and lymphocyte counts) results, this study provides evidence that intravenous treatment of MS patients with the anti-TNF antibody cA2 may lead to intrathecal immune activation and may therefore be harmful for MS patients. One has to bear in mind that, because of the small number of patients treated and the fact that each patient received only two infusions, this evidence is only preliminary.

One possible explanation for these unexpected results is that cA2 may not be able to cross the blood-brain barrier and therefore does not reach the MS plaques, since we did not detect the antibody in the CSF after treatment. However, one could argue that a defective blood-brain barrier, as shown by gadolinium enhancement on MRI, would allow passage of antibodies into MS lesions, and that absence of cA2 from the CSF is no proof of its absence from MS lesions. A second possible explanation is that TNF alpha is not of the same importance for the pathogenesis of MS as it appears to be for CD and RA. However, neither possibility explains the impression that there was an intrathecal immune activation. Given the limited and preliminary nature of the data available, an explanation of this phenomenon can only be speculative and premature. Other studies are required to confirm our observations and to provide a stronger basis for their explanation. For the time being it seems wise to take measures that enable prompt recognition of signs of immune activation in MS patients who are treated with (experimental) TNF alpha antagonists, preferably by making use of frequent MRI monitoring.

  • Copyright 1996 by Advanstar Communications Inc.

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