Small‐Fiber Neuropathy in a Pediatric Patient Following Anti‐Tumor Necrosis Factor‐α Therapy for Ulcerative Colitis

This is the authors' abstract. We don't add key points for this paper.

Neurological involvement in the inflammatory bowel disease (IBD) population is frequently underecognized in spite of having significant morbidity. Its exact prevalence is still unknown, varying between 0.2% and 47.5%, depending on disease definitions and diagnostic methodology used (1). These complications may represent immune-mediated phenomenon directly attributable to IBD or associated with anti-tumor necrosis factor alpha (TNF-α), or non-immune–mediated manifestations either secondary to a micronutrient deficiency, a prothrombotic state, or be medication-induced (1–3). Here, we report the case of a 17-year-old girl with ulcerative colitis and autoimmune hepatitis who developed small-fiber neuropathy (SFN) associated with high anti-GM2 ganglioside titers while on anti-TNF-α therapy. Peripheral neuropathies associated with IBD in the pediatric population have rarely been described and to our knowledge this is the youngest patient reported in the literature presenting with this type of anti-TNF-α–related neurological complication. CASE REPORT This case is of a 17-year-old girl diagnosed with autoimmune hepatitis and ulcerative colitis. Although her hepatitis had remained clinically quiescent on azathioprine, her bowel disease proved to be steroid dependent. A year and half after initiation of anti-TNF-α (infliximab followed by adalimumab), the patient developed burning and stabbing lower back pain radiating to her lower limbs. She was also reporting tingling and numbness sensation in her feet. Her symptoms persisted despite high doses of gabapentin and narcotic analgesics. She was referred to neurology clinic for further evaluation. Neurological examination, electrophysiology, cerebral spinal fluid analysis, spinal and lower extremities magnetic resonance imaging, and extensive laboratory studies proved normal. Distal leg skin biopsy analysis using current published protocols and normative values, however, showed an average intra-epidermal nerve fiber density of only 0.7 fibers/mm, significantly under the 5th percentile cutoff value of 11.9 fibers/mm (for females 18–29 years of age) (4), consistent with SFN (4). An enzyme-linked immunosorbent assay (ELISA) for serum antibodies (IgG and IgM) to major gangliosides and anti-MAG (myelin associated glycoprotein) was requested and revealed a significantly positive anti-GM2 ganglioside IgM titer but negative IgG. Immunohistochemistry performed on the distal leg skin biopsy revealed dot-like C5–9b (MAC: membrance activated complex) deposition at sites where small nerve fibers are normally present (dermo-epidermal junction, sweat glands, and piloerector smooth muscle (Fig. 1), suggesting a humoral immune mediated process). Moreover, indirect immunofluorescence showed increased skin deposition of IgM when comparing our patient's pre-therapy plasma (A) with healthy-control plasma (B), therefore confirming the immunopathological role of these anti-gangliosides (Fig. 2).FIGURE 1: Immunohistochemistry for membrane attack complex (C5b-9). Pre-IVIg: MAC deposits at sites where small nerve fibers are normally present (A: dermo-epidermal junction, B: sweat gland surface, and C: smooth muscle). Post-IVIg: Absence of MAC deposits over D: dermo-epidermal junction and E: smooth muscle.FIGURE 2: Indirect immunofluorescence for human IgM. Indirect IF shows increased skin deposition of IgM using patient's pre-therapy plasma (A) compared to control patient's plasma (B).Based on these findings, an autoimmune SFN possibly related to anti-TNF-α therapy was suggested. Adalimumab was discontinued and the patient was eventually started on Vedolizumab for the treatment of her refractory colitis. Given the persistence of her debilitating neurological symptoms 5 months after discontinuation of anti-TNF-α therapy, the patient was given 1 dose of IVIg (1 g/kg). Her symptoms improved remarkably and the patient was pain-free within 6 weeks of treatment. Repeat serology and distal leg skin biopsy 4 months later showed disappearance of anti-GM2 antibodies IgM and absence of MAC deposition (Fig. 1) with increased fiber density compared to the pre-treatment biopsy (2.9 fibers/mm). DISCUSSION Our case describes a distinct clinico-pathological pattern of auto-immune SFN associated with IBD and anti-TNF-α therapy. An immune-mediated pathogenesis is suggested by the presence of MAC deposition and high titer of anti-GM2 ganglioside antibodies. This hypothesis is supported by complete clinical resolution of neuropathic pain and absence of MAC deposition with partial small-fiber density normalization following discontinuation of anti-TNF-α treatment and IVIg administration. Systematic studies evaluating the frequency of neurological complications and their patterns in patients with IBD are limited and results have been inconsistent. Case reports and small series have reported a wide spectrum of neuropathological manifestations including demyelinating central nervous system disease, and peripheral neuropathy (1). Since anti-TNF-α therapy was first approved in 1996, an associated risk of neurological adverse event has been suggested with post-marketing surveillance estimating its incidence at less than 1 event per 1000 patient during anti-TNF-α therapy (5,6). Specific to pediatric, a large study evaluating the safety profile of biological agents in more than 600 children with IBD was reporting 3 cases of demyelinating disease over a median follow-up of 28 months (7). Mainly 3 pathophysiological mechanisms for anti-TNF-α associated neuropathies have been suggested, including immune attacks against nerve components, vasculitis-induced nerve ischemia and inhibition of signaling support for axons (2). TNF-α is a cytokine with dual properties for which biological activity depends upon binding to 2 different receptors. While TNF-α receptor 1 (TNFR1) appears to exert most of the inflammatory effects, TNF-α receptor 2 (TNFR2) displays immunosuppressive properties by promoting regulatory T-cells and inducing apoptosis of autoreactive T-cells (2,8). Therefore, it is hypothesized that TNF-α blockade may trigger a specific autoimmune attack depending on the TNF receptor type activated, thus disturbing the instrinsic equilibrium of the immune system locally in the nervous system (2). The presence of MAC deposition on skin biopsy associated with high titer of anti-GM2 IgM suggests an autoimmune mechanism of neural damage with complement-mediated cell lysis. This hypothesis is further supported by the disappearance of these complement deposits on repeat skin biopsy correlating with absent anti-GM2 titer, increased intra-epidermal nerve fibers and complete resolution of our patient's symptoms. Moreover, experimental models of dysimmune neuropathies have previously demonstrated complement-mediated cell lysis induced by anti-GM2. To date, only a few cases have, however, reported peripheral neuropathies associated with anti-GM2 ganglioside and never with SFN (9). Response to IVIg may be suggested by the temporal nature of resolution of symptoms and pathologic findings in this case, but is not confirmatory. Finally, although an anti-TNF-α induced dysimmune neuropathy with induction of pathogenic autoantibodies is highly suspected, an independent association with our patient's underlying autoimmune disorder cannot be excluded. CONCLUSIONS Our case highlights important learning points. First, peripheral neuropathies, including SFN, may represent immune-mediated complications in patients with IBD either related to their underlying autoimmune pathology or occurring following exposure to anti-TNF-α treatment. Second, patients presenting predominantly with sensory neuropathy should undergo skin biopsy in order to confirm the diagnosis of SFN since neurological examination and electrophysiology studies are typically normal. Furthermore, serologic evaluations for ganglioside antibodies should be considered. Third, if causality is suspected, anti-TNF-α should be discontinued and additional immunomodulatory therapy may be considered if no improvement is observed. Clinicians treating IBD patients with anti-TNF-α should monitor for neurological symptoms and be aware of how to recognize and diagnose SFN to provide timely tailored treatment and prevent significant comorbitites.