Baylor University Medical Center Proceedings April 2014, Volume 27, Number 2 | Page 40

Table. Laboratory test results Laboratory test Result Sodium (mEq/L) 135 Potassium (mEq/L) 4.1 Blood urea nitrogen (mg/dL) Serum creatinine (mg/dL) 9 0.45 CO2 (mEq/L) 29 Alanine aminotransferase (U/L) 23 Aspartate aminotransferase (U/L) 25 Albumin (g/dL) 3.9 Bilirubin (mg/dL) 0.4 Erythrocyte sedimentation rate (mm/hr) 76 C-reactive protein (mg/L) 11.6 Rheumatoid factor (IU/mL) 7 Creatine kinase (ng/mL) 20 Antinuclear antibodies Negative Heavy metal screen Negative Cyclic citrullinated peptide antibodies Negative Acetylcholine receptor antibodies Negative Anti–muscle-specific tyrosine kinase antibodies Negative HIV 1, 2 antibodies Nonreactive Hepatitis panel Nonreactive Immunoglobulin A (mg/dL) 164 DISCUSSION Demyelinating neuropathies have been reported as rare adverse events with anti–TNF-α therapy. The reported culprit has more often been infliximab than etanercept or adalimumab. Acute or chronic demyelinating neuropathies may occur a few months after the institution of TNF-α treatment, very often associated with conduction blocks on nerve conduction studies. However, discontinuation of the offending drug and treatment for demyelinating neuropathies have been associated with improvement in the neuropathy (3–5). The proposed pathogeneses of TNF-α-blocker–associated neuropathies include both a T-cell and humoral immune attack against peripheral nerve myelin and inhibition of vital axonal signaling functions. Vasculitis-induced nerve ischemia, either from the underlying condition or enhanced by the drugs, remains a possibility in some cases. Neuromuscular biopsies in several patients, especially with mononeuritis simplex or multiplex, have revealed necrotizing vasculitis (6). The temporal relationship between initiation of TNF-α antagonist therapy and the onset or progression of vasculitis suggests that TNF-α inhibition triggers or exacerbates vessel inflammation (6). Proposed mechanisms whereby TNF-α inhibitors promote vasculitis include 1) development of antidrug or autoantibodies during TNF-α blockade that form immune complexes that deposit in the walls of small blood vessels to activate complement and trigger a type III hy114 persensitivity reaction; 2) changes in T-cell cytokine production; 3) elevation of nuclear antigen levels in the blood because of increased apoptosis of cells targeted by TNF-α inhibitors; and 4) an increase in the immunogenic load related to downregulation of C-reactive protein by TNF-α inhibitors (7, 8). Adalimumab (Humira; Abbott, Abbott Park, IL) is a recombinant human IgG1 monoclonal antibody specific for human TNF-α. The drug was developed using phage display technology resulting in an antibody with human -derived heavy- and light-chain variable regions and human IgG-1 constant regions. Adalimumab binds specifically with TNF-α, blocking its interaction with the p55 and p75 cell surface TNF receptors and thereby modulating TNF-induced or -modulated biological responses. Neurologic deficits seen in patients who are receiving adalimumab include Guillain-Barré syndrome (9), wrist drop (10), progressive sensory demyelinating polyneuropathy (11), and optic neuropathy (12–14). Alexopoulou et al reported the other case of acute bilateral phrenic neuropathy following treatment with adalimumab (15). This patient was treated with adalimumab for psoriasis and developed acute bilateral phrenic neuropathy after the fourth dose. She was treated with oxygen, and her symptoms resolved 4 weeks following the discontinuation of adalimumab. This is the second reported case of diaphragmatic paralysis in association with adalimumab use. In this case, the temporal association of the phrenic nerve paralysis with the administration of adalimumab and the absence of any other known trigger suggest adalimumab to be the culprit agent for this condition. The patient had no evidence of other causes of mononeuropathies, including diabetes mellitus, amyloidosis, infections (e.g., HIV), malignancy, myasthenia gravis, and amyotrophic lateral sclerosis. Although monofocal motor neuropathy with conduction block and electrophysiological evidence of demyelinating neuropathy might be a rare side effect of adalimumab and other TNF-α blockers, these agents should be considered in the differential diagnoses of these neuropathies. 1. 2. 3. 4. 5. 6. 7. 8. Stübgen JP. Tumor necrosis factor-alpha antagonists and neuropathy. Muscle Nerve 2008;37(3):281–292. Ramos-Casals M, Brito-Zerón P, Muñoz S, Soria N, Galiana D, Bertolaccini L, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore) 2007;86(4):242–251. Cocito D, Bergamasco B, Tavella A, Poglio F, Paolasso I, Costa P, Ciaramitaro P, Isoardo G. Multifocal motor neuropathy during treatment with infliximab. J Peripher Nerv Syst 2005;10(4):386–387. Singer OC, Otto B, Steinmetz H, Ziemann U. Acute neuropathy with multiple conduction blocks after TNFα monoclonal antibody therapy. Neurology 2004;63(9):1754. Tektonidou MG, Serelis J, Skopouli FN. Peripheral neuropathy in two patients with rheumatoid arthritis receiving infliximab treatment. Clin Rheumatol 2007;26(2):258–260. Richette P, Dieudé P, Damiano J, Lioté F, Orcel P, Bardin T. Sensory neuropathy revealing necrotizing vasculitis during infliximab therapy for rheumatoid arthritis. J Rheumatol 2004;31(10):2079–2081. Jarrett SJ, Cunnane G, Conaghan PG, Bingham SJ, Buch MH, Quinn MA, Emery P. Anti-tumor necrosis factor-alpha therapy-induced vasculitis: case series. J Rheumatol 2003;30(10):2287–2291. Cunnane G, Warnock M, Fye KH, Daikh DI. Accelerated nodulosis and vasculitis following etanercept therapy for rheumatoid arthritis. Arthritis Rheum 2002;47(4):445–449. Baylor University Medical Center Proceedings Volume 27, Number 2