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Tumour necrosis factor neutralization in MS: a cautionary tale.

Multiple sclerosis (MS) is thought to be an autoimmune process directed against one or more unidentified central nervous system (CNS) antigens. The inflammatory response that precedes MS relapses and continues across their course is characterized by increased expression of numerous cytokines. Tumour necrosis factor (TNF) is prominent among them. TNF protein and TNF mRNA are present within active MS demyelinating foci, even in those biopsied at disease onset and perhaps even those biopsied so early that demyelination has yet to begin. TNF presence correlates inversely with mature oligodendrocyte survival, (1,2) a finding consistent with a direct toxic effect of TNF for oligodendrocytes as has been shown in vitro (3) and in vivo. (4) TNF promotes astrocyte proliferation, (5) a finding germane to the reactive gliosis that becomes prominent as MS plaques evolve. TNF, released at low levels under normal circumstances by glia, positively regulates synaptic transmission in the brain and is required for normal cognitive function. Effects of TNF within the brain vary with cytokine concentration. Too little or too much can have negative consequences. Transgenic mice lacking TNF are cognitively impaired. (6) Mice can also be engineered to overexpress TNF in the brain. Mice of one overexpressing line develop spontaneous myelin pathology, mice of a second line develop experimental autoimmune encephalomyelitis (EAE) of exacerbated severity in response to immunization with myelin protein, while in mice of a third line, no pathology is evident. Mice of all three lines are cognitively impaired. (6,7) Excess TNF abruptly induces conduction block in axons. (8) Not surprisingly, TNF is widely held to contribute to CNS damage in MS.

TNF synthesis by blood-derived mononuclear cells from MS patients increases prior to onset of exacerbations as compared with other times. (9-10) TNF mRNA is over-expressed by blood mononuclear cells from MS patients with active disease as opposed to stable patients or healthy controls. (11) These findings have been viewed as providing evidence in support of a disease-promoting role for TNF in MS. As we shall see, the situation is not so simple.

EAE is widely studied as an animal model for MS. Anti-TNF monoclonal antibodies or soluble TNF receptors neutralize TNF. Both reduce the severity of EAE in mice and rats, (12-16) as can deletion of TNF-receptor I. (17) TNF, when administered to rats worsens disease (18) while in mice recovered from EAE, TNF promptly provokes relapses. (19) Additionally, the amount of TNF produced by myelin basic protein-specific T-cell clones correlates strongly with their capacity to induce paralysis in mice. (20) Collectively, these findings were, when published, thought to point to a disease promoting role for TNF in EAE and by analogy to suggest a like role for TNF in MS.

There are two TNF receptors-TNF-Rp55 (TNF-RI) and TNF-Rp75 (TNF-RII). Both, when soluble and circulating, can capture and neutralize TNF. Lenercept is a dimeric recombinant protein in which the extracellular domain of TNF-RI is fused to the human immunoglobulin (Ig)G1 heavy chain. Fusion lengthens serum half-life, and introduces bivalency which increases affinity for TNF. The maneouver also permits effector mechanisms mediated via the Fc domain of IgG to come into play. Lenercept potently inhibits clinical symptoms of EAE in rats despite no effect on CNS inflammatory infiltrates. (21)

Lenercept was tested in a double-blind, randomized, placebo-controlled Phase II trial in 168 MS patients, most with relapsing-remitting MS (RRMS). (22) Patients received 10, 50, 100 mg of lenercept or placebo IV every 4 weeks for up to 48 weeks. The primary end-point was the cumulative number of newly active lesions identified on the first six treatment scans. Magnetic resonance imaging (MRI) scans and clinical evaluations were performed at screening, at baseline, and every 4 weeks (immediately before dosing) through study week 24. The protocol called for an analysis once all patients had completed 24 weeks of treatment and their MRI scans had been scored. When this was done the study was stopped. Fifty and 100 mg lenercept-treated patients had more relapses than placebo-treated patients, relapses lasted longer and tended to be more severe (Table 1). MS-related complaints voiced by patients were also much increased (Table 2). Despite these untoward results, no meaningful difference between treatment groups was noted in terms of any MRI measure or in changes in the Expanded Disability Status Scale (EDSS) score. There were 10 study centres; all showed a like effect. Relapse frequency versus placebo increased after each dose including the first. Exacerbations were not predicted by age, sex, MS category (progressive patients also had attacks), exacerbation frequency before study entry, baseline EDSS, or baseline number of newly active lesions.

The lack of MRI effect despite a clear-cut increase in attack frequency is, at first glance, surprising. MRI has been touted as a better guide to therapeutic efficacy than clinical evaluation and as a sensitive indicator of bad outcome. The opposite pertained here. In a study of two MS patients treated with an anti-TNF monoclonal antibody, increased numbers of gadolinium (Gd)-enhancing lesions were observed within seven days of the first dose, with return to baseline within 2 to 3 weeks. (23) Had MRI activity occurred early after lenercept dosing and been transient, it would have been missed on scans performed 4 weeks later. Perhaps so, but the relapses themselves were far from transient (Table 1). There was no shortage of MRI activity in any group. Across groups, more than 90% of newly active lesions were Gd+. Eighty percent of Gd+ scans are clinically silent. Perhaps Gd+ scans linked to relapses were lost in a 'background' of clinically silent scans.

I was an investigator in the lenercept trial. I was stunned to learn that the drug had provoked relapses. Investigators at the other centres were nonplussed as well. We simply did not twig what was happening nor did our patients. Six patients withdrew during the first 6 months of the trial. Only one, on 100 mg of lenercept, withdrew because of exacerbation-related symptoms. In retrospect, I was ill-prepared to think that a drug with a seemingly strong rationale for a likelihood of efficacy might be harmful. Chastened by my lenercept experience, I now ask the 'H question' (H for harmful) about many drugs.

Even when the code was broken, the increase in relapses above expected frequency would have been missed, absent the placebo group, and a deleterious effect would never have been discerned had sole reliance been placed on MRI. Might benefit also be missed when reliance on MRI activity is total? Note that a robust clinical benefit of lenercept occurred in EAE with no loss of CNS inflammatory infiltrates, (21) again suggesting weak linkage between symptoms and pathology. These findings have made me cautious in my interpretation of MRI results, absent corroborating clinical data. They further point to the need for some sort of a control measure even in open-label pilot trials.

Anti-TNF monoclonal antibodies (infliximab and adalimumab) and etanercept (a TNF-RII-fusion protein that, as with lenercept, captures TNF) are approved treatments for rheumatoid arthritis (RA), psoriasis, Crohn's disease, and ankylosing spondylitis. Acute demyelinating episodes are an infrequent, but feared complication of these treatments. (24) A few of the recorded episodes have occurred on a background of established MS. Most others experiencing an episode, and with no prior MS history, have come to satisfy diagnostic criteria for MS, with typical MRI findings and spinal fluid oligoclonal bands duly documented.

The complication has been seen with all four diseases for which anti-TNF therapy is approved. Episodes can occur, and recur, after months or years of complete TNF neutralization in the blood. Given the delay, it is unlikely that TNF depletion actually causes MS; more likely previously subclinical MS is unmasked. Delay suggests that the attacks are triggered by some intermittently expressed second stimulus that is somehow potentiated by TNF depletion. In the same vein, new onset RA is seen after a delay in MS patients who are otherwise being successfully treated with interferon beta (IFNB). In addition, psoriasis may worsen in MS patients receiving IFNB. A drug that treats one autoimmune disease successfully may worsen another.

Animal models of MS can deceive. They surely did so with lenercept. Animal work, published after the lenercept trial was closed, produced disturbing surprises. In SJL/TNF-knockout mice, EAE induced with mouse spinal cord homogenate (antigen 1) turned out to be inordinately severe, suggesting an unanticipated protective role for TNF in this form of EAE. (25) Yet, in these same SJL/TNF-knockouts, proteolipid peptide 139-151-induced EAE (antigen 2) was of the same severity as in SJL controls (25) pointing to no role for TNF in a different form of EAE in the same mice. In TNF-knockout C57/BL6 mice (26) immunized with myelin oligodendrocyte glycoprotein (MOG) (antigen 3) inordinately severe disease was observed with severity reduced when TNF was administered. However, in an opposing study of MOG-induced EAE, also in C57/Bl6 knockouts (antigen 3 again), EAE onset was delayed although TNF-deficient mice eventually developed peak disease severity similar to controls. Even so, overall disease course was reduced by 40%. (27) In yet another study, TNF-deficient SJL/J mice immunized with myelin basic protein (antigen 4) had delayed disease onset but they eventually developed disease of a severity similar to that seen in controls. (28) When different EAE models give discordant results in response to different antigens, opposing results in different strains, and even in the same strain, can any EAE model predict responsiveness in MS? Clearly, EAE models failed to predict response to TNF depletion in MS. Such failures may not be unique.

It is unlikely that intravenously administered anti-TNF antibodies, or TNF capture molecules, cross the blood-brain barrier (BBB) to any appreciable extent so that their site of action is almost surely outside the CNS. As expected in a study of anti-TNF-antibody treated mice, TNF was absent from the serum, but present in macrophages and microglia in the brain. Intracerebral injection of anti-TNF antibody attenuated established EAE. Systemic administration of anti-TNF antibody was much less effective. (16) TNF-knockouts lack TNF in all compartments so they may not be valid predictors of response to agents that do not enter the CNS. What cytokines or cytokine-depleting agents do outside the CNS may be quite different from what they do within the CNS.

Relapses did not significantly worsen the EDSS score in the lenercept trial. This may simply reflect the limited size of the groups studied, the brief duration of the trial, the slow tempo at which disability worsens, or the insensitivity of the EDSS instrument. Yet, even agents that profoundly lessen relapse frequency in MS can fail to demonstrate any favourable effect on the evolution of the EDSS when compared with placebo controls. The lack of correlation seen here with worsening, and elsewhere with improvement, may be artefactual in part, but probably not totally.

Since TNF neutralization with anti-TNF monoclonal antibodies, or with TNF-Rs, worsens MS, one may ask whether other agents that reduce TNF availability, might also worsen MS. Pentoxifylline is a methyl xanthine derivative, a phosphodiesterase inhibitor and a cAMP activator that inhibits TNF synthesis. The drug decreases the viscosity of blood and is approved for the treatment of peripheral arterial disease. The agent was tested in various EAE models many years ago with conflicting results. It was also tested in a pilot study of 14 progressive MS patients treated for up to 2 years. (29) TNF synthesis was reduced in patients taking 2400-3200 mg/day. Disease worsened in 12 of 14 patients during the study based on clinical, MRI, or visual evoked potential assessment. The authors were prudent. They concluded that there was 'no hint of efficacy' and that pentoxifylline lacked promise.

Cyclo propyl-substituted fluoroquinolone (FQ) antibiotics, (ciprofloxacin is the most studied), exert immuno-modulatory effects both in vitro and in vivo. (30) FQ antibiotics accumulate in monocytes and macrophages to levels up to 10-fold those found in the blood. Ciprofloxacin can clear bacteria that are resistant to ciprofloxacin by means of its immune-enhancing properties. (30) FQs exert their immunomodulatory effects preferentially in the presence of an additional stimulus such as that provided by mitogenic lectins or the lipopolysaccharide (LPS) released by gram-negative bacteria as endotoxin. LPS potently induces TNF synthesis. Ciprofloxacin, like pentoxifylline, is a phosphodiesterase inhibitor, a cAMP activator and hence a potent inhibitor of TNF production. Additionally, there is evidence for an inhibitory action of FQ antibiotics on NFkB, a transcription factor central to pro-inflammatory cytokine release, as well as on Toll-like receptor 4, the downstream element that permits LPS to induce TNF synthesis. Thus, ciprofloxacin profoundly inhibits LPS-driven TNF synthesis by monocytes in vivo at three gene transcription levels. In these ways it protects against lethal challenge with LPS in mice. (31,32) In human sepsis, ciprofloxacin (400 mg twice a day) similarly lowers TNF levels. (33) At concentrations achievable under normal clinical conditions, it profoundly suppresses TNF synthesis in response to LPS in whole blood cultures from healthy volunteers (P<0.001). (34) Importantly, ciprofloxacin inhibits IL-10 synthesis as well (P<0.009). (34)

When a drug shows a clinical benefit, regulatory agencies usually require corroborating data from a second trial. When a drug is deleterious, a confirming trial is unethical. If one postulates that there is a substantial risk that a drug might be deleterious, it is likewise unethical to test the postulate. With the above caveat in mind, I have observed multiple instances of MS relapses, many with substantial long-term residual deficit, following within days or a week or two of a brief course of ciprofloxacin, usually given to treat a urinary tract infection. These were not pseudo-exacerbations. In many instances they began after fever had resolved. I strongly suspect that the antibiotic is responsible.

The established trigger for MS relapses is acute viral infectious illness. Activation of the immune response occurs during a viral illness and is thought to kindle memory Th1 cells specific for CNS antigens in a spill-over effect. Kindled Th1 cells then make their way into the CNS and attack oligodendrocytes. MS relapses are less often triggered by urinary tract infections, presumably because the immune response to extracellular bacteria moves along a different path than the response that combats intracellular viruses. When they do occur is the infection alone responsible or is the treatment also implicated?

TNF depletion alone does not trigger MS relapses. In the lenercept trial, attack frequency was increased in each of the 6 months of the trial, but in different patients from one month to the next, even while TNF levels were reduced across the entire 6 months of the trial. Likely, TNF depletion augments the capacity of some other trigger to provoke MS attacks. Most urinary tract infections are caused by gram-negative bacteria. Gram-negative bacteria release endotoxin and endotoxemia-provoked fever is frequent during urinary tract infections. That ciprofloxacin inhibits TNF release is best shown in the presence of endotoxin. The endotoxemia-driven TNF surge is followed by a TNF-induced rise in interleukin (IL)-10 (35) a cytokine that blocks production of many pro-inflammatory cytokines. LPS-driven, TNF-induced IL-10 synthesis is markedly curtailed by ciprofloxacin in man (P<0.001). (34) TNF induction of IL-10 is likewise blocked by anti-TNF antibody. (35)

IL-10, an anti-inflammatory cytokine, is a potent inhibitor of IFN[gamma] synthesis and of Th1 cell kindling. Secreted IL-10, in a second negative feedback loop, also down regulates TNF production. IL-10 levels are reduced during MS relapses and rise as attacks end suggesting that IL-10 deficiency may permit relapses to begin and that IL-10 rebound may contribute to their ending. Perturbed TNF/IL-10 regulatory pathways, mediated by TNF neutralizing agents, perhaps including ciprofloxacin and other FQ antibiotics, may foster disease activity in MS. Clinicians may wish to pay attention to the possibility.

Key Points

* TNF protein and TNF mRNA are present within active MS demyelinating foci--TNF presence correlates inversely with mature oligodendrocyte survival.

* TNF is widely held to contribute to CNS damage in MS.

* In a double-blind, randomized, placebo-controlled Phase II trial in RRMS patients, lenercept-treated patients had more relapses than placebo-treated patients, relapses lasted longer and tended to be more severe.

* When different EAE models give discordant results in response to different antigens, opposing results in different strains, and even in the same strain, can any EAE model predict responsiveness to MS?

* TNF depletion alone does not trigger MS relapses--it is likely that it augments the capacity of some other trigger to provoke MS attacks.

Conflicts of Interest

Dr Arnason has served as a consultant to Bayer-Schering, Acorda Inc, Sonofi-Aventis, Novartis, Questcor Inc., Teva, and Serono. He has current grant support from Questcor. He has been an investigator in clinical trials sponsored by Bayer-Schering, Biogen-Idec, Teva, Serono, Novartis, Acorda.

Received: 18 March 2010

Accepted: 24 March 2010

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BGW Arnason

Department of Neurology, University of Chicago, USA

Address for Correspondence

Barry GW Arnason

Department of Neurology

University of Chicago

Surgery Brain Research Institutes

5812 South Ellis Avenue

SBRI J209 (MC 2030)

Chicago

IL 60637

USA

Tel: +1 773 702 6386

Fax: +1 773 702 9060

E-mail: barnason@neurology.bsd.uchicago.edu
Table 1: MS exacerbation frequency and duration over
the first 24 weeks of the lenercept trial

                           Placebo    10 mgm      50 mgm
                                      Lenercept   Lenercept
                           n=43       n=44        n=40

a) Patients with an        15 (35%)   21 (48%)    28 (70%)
   exacerbation

b) Number of               22         28          37
   exacerbations

c) Annual exacerbation     1.1        1.38        2.00
   rate

d) Mean duration of        28.3       38.6        41.6
   exacerbations in days

e) Exacerbation days       14.5 ***   24.6        38.5
   per patient

                           100 mgm      P-value
                           Lenercept
                           n=40

a) Patients with an        27 (67.5%)   0.003 *
   exacerbation

b) Number of               33           0.007 **
   exacerbations

c) Annual exacerbation     1.79
   rate

d) Mean duration of        42.0
   exacerbations in days

e) Exacerbation days       34.7
   per patient

* Chi-square tests:global.

** Kruskal-Wallis test.

*** b x d/N

Table 2: MS-related patient complaints over the course
of the lenercept trial

Complaint             Placebo Group   Pooled 50 and 100 mg    Ratio
                      n=43            Lenercept groups n=80

Sensory (%)           44              60.5                    1.38/1
Vision impaired (%)   19              34.0                    1.79/1
Fatigue (%)           14              26.5                    1.89/1
Limb weakness (%)     19              38.0                    2.00/1
Spasm (%)             2               10.0                    5.00/1
Vertigo (%)           2               14.0                    7.00/1
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Title Annotation:multiple sclerosis
Author:Arnason, B.G.W.
Publication:The International MS Journal
Article Type:Clinical report
Geographic Code:1USA
Date:Jul 1, 2010
Words:4177
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