CNS Demyelination with TNF-α Blockers

Five anti-TNF-α blockers are approved for clinical use: etanercept (circulating receptor fusion protein), infliximab, adalimumab, and golimumab (IgG monoclonal antibodies), and certolizumab (PEGylated Fab1 fragment of an IgG1 monoclonal antibody) [15]. Both receptor and antibody based TNF-α blockers act as antagonists by blocking tmTNF interactions with TNFR1/2, and as agonists, by inverting signal leading to apoptosis, cell activation, or cytokine inhibition [5, 16, 17]. Etanercept also binds to lymphotoxin LTα3, which is structurally similar to sTNF, with equivalent or greater affinity than sTNF [16].

Compared with the traditional DMDs, TNF-α blockers are more efficacious, with faster onset of action and more effective control of disease progression. These characteristics have made them an appealing option in refractory cases [18, 19].

TNF-α blockers present a revolutionizing therapeutic choice for inflammatory diseases such as RA, AS, plaque psoriasis, psoriatic arthritis, juvenile polyarticular rheumatoid arthritis, and inflammatory bowel disease (CD and ulcerative colitis). TNF-α blockers are also used off-label for a number of other inflammatory conditions such as sarcoidosis, hidradenitis suppuritiva, Adamantiades-Behcet's disease, pyoderma gangrenosum, dermatomyositis, scleroderma, noninfectious uveitis, and others [20, 21]. Novel indications for the use of TNF-α blockers are under investigation, and new TNF-α blockers are being evaluated.

Initial studies in experimental autoimmune encephalomyelitis (EAE) animal models of multiple sclerosis (MS) showed beneficial effects of TNF-α blockers. Subsequently, given their anti-inflammatory effects, clinical trials of infliximab [22] and lenercept [23] (a receptor-based TNF-α blocker) were carried out in people with MS with surprisingly unfavorable results. Specifically, in an open label phase I trial with infliximab, 2 patients with rapidly progressive MS showed increased disease activity and MRI lesion load [22]. Furthermore, a randomized double-blind placebo-controlled multicenter trial in 168 relapsing-remitting MS patients with lenercept was stopped prematurely due to a dose-dependent increase in relapse rate, attack duration, and severity of exacerbations [23].

These trials suggested that non-selective inhibition of TNF-α is harmful in MS and that TNF-α exerts both potent pro-inflammatory effects and essential protective functions in the CNS under pathological conditions [9••].

The efficacy of TNF-α blockers in inflammatory conditions has increased their use. Despite their relatively safe profile, well-known adverse events include injection site reactions, risk of infections (especially tuberculosis reactivation), congestive heart failure, hemocytopenia, and T-cell lymphomas [24, 25]. Reports of autoimmune diseases, including lupus-like syndromes and vasculitis [26], diabetes mellitus, psoriasis, interstitial lung diseases, sarcoidosis, autoimmune hepatitis, uveitis, antiphospholipid syndrome, myositis, and myasthenia gravis have also been published [1, 27‐29].

With the widespread use of TNF-α blockers, a growing number of demyelinating events have been reported, including CNS demyelinating disorders [MS, optic neuritis (ON), acute transverse myelitis (TM)], as well as peripheral nervous system disorders (Guillain-Barré syndrome, Miller Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy with conduction block, mononeuropathy multiplex, and axonal sensorimotor polyneuropathies) [1, 30]. It still remains unclear whether these events are coincidental or are actually side effects of anti-TNF-α use. Even more elusive remains the underlying pathogenic mechanism [3].

The pleiotropic functions of TNF-α often show contradictory effects, particularly in the CNS. TNF-α and its receptors can either promote neuroinflammation and secondary neuronal damage, or exert protective functions under pathological conditions. Furthermore, TNF-α exerts distinctive actions at different stages of autoimmune demyelination: sTNF, but not tmTNF, promotes inflammation and disease onset, whereas sTNF and/or tmTNF have protective functions in established disease by reducing the extent and severity of autoimmune inflammation. sTNF mediates the proinflammatory effects of TNF-α via TNFR1 signaling. TNFR1 plays a critical role for the onset of CNS autoimmune disease, through induction of a pro-inflammatory environment in the CNS, but subsequently suppresses local inflammation either indirectly, mediating neuroprotection, or directly, promoting repair processes [9••]. Elevated production of TNF-α was observed in patients and animal models of MS. TNF-α overexpressing transgenic mice develop spontaneous demyelination that reverses with anti-TNF-α administration [9••], whereas demyelination is delayed in TNF-α deficient mice [31]. TNF-α has been found to increase permeability of the BBB [14] and high levels of TNF-α were found in active central and peripheral demyelinating lesions [32, 33] as well as in the serum, cerebrospinal fluid (CSF), and brain plaques of MS patients [34] correlating with disease severity or exacerbation [35, 36]. It was recently shown that TNF-α is predominantly produced by both macrophages and microglia during acute EAE and is decreased during remission, whereas TNF-α is sustained by infiltrating macrophages in progressive EAE, enhancing clinical disability and CNS inflammation [37•]. TNF-α has also been implicated in promoting macrophage polarization to a pro-inflammatory M1 phenotype [38•]. Additionally, TNF-α seems to exert a protective role in the periphery and a pathogenic role in the CNS by suppressing encephalitogenic T cell production of Th1 and Th17 in lymphoid organs, while promoting immunocyte infiltration in the CNS through chemokine production, exacerbating disease severity [39]. Inhibition of both sTNF and tmTNF does not seem to protect against demyelination [8].

Besides being crucial in host defense and inflammation and accelerating acute demyelinating processes, TNF-α is also necessary for triggering remyelination [8, 39] and promoting the proliferation of oligodendrocyte precursor cells [40]. In later stages of MS, TNF-α has shown immunosuppressive properties. In early studies of animal models, inhibition of TNF-α resulted in EAE improvement or protection against demyelination [31, 41‐43]. In recent studies, selective inhibition of sTNF was found to be beneficial during EAE, implying that the protective effects of TNF-α are exerted through the interaction of tmTNF with TNFR2 [8]. Evidence from EAE models suggest that remyelination in the CNS necessitates the expression and activity of TNFR2 and CXCR4 by oligodendrocyte progenitor cells, promoting their proliferation and differentiation into mature oligodendrocytes [40], and that selective inhibition of tmTNF/TNFR2 leads to demyelination and oligodendrocyte apoptosis [44].

Interestingly, MS susceptibility has been associated with a single nucleotide polymorphism (SNP) in a gene, encoding TNF receptor 1 (TNFR1), the TNFRSF1A gene. This SNP in TNFR1 leads to expression of a soluble form of TNFR1 that inhibits TNF-α in humans and this may play a role in MS development in some individuals, possibly mimicking the effects of TNF-α blockers [45].

Since TNF-α is implicated in demyelinating processes, TNF-α blockers were considered as a potential therapeutic choice in MS. However, the negative outcomes of these agents in MS trials [22, 23] and the reports of demyelinating events following their use for other disorders raised the suspicion that use of these drugs could be a risk factor of demyelination. In an attempt to clarify the potential biological role of TNF-α blockers in triggering or aggravating demyelination, several theories have been proposed [46]:

The large number of CNS and peripheral demyelinating disorders after TNF-α blocker administration published in the literature [2, 30, 49‐54, 55•, 56, 57••, 58‐90, 91•, 92••, 93] and the 2 clinical trials of TNF-α blockers in MS patients showing an increase of demyelinating events [22, 23] raise the question of a possible association. Moreover, many theories support a possible correlation of non-selective TNF-α blockade with demyelination.

Some of the published cases meet the Miller criteria [96], attributing the CNS demyelinating events to the TNF-a blockade. According to Miller criteria, the definition of drug-induced illness comprises 8 elements and requires the presence of at least 4: temporal association, improvement of symptoms after treatment discontinuation, positive rechallenge phenomenon, and other CNS demyelinating events reported in the literature [96]. In most cases, a temporal relation to anti-TNF-α treatment is suggested [72], with resolution of symptoms after treatment discontinuation [27, 97]. Few cases show a rechallenge phenomenon and even fewer argue in favor of the onset of a demyelinating process directly after anti-TNF-α exposure [67].

The peak age of MS onset is 20–40 years old, whereas the mean age of RA onset is 40–60 years old. In our review, the mean age of the patients who developed CNS demyelination was 45.47 years. This delayed onset of demyelination could suggest a possible association with anti-TNF-α use.