- Case report
- Open Access
- Open Peer Review
Etanercept may induce neurosarcoidosis in a patient treated for rheumatoid arthritis
- Cécile-Audrey Durel†2Email author,
- Elodie Feurer†1,
- Jean-Baptiste Pialat3,
- Emilie Berthoux2,
- Roland D Chapurlat1 and
- Cyrille B Confavreux1
© Durel et al.; licensee BioMed Central Ltd. 2013
- Received: 17 September 2013
- Accepted: 23 December 2013
- Published: 28 December 2013
TNFα blockers have drastically improved rheumatoid arthritis prognosis by preventing joint destruction in DMARD resistant patients. Altering cytokine balance in immune diseases may expose to paradoxical adverse events.
We present the case of a 40-year-old woman, with a confirmed erosive and seropositive RA, successfully treated by TNFα blocker (etanercept) for seven years, and who developed a severe neurosarcoidosis. She had lymphocytic meningitis, bilateral peripheral facial paralysis and anosmia, associated with bilateral hilar lymph nodes, papilloedema, anterior uveitis and elevated serum angiotensin-converting enzyme level. Magnetic resonance imaging showed a bilateral thickening of the Gasser’s ganglia walls and enhanced signal of the vestibulocochlear, the facial and the proximal portion of trijeminal nerves.
This case raised the issue of the imputability of etanercept in the development of neurosarcoidosis. Neurological symptoms onset in patients on TNFα blockers should lead to exclude infections, induced lupus but also paradoxical neurosarcoidosis.
- Rheumatoid arthritis
- Facial palsy
- TNF alpha blockers
Tumor necrosis factor alpha (TNFα) blockers have drastically improved the prognosis of rheumatoid arthritis by preventing joint destruction in DMARD resistant patients. We present the case of a RA patient on etanercept who suddenly developed neurosarcoidosis.
Paradoxical neurosarcoidosis appeared as the RA was in complete remission on etanercept monotherapy for several years. Since we did not obtain histological confirmation, this case is not a definite neurosarcoidosis according to Zajicek’s criteria . The delay of one month to perform biopsy while already on steroids may be the reason for non contributive histology. Nevertheless, we eliminated other neurological diseases and the diagnosis was supported by neurological impairment (lymphocytic meningitis, bilateral peripheral facial paralysis, anosmia, eyesight deficiency, papilloedema) associated with anterior uveitis, eye and mouth dryness, weight loss, hypercalcemia and hyperproteinemia. The presence of evidences for systemic sarcoidosis criteria with bilateral hilar lymph nodes, lymphocytic alveolitis, and elevated serum angiotensin-converting enzyme level classified this case as probable . More recently, chest radiograph and angiotensin-converting enzyme of Zajicek’s criteria have been shown to be of insufficient diagnostic value by Marangoni and replaced by chest high resolution computed tomography and broncheoalveolar lavage, with a CD4/CD8 lymphocytic ratio higher than 3.5, of better positive predictive value . According to these revised criteria, our case is still considered as probable .
TNFα blockers have already been associated in some cases with “paradoxical” systemic sarcoidosis  but only two cases of neurosarcoidosis have been reported and none with etanercept. One occurred in another RA female patient treated by infliximab and methotrexate . The second one refers to a man on adalimumab for an ankylosing spondylitis, who developed seizures . These three cases raise the issue of TNFα blockers imputability on the onset of neurosarcoidosis. Interestingly, some TNFα-blocker-induced sarcoidosis patients did not relapse after rechallenging . However, there are biological arguments to support imputability of TNFα blockers to sarcoidosis onset as a “class effect” rather than a drug specific phenomen regarding sarcoid-like granulomatous disease occurring during all three anti-TNF therapies. About 40 cases of sarcoid-like granuloma development during anti-TNF therapy have been actually reported in the literature. First, the key pathophysiological feature of sarcoidosis is granuloma. It aims at isolating pathogens and restricting inflammation. As sarcoidosis preferentially involves skin, lungs and eyes, one mechanism relies on the direct exposure to environmental antigens . Thus the induced immunosuppressive condition may favor development of microorganisms involved in sarcoidosis development (Propionibacterium acnes or granulosum). A second mechanism in sarcoidosis is that granulomas are characterized by local proinflammatory activated CD4 + T lymphocytes with Th1 profile (IFNγ, IL2) stimulating TNFα production by macrophages. Sarcoidotic patients have simultaneously systemic anergy due to the suppressive abilities of regulatory CD4 + CD25 + FoxP3 T lymphocytes partly triggered by TNFα. Thus TNFα blockade, independently to its anti-inflammatory effect, may be able to stimulate Th17 pathway (IL17, IL23)  and to alter T-reg lymphocyte subpopulations .
By contrast some studies reported refractory sarcoidosis cases successfully treated by TNFα blockers especially adalimumab and infliximab . Indeed, monoclonal TNFα blockers antibodies are considered to be more effective to block granuloma formation rather than etanercept which partially preserves the mechanisms leading to granuloma formation. This could explain a lack of efficacy of etanercept in granulomatous diseases (e.g. refractory sarcoidosis, crohn’s disease).
In addition to paradoxical neurosarcoidosis, other neurological adverse events have been reported with the use of TNFα blockers such as multiple sclerosis , polycranial neuritis, chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy . TNFα blockers may trigger the demyelinating process which can evolve independently afterwards . Thus physician should pay a particular attention to patients on TNFα blocker therapy who present any new neurological symptoms.
In conclusion, this case of paradoxical neurosarcoidosis induced by TNFα blockade in a RA patient underlines the risk to destabilize autoimmune profile when using targeted therapies and promote unexpected immune disease.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
- Zajicek JP, Scolding NJ, Foster O, Rovaris M, Evanson J, Moseley IF, et al: Central nervous system sarcoidosis–diagnosis and management. QJM Mon J Assoc Physicians. 1999, 92 (2): 103-117. 10.1093/qjmed/92.2.103.View ArticleGoogle Scholar
- Marangoni S, Argentiero V, Tavolato B: Neurosarcoidosis. Clinical description of 7 cases with a proposal for a new diagnostic strategy. J Neurol. 2006, 253 (4): 488-495. 10.1007/s00415-005-0043-5.View ArticlePubMedGoogle Scholar
- Tong D, Manolios N, Howe G, Spencer D: New onset sarcoid-like granulomatosis developing during anti-TNF therapy: an under-recognised complication. Intern Med J. 2012, 42 (1): 89-94. 10.1111/j.1445-5994.2011.02612.x.View ArticlePubMedGoogle Scholar
- Sturfelt G, Christensson B, Bynke G, Saxne T: Neurosarcoidosis in a patient with rheumatoid arthritis during treatment with infliximab. J Rheumatol. 2007, 34 (11): 2313-2314.PubMedGoogle Scholar
- Mao-Draayer Y, Cash T: Neurosarcoidosis in a patient treated with tumor necrosis factor alpha inhibitors. J Neurol. 2013, 260 (2): 651-653. 10.1007/s00415-012-6726-9.View ArticlePubMedGoogle Scholar
- Van der Stoep D, Braunstahl G-J, van Zeben J, Wouters J: Sarcoidosis during anti-tumor necrosis factor-alpha therapy: no relapse after rechallenge. J Rheumatol. 2009, 36 (12): 2847-2848. 10.3899/jrheum.090307.View ArticlePubMedGoogle Scholar
- Iannuzzi MC, Rybicki BA, Teirstein AS: Sarcoidosis. N Engl J Med. 2007, 357 (21): 2153-2165. 10.1056/NEJMra071714.View ArticlePubMedGoogle Scholar
- Bosè F, Raeli L, Garutti C, Frigerio E, Cozzi A, Crimi M, et al: Dual role of anti-TNF therapy: enhancement of TCR-mediated T cell activation in peripheral blood and inhibition of inflammation in target tissues. Clin Immunol Orlando Fla. 2011, 139 (2): 164-176. 10.1016/j.clim.2011.01.015.View ArticleGoogle Scholar
- Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al: IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005, 201 (2): 233-240. 10.1084/jem.20041257.View ArticlePubMedPubMed CentralGoogle Scholar
- Russell E, Luk F, Manocha S, Ho T, O’Connor C, Hussain H: Long term follow-up of infliximab efficacy in pulmonary and extra-pulmonary sarcoidosis refractory to conventional therapy. Semin Arthritis Rheum. 2013, 43 (1): 119-124. 10.1016/j.semarthrit.2012.10.008.View ArticlePubMedGoogle Scholar
- Hamon MA, Nicolas G, Deviere F, Letournel F, Dubas F: Demyelinating neuropathy during anti-TNF alpha treatment with a review of the literature. Rev Neurol. 2007, 163 (12): 1232-1235. 10.1016/S0035-3787(07)78408-4.View ArticlePubMedGoogle Scholar
- Jarand J, Zochodne DW, Martin LO, Voll C: Neurological complications of infliximab. J Rheumatol. 2006, 33 (5): 1018-1020.PubMedGoogle Scholar
- Seror R, Richez C, Sordet C, Rist S, Gossec L, Direz G, et al: Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey. Rheumatol Oxf Engl. 2013, 52 (5): 868-874. 10.1093/rheumatology/kes375.View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/13/212/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.