Clin Rheumatol (2009) 28:1337–1340 DOI 10.1007/s10067-009-1241-9
CASE REPORT
Acute bilateral phrenic neuropathy following treatment with adalimumab Alexandra Alexopoulou & John Koskinas & Aspasia Soultati & Panayiotis Katsaounis & Konstantin Kilidireas & Constantin Papageorgiou & Christina Antoniou & Andreas Katsambas & Athanasios Archimandritis
Received: 15 April 2009 / Accepted: 17 July 2009 / Published online: 10 August 2009 # Clinical Rheumatology 2009
Abstract The recombinant human IgG1 monoclonal antibody specific for human TNF-a adalimumab (Humira) has been recently introduced for the treatment of moderate/severe psoriasis. Neurological diseases have been rarely described as adverse events of anti-TNF agents. A case of acute respiratory failure due to diaphragmatic weakness following adalimumab therapy for psoriasis is described. A 65-year-old female patient presented with jaundice followed 2 days later by severe dyspnea and tachypnea which worsened when patient was lying flat, 1 week after the fourth dose of adalimumab. Isoniazid and vitamin B6 were co-administered with adalimumab. A symmetric elevation of diaphragms was shown on radiography and fluoroscopy. A pulmonary restrictive defect with a prominent decline of forced vital capacity (FVC) when the patient was on supine position was recorded. In the absence of specific limb electrophysiological abnormalities, acute bilateral symmetric phrenic neuropathy was diagnosed. A. Alexopoulou (*) 2nd Department of Medicine, University of Athens Medical School, Hippokration General Hospital, 40 Konstantinoupoleos Street, 16342 Athens, Greece e-mail:
[email protected] J. Koskinas : A. Soultati : P. Katsaounis : C. Papageorgiou : A. Archimandritis 2nd Department of Medicine, University of Athens Medical School, Hippokration General Hospital, 11527 Athens, Greece K. Kilidireas Department of Neurology, University of Athens Medical School, ‘Aeginition’ Hospital, Athens, Greece C. Antoniou : A. Katsambas First Department of Dermatology, University of Athens Medical School, “Andreas Sygros” Hospital, Athens, Greece
The patient was a borderline candidate for mechanical ventilation for 3 weeks. Conservative treatment with oxygen was administered and both respiratory and liver disorder resolved 4 weeks following admission. A causal relationship of phrenal neuropathy with adalimumab is herein discussed. Keywords Adalimumab . Anti-TNF agents . Phrenic neuropathy Backround Three anti-TNF agents are currently approved for the treatment of rheumatic [1], digestive [2], and cutaneous diseases [3], namely infliximab, etarnecept, and adalimumab. More than 1 million patients with the above diseases have been treated with anti-TNF agents [1] and the spectrum of diseases the drugs are being used for is rapidly expanding. The recombinant human IgG1 monoclonal antibody specific for human TNF-a adalimumab (Humira) has been recently introduced for the treatment of moderate/ severe psoriasis [3, 4]. Despite the fact that these drugs have been studied extensively and have been considered safe and well tolerated, reports of adverse reactions including infections, a higher risk of cancer and lymphoma, cardiovascular disease, and demyelinating disorders are increasing [5]. Neurological diseases have been rarely described as adverse events of anti-TNF agents [6]. We herein describe a patient with psoriasis who developed acute isolated bilateral phrenic neuropathy 8 weeks following initiation of treatment with adalimumab.
Case report A 65-year-old female patient was admitted for acute hepatitis with jaundice. She had been treated with the anti-TNF-a factor
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adalimumab (inj Humira®, 40 mg subcutaneously, every 2 weeks) for pustular psoriasis. She had received four doses of the drug until admission. Isoniazid (Dianicotyl®) tab 300 mg daily, along with vitamin B6 supplementation, was coadministered. At the time of initiation of both drugs, her chest X-ray and liver function tests were normal. One week prior to admission and following the fourth dose of adalimumab, abdominal discomfort ensued followed by jaundice a few days later. Laboratory evaluation showed AST 2,285 U/l, SGPT 1,460 U/l, total bilirubin 27.5 mg/dl, direct bilirubin 19.2 mg/dl, ALP 184 mg/dl, and γGT 158 mg/dl. Both adalimumab and isoniazid were discontinued. Physical examination showed dyspnea, tachypnea, and crackles in both lower lung fields. Elevation of both diaphragms was noted on chest radiography (Fig. 1). Her blood gases on admission in room air were: pH 7.47, PaO2 58 mmHg, PaCO2 27 mmHg, SaO2 90%, and HCO3 23 mEq/l. Treatment with O2 was administered. Over the following 2 days, her respiratory distress increased further and her blood gases were in FiO2 50%: pH 7.47, PaO2 60 mmHg, PaCO2 30 mmHg, SaO2 91%, and HCO3 24 mEq/l. Her dyspnea worsened further when she was lying flat. No history of diabetes mellitus, hyperlipidemia, or alcohol consumption was present. Serology for hepatitis A, B, C, human immunodeficiency virus, Epstein Barr, and CMV was negative. Antinuclear, gastric parietal cell, mitochondrial, microsomal, smooth muscle, antineuronal, cardiolipin, thyroid, MuSK, and acetylcholine receptor binding autoantibodies were all negative. TSH, B12, complement components, and immunoelectrophoresis were normal. Computed tomography (CT) scans of both abdomen and thorax were unremarkable except for atelectasis in lower pulmonary fields bilaterally. No cardiac disease was evident in chest radiography and echocardiography. Fluoroscopy study revealed reduced bilateral diaphragmatic movements with
Clin Rheumatol (2009) 28:1337–1340 Table 1 Pulmonary function tests demonstrate a restrictive defect which worsens when the patient is lying down Parameter
FVC (l) FEV1 (l) FEV1% (%) PEF (l/s) FEF2575 (l/s)
Standing
Lying down
Pre #1
% Predicted
Pre #2
% Predicted
1.81 1.12 61.9 3.06 0.48
78 58 80 56 18
1.22 1.06 86.9 2.91 1.30
53 55 113 53 49
respiration. Spirometry showed a rather restrictive defect which deteriorated further in supine position (Table 1). On neurologic examination, tendon reflexes and cranial nerve functions were preserved. Neither focal neurologic deficits nor eyelid ptosis was noted. Sensory and motor conduction velocities in upper and lower limbs and muscle action potential did not reveal any specific disorder. No electrophysiological studies for diaphragm were performed. Supportive care with supplemental oxygen to keep her oxygen saturation above 90% was administered. One week postadmission, her liver function tests started to ameliorate gradually and 2 weeks thereafter her arterial blood gases also improved (FiO2 35%, pH 7.43, PaO2 86 mmHg, PaCO2 34 mmHg, SaO2 96.%, and HCO3 23 mEq/l). At the fourth week post-admission, her liver function tests approached normal values and her oxygen saturation was above 90% on room air. Her chest radiography normalized and the patient was discharged. Two months later, she presented for a follow-up visit with normal liver function tests, normal pulmonary function tests (PFTs), and an oxygen saturation of 98% on room air. Liver biopsy performed 5 months later, when the patient underwent a laparoscopic cholocystectomy for acute cholecystitis, revealed normal histology.
Discussion
Fig. 1 Chest X-ray demonstrating elevation of diaphragms bilaterally
In the index patient, the lack of any specific neurological deficits, acetylcholine receptor binding autoantibodies, and the absence of any specific findings in limb nerve electrophysiological studies render disorders of neuromuscular transmission, i.e., myasthenia gravis and Eaton–Lambert syndrome rather unlikely. In addition, the diagnosis of other muscle diseases, i.e., polymyositis/dermatomyositis could not be established due to lack of clinical or laboratory evidence. Isoniazid-induced neuropathy could not be considered as a putative diagnosis since the patient has taken vitamin B6 in the recommended dose. No facilities for phrenic nerve conduction studies or diaphragmatic electromyography were available in our hospital; therefore, the diagnosis of phrenic neuropathy was based
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on radiography and PFTs. The PFTs of the index patient showed a restrictive ventilatory defect coupled with a reduced arterial O2 tension on room air and a reduction in lung volumes with elevated hemidiaphragms bilaterally. Measurements of forced vital capacity (FVC) in upright and supine position corroborated the entertained diagnosis since there was a reduction of FVC by 33% in the supine position over the upright value. These studies though not diagnostic are suggestive of diaphragmatic dysfunction [7, 8]. The respiratory failure was attributed to diaphragmatic dysfunction rather than parenchymal disease and resulted in the described atelectatic changes on both lung bases in CT scan. Acute phrenic neuropathy can be the initial presentation of several diseases such as Guillain–Barre syndrome, motor neuron disease, vasculitis, sarcoidosis, multifocal motor neuropathy, Lyme disease, diabetic neuropathy, and radiation- or surgery-induced phrenic nerve damage [9]. However, all the above neurological entities were reasonably excluded in the index patient, who had no other clinical or electrophysiological manifestations of a widespread neurological disease but the neurologic involvement was restricted to phrenic nerves. A more systemic disease such as vasculitis could not be established due to absence of further clinical or laboratory features. Bilateral phrenic neuropathy has also been described in the context of brachial plexus neuropathy (neuralgic amyotrophy) characterized by proximal limb pain, weakness, and paresthesias [10–14]. Isolated bilateral phrenic neuropathy without involvement of the brachial plexus is considered unusual [8, 10, 12–14] and some investigators speculate that it is a unique distinguishable entity [12]. The respiratory failure in the index patient was life threatening since she was, for a long time, a candidate for mechanical ventilation. Nevertheless, her recovery was rather rapid compared to that reported in the literature. In patients with bilateral diaphragmatic paresis, recovery of diaphragmatic strength may occur but may be delayed lasting a few years [8, 12–14]. Anti-TNF-a therapies have been associated with the development of peripheral neuropathies [6]. A temporal relationship of diaphragmatic damage with the administration of adalimumab was evident in the case described. In addition, a relatively rapid improvement compared to that reported in the literature following adalimumab withdrawal without any additional treatment was strongly suggestive of a drug-related cause. To our knowledge, our patient is the first case of acute bilateral phrenic neuropathy related with anti-TNF-a treatment. Altered immunity due to increasing number and activity of autoreactive T cells induced by the anti-TNF-a treatment [6] may have triggered an immunemediated neurologic disease in the case described. Liver involvement accompanied the diaphragmatic weakness. The patient presented with acute icteric hepatitis
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and shortly thereafter experienced acute dyspnea. Since virological and tests for autoimmunity were negative, the acute hepatitis was considered isoniazid induced due to temporal relationship with the administration of this particular drug. Even though there are case reports describing drug-induced acute hepatitis temporally related to anti-TNF-a treatment, the episodes of hepatitis reported were rather mild and anicteric not resembling to the current case [15, 16]. In the case described, liver biopsy was not performed at acute phase since tachypnea prevented patient from holding her breath. Liver histology 5 months following normalization of liver tests did not show findings consistent of acute or chronic liver disease. In conclusion, a case of acute bilateral isolated phrenic neuropathy with severe respiratory failure, temporally related to adalimumab therapy in a patient with psoriasis, is herein described. Although a causal relationship between diaphragmatic damage and anti-TNF-a therapy could not be proven, clinicians should be aware of this possibility and monitor patients who are receiving anti-TNF-a agents for neurological symptoms and signs.
Disclosures None
References 1. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275–2285 2. Sandborn WJ, Rutgeerts P, Enns R et al (2007) Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 146:829–838 3. Katsambas A (2008) Treating psoriasis as a chronic systemic inflammatory disease. Br J Dermatol 158:558–566 4. Papoutsaki M, Costanzo A, Chimenti MS, Chimenti S (2008) Adalimumab for the treatment of severe psoriasis and psoriatic arthritis. Expert Opin Biol Ther 8:363–370 5. Ramos-Casals M, Solans R, Rosas J et al (2008) Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients. Medicine (Baltimore) 87:210–219 6. Stübgen JP (2008) Tumor necrosis factor-alpha antagonists and neuropathy. Muscle Nerve 37:281–292 7. Chan CK, Loke J, Virgulto JA, Mohsenin V, Ferranti R, Lammertse T (1988) Bilateral diaphragmatic paralysis: clinical spectrum, prognosis, and diagnostic approach. Arch Phys Med Rehabil 69:976–979 8. Kumar N, Folger WN, Bolton CF (2004) Dyspnea as the predominant manifestation of bilateral phrenic neuropathy. Mayo Clin Proc 79:1563–1565 9. Gilchrist JM (2002) Overview of neuromuscular disorders affecting respiratory function. Semin Respir Crit Care Med 23:191–200 10. Valls-Solé J, Solans M (2002) Idiopathic bilateral diaphragmatic paralysis. Muscle Nerve 25:619–623
1340 11. Nardone R, Bernhart H, Pozzera A, Taddei M, Tezzon F (2000) Respiratory weakness in neuralgic amyotrophy: report of two cases with phrenic nerve involvement. Neurol Sci 21:177–181 12. Lin PT, Andersson PB, Distad BJ et al (2005) Bilateral isolated phrenic neuropathy causing painless bilateral diaphragmatic paralysis. Neurology 65:1499–1501 13. Tsao BE, Ostrovskiy DA, Wilbourn AJ, Shields RW Jr (2006) Phrenic neuropathy due to neuralgic amyotrophy. Neurology 66:1582–1584
Clin Rheumatol (2009) 28:1337–1340 14. Lahrmann H, Grisold W, Authier FJ, Shields RW Jr (1999) Neuralgic amyotrophy with phrenic nerve involvement. Muscle Nerve 22:437–442 15. Thiéfin G, Morelet A, Heurgué A, Diebold MD, Eschard JP (2008) Infliximab-induced hepatitis: absence of cross-toxicity with etanercept. Joint Bone Spine 75:737–739 16. García Aparicio AM, Rey JR, Alvarez JS (2007) Successful treatment with etanercept in a patient with hepatotoxicity closely related to infliximab. Clin Rheumatol 26:811–813
