251well understood what other baseline characteristics predispose patients to develop
demyelinating disease after anti-TNF therapy.
In a prospective study of 77 patients who were eligible to receive anti-TNF
therapy for either RA or spondylarthropathies, all patients underwent a baseline
neurological exam and both brain and cervical spine MRI. Two of these patients
did not receive anti-TNF therapy due to lesions detected on brain MRI compatible
with demyelinating diseases [ 88 ]. Neither of these two patients had neurological
symptoms after 2 years of follow-up. Among the other 75 patients who received
anti-TNF therapy, three patients developed demyelinating diseases with peripheral
neuropathy in two and optic neuritis in one [ 88 ]. The onset of neurological symp-
toms occurred between 6 and 25 months after starting anti-TNF in the cohort
examined by Kaltsonoudis et al. [ 88 ]. It is unclear whether there is an anti-TNF
therapy dose- dependent effect on the development of demyelinating diseases.
More data is needed to determine whether there is a gender predisposition for this
neurologic complication.
Pathophysiology
The pathophysiology of anti-TNF-associated demyelinating disease has not
been clearly delineated, but several hypotheses have been proposed. MS is an
autoimmune inflammatory condition where T cells react against self-myelin
antigens [ 88 ]. Experimental autoimmune encephalomyelitis (EAE) is an ani-
mal model for MS where animals are injected with an encephalogenic myelin
protein and subsequently develop a demyelinating, relapsing illness akin to
MS. EAE is mediated by autoreactive myelin-specific T cells [ 89 ]. Anti-TNF
agents were previously shown to have beneficial effect on animal model of MS
[ 88 ]. Administration of anti-TNF agents may have local anti-inflammatory
effects in tissues such as the joints and intestine. These agents can also upregu-
late the autoimmune response by activation and survival of peripheral autore-
active myelin-specific T cells which then enter the CNS causing demyelination
[ 85 , 88 ].
Another proposed pathogenic mechanism by which anti-TNF agents cause
demyelinating disease is through activation of a latent infection [ 88 ]. In the pres-
ence of anti-TNF therapy, an unmasked latent viral infection can activate myelin-
reactive T cells via molecular mimicry [ 88 ]. These activated myelin-specific T cells
then migrate into the central nervous system and release cytokines that recruit and
activate macrophages as well as more T cells which lead to myelin destruction [ 88 ,
90 , 91 ].
While TNF-α could have a detrimental effect on RA and IBD, its exact role in the
CNS is unclear. Anti-TNF therapy could inhibit TNF-α-induced interleukin-10 (IL-
10) and prostaglandin E2 production resulting in increased IL-12 production. IL-12
subsequently induces IFN-gamma expression which exacerbates MS [ 85 , 90 ].
14 Noninfectious and Nonmalignant Complications of Anti-TNF Therapy