Bilateral diaphragmatic paralysis associated with the use of the tumor necrosis factor-alpha inhibitor adalimumab Mina Mecheal Benjamin, MD, Alan William Martin, MD, and Randall Lee Rosenblatt, MD
A 51-year-old woman was referred for evaluation of progressive dyspnea of 3 months’ duration. She had received 3 doses of adalimumab for treatment of rheumatoid arthritis prior to the onset of her dyspnea. Her chest examination revealed absent diaphragmatic movement with inspiration. Spirometry showed a severe restrictive defect. Radiologic studies confirmed the diagnosis of bilateral diaphragmatic paralysis. Laboratory and radiologic workup excluded other possible causes of the diagnosis. Adalimumab was discontinued, and she was treated with bilevel positive airway pressure ventilation and intravenous immunoglobulin. Three months later, the diaphragmatic paralysis persisted. This is the second reported case of bilateral diaphragmatic paralysis occurring in a patient who had received adalimumab. Acute neuropathies are rare side effects of tumor necrosis factor-alpha inhibitors.
umor necrosis factor alpha (TNF-α) inhibitors currently play a major role in the management of several autoimmune diseases. Inﬂiximab was the ﬁrst agent to be approved by the Food and Drug Administration (FDA) in 1998. TNF-α blockers are approved for the management of moderate to severely active rheumatoid arthritis or psoriatic arthritis, active ankylosing spondylitis, moderate to severely active Crohn’s disease, and active ulcerative colitis in patients with an inadequate response to conventional therapy (1). Five anti-TNF agents have been approved by the FDA: inﬂiximab, adalimumab, etanercept, golimumab, and certolizumab. These agents have demonstrated acceptable safety and tolerability proﬁles. As with all immunosuppressants and immunomodulating therapies, TNF inhibitors increase the risk of infections. Several autoimmune adverse events have been reported, ranging from asymptomatic immunological alterations to life-threatening autoimmune diseases (2). We report a case of bilateral diaphragmatic paralysis that occurred following the institution of adalimumab.
CASE PRESENTATION A 51-year-old white woman was referred to Baylor University Medical Center at Dallas for an evaluation of dyspnea. Approximately 3 months prior to her referral, she experienced dyspnea and pleuritic chest pain and was seen in a local emergency department, where she was prescribed a short course of corticosteroids. One year prior to her symptoms, she was Proc (Bayl Univ Med Cent) 2014;27(2):113–115
diagnosed with rheumatoid arthritis with symptoms of morning stiﬀness and pain in the metacarpal and shoulder joints. She was initially treated with prednisone, methotrexate, and sulfasalazine. However, she failed to respond, and adalimumab was instituted. After three doses of adalimumab, she began to experience progressive dyspnea and marked orthopnea. She had no previous history of any respiratory symptoms and no other signiﬁcant medical history. She denied cough, chest pain, or lower extremity swelling. On examination, she was tachypneic and using her sternocleidomastoid and scalene muscles. Her chest examination revealed dullness to percussion in both bases, paradoxical inward movement of the abdominal wall, and poor diaphragmatic movement with inspiration. Her jugular veins were not distended, and there was no leg edema. Her heart sounds were normal. Neurologic examination disclosed no abnormalities. A chest radiograph showed small lung volumes and a normal cardiac silhouette. Her computed tomography scan did not reveal any signiﬁcant pleural, parenchymal, or mediastinal abnormalities. Spirometry revealed a forced vital capacity (FVC) of 0.39 L (12% of predicted), forced expiratory volume in 1 second (FEV1) of 0.38 L (14% of predicted), and FEV1/FVC of 97%, consistent with a severe restrictive defect. Respiratory muscle force testing showed a negative inspiratory force of –14 (17% of predicted) and an expiratory force of +24 (16% of predicted). A ﬂuoroscopy sniﬀ test conﬁrmed the diagnosis of bilateral diaphragmatic paralysis. Her laboratory workup did not reveal any ﬁndings associated with the known causes of diaphragmatic paralysis, as shown in the Table. Adalimumab was stopped, and she was empirically started on monthly intravenous immunoglobulin infusions. Bilevel positive airway pressure was instituted to be used at night, and intermittent positive pressure ventilation with a 40 cm pressure limit was prescribed to assist with chest wall expansion. Three months later, she continued to show diaphragmatic paralysis but was less dyspneic. From the Department of Internal Medicine (Benjamin, Rosenblatt) and the Division of Neurology (Martin), Baylor University Medical Center at Dallas. Corresponding author: Mina Mecheal Benjamin, MD, Department of Internal Medicine, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, TX 75246 (e-mail: [email protected]
Table. Laboratory test results Laboratory test
Blood urea nitrogen (mg/dL) Serum creatinine (mg/dL)
Alanine aminotransferase (U/L)
Aspartate aminotransferase (U/L)
Erythrocyte sedimentation rate (mm/hr)
C-reactive protein (mg/L)
Rheumatoid factor (IU/mL)
Creatine kinase (ng/mL)
Heavy metal screen
Cyclic citrullinated peptide antibodies
Acetylcholine receptor antibodies
Anti–muscle-specific tyrosine kinase antibodies
HIV 1, 2 antibodies
Immunoglobulin A (mg/dL)
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.
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9. Shin IS, Baer AN, Kwon HJ, Papadopoulos EJ, Siegel JN. GuillainBarré and Miller Fisher syndromes occurring with tumor necrosis factor alpha antagonist therapy. Arthritis Rheum 2006;54(5):1429– 1434. 10. Alentorn A, Albertí MA, Montero J, Casasnovas C. Monofocal motor neuropathy with conduction block associated with adalimumab in rheumatoid arthritis. Joint Bone Spine 2011;78(5):536–537. 11. Lozeron P, Denier C, Lacroix C, Adams D. Long-term course of demyelinating neuropathies occurring during tumor necrosis factor-alpha-blocker therapy. Arch Neurol 2009;66(4):490–497.
12. Chung JH, Van Stavern GP, Frohman LP, Turbin RE. Adalimumabassociated optic neuritis. J Neurol Sci 2006;244(1–2):133–136. 13. Kim A, Saﬀra N. A case report of adalimumab-associated optic neuritis. J Ophthalmic Inﬂamm Infect 2012;2(3):145–147. 14. von Jagow B, Kohnen T. Anterior optic neuropathy associated with adalimumab. Ophthalmologica 2008;222(4):292–294. 15. Alexopoulou A, Koskinas J, Soultati A, Katsaounis P, Kilidireas K, Papageorgiou C, Antoniou C, Katsambas A, Archimandritis A. Acute bilateral phrenic neuropathy following treatment with adalimumab. Clin Rheumatol 2009;28(11):1337–1140.
Avocations Perception He had seen a falling robin in the blooming pansies. Compelled by an inner urge rushed to his aid. Flaccid bird was now nestled in the doctor’s palm. Fetched water from the fountain; Moistened bird’s beak. Reﬂexive movement of the tongue gave a ﬂicker of hope. Accustomed to dispensing care. The ﬁngers were in action— Massaging chest of the bird, helping him to breathe. All the while lips whispered gentle comforting sounds. Suddenly, the bird moved, Raised the head and shook stupor oﬀ. Flew past the hypnotic berries he had eaten earlier. People in the crowded oﬃce stood on their feet, Watching the entire scene through the glass window. Someone boasted with glee: “That is my doctor.” Lobby full of waiting patients clapped in approval!
—Amanullah Khan, MD, PhD Dr. Khan (e-mail: [email protected]
) is an oncologist at Baylor Medical Center at McKinney. In addition to publishing over 100 research articles, he is an award-winning poet who has written poems in three languages.
Bilateral diaphragmatic paralysis associated with the use of the tumor necrosis factor-alpha inhibitor adalimumab