Table of Contents Author Guidelines Submit a Manuscript
Case Reports in Medicine
Volume 2016 (2016), Article ID 1423131, 6 pages
Case Report

Adalimumab Induced or Provoked MS in Patient with Autoimmune Uveitis: A Case Report and Review of the Literature

1Division of Neurology, Department of Internal Medicine, Aleppo University Hospital, Aleppo, Syria
2Division of Rheumatology, Department of Internal Medicine, Aleppo University Hospital, Aleppo, Syria

Received 16 June 2016; Accepted 3 October 2016

Academic Editor: Malcolm E. Molyneux

Copyright © 2016 Rana Alnasser Alsukhni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Anti-tumor necrosis factor α (anti-TNF-α) agents have been widely used in the field of autoimmune diseases and have proved decisive efficacy and relative safety. Data concerning their adverse effects has been lately describing central nervous system (CNS) demyelination process at escalating basis. Case Presentation. A 23-year-old male with autoimmune uveitis and a family history of multiple sclerosis (MS) developed two neurological attacks, after Adalimumab infusion, simultaneously with several cerebral lesions on magnetic resonance imaging (MRI). Hence the diagnosis of Adalimumab induced MS was suspected. Conclusion. This case is reported to tell physicians to be cautious when using anti-TNF-α in patients with family history of MS and to reconsider the risk of MS in patients with autoimmune diseases.

1. Introduction

TNF-α is a well-known proinflammatory and immunoregulatory cytokine. It mediates inflammatory cell recruitment to the site of the infection by activating endothelial cells. Elevated levels of this cytokine, however, were detected both locally and systemically in patients with inflammatory disorders like arthritis [1]. Drugs that block the effect of TNF-α have shown beyond dispute role in modulating the activity of many autoimmune diseases. Depending on their mechanism of action, anti-TNF-α drugs are divided into monoclonal antibodies (Infliximab, Adalimumab, Golimumab, and Certolizumab) and soluble TNF-α receptors (Etanercept). Many side effects have been recorded during the relatively short history of utilizing anti-TNF-α in the field of autoimmune diseases such as infectious disease [2], autoimmune disease [3, 4], blood dyscrasia [5, 6], pulmonary fibrosis [7], congestive heart failure [8], and malignancies [9] among other adverse effects such as central and peripheral demyelination of the nervous system and optic neuritis.

CNS demyelination was conducted by several reports suggesting triggering or exacerbating demyelination diseases induced by treatment with anti-TNF-α.

In Table 1 we review the most important studies in medical literature concerning this idea.

Table 1

2. Case Presentation

A 23-year-old Arabic gentleman from Syria had a positive family history of MS affecting two of his uncles (maternal and paternal uncles; no blood relationship existed between the parents) and idiopathic epilepsy affecting his sister. His past medical history was positive for chronic autoimmune uveitis since the age of 13. It was then treated with Methotrexate with poor response, and thus it was substituted for combination of Cyclosporine and Azathioprine which achieved a better control. A year ago, Azathioprine was suspended for a while because of the political situation and Adalimumab was initiated. Few days following the second dose of Adalimumab, the patient developed right hemibody anesthesia which lasted two weeks and was successfully treated with intravenous methylprednisolone. Adalimumab was then stopped and both of Azathioprine at a dose of 3 mg/kg and oral prednisolone were initiated. Five months later, brain magnetic resonance imaging (MRI) was requested and revealed multiple periventricular and juxtacortical lesions with high T2 signal intensity along with T2 hypersignal lesion in the spinal cord at the level of the fourth cervical vertebra C4; none of these lesions were contrast enhancing (Figure 1).

Figure 1: (a, b, c, and d) Flair MRI slices (axial and coronal slices) show periventricular and juxtacortical high intensity lesions. (e) Axial T2 MRI shows multiple juxtacortical high intensity lesions. (f) Sagittal T2 MRI of the cervical spinal cord shows T2 hyperintense lesion at the level of C4.

Visually evoked potentials (VEP) were also performed and were normal. Cerebrospinal fluid (CSF) analysis was normal and negative for oligoclonal bands (OCBs).

Eight months following Adalimumab infusion, the patient had right lower limb paresis which was also successfully treated with methylprednisolone, and normal strength was restored within three weeks. Six months after then, the patient was referred by a rheumatologist to a neurology clinic for consultation and followup though there has been no new attack since then.

Neurological examination was normal except for anisocoria with slightly irregular pupils and bilaterally sluggish reaction to light (an abnormality that was explained by chronic uveitis) with normal fundoscopy and visual acuity. Mild right facial and body hemihypoesthesia, absent abdominal reflexes over the right side, generalized hyperreflexia (+3), and mild right lower limb spasticity were also noticed. To find out the relationship between the uveitis and the neurological attacks, the type of uveitis was reassessed and revealed hints of anterior and intermediate uveitis with no signs of active inflammation. An X-ray of sacroiliac joints and chest X-ray were then requested to rule out both subclinical ankylosing spondylitis and sarcoidosis and were both normal. Brain MRI with contrast was repeated and revealed no new lesions comparing with the previous one (Figure 2).

Figure 2: (a and b) Axial T2 MRI shows multiple periventricular and juxtacortical high intensity lesions. (c) Coronal flair MRI shows periventricular and juxtacortical high intensity lesions.

The previous laboratory study was reviewed and showed normal ordinary labs including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Antinuclear antibodies (ANA), rheumatic factor (RF), and antineutrophil cytoplasmic antibodies C-ANCA and P-ANCA were all negative. Human leukocyte antigen (HLA) analysis revealed HLA-B27. CSF analysis showed acellular fluid with immunoglobulin G (IgG) index of 0.53, normal protein, lactate dehydrogenase (LDH), and glucose levels. Despite the lack of enhancement, diagnosis of Adalimumab induced MS was suspected in this patient with HLAB-27 associated uveitis depending on Mcdonald’s criteria for space and time distribution and the temporal relationship between the first neurological attack and drug initiation besides the positive family history of MS. Since there were no active lesions on MRI, treatment plan was continued with no modification and regular clinical and radiological followup was suggested.

3. Discussion

This case describes two separate neurological attacks in a young patient with HLA-B27 associated uveitis and a family history of multiple sclerosis. Although neurological attacks meet Mcdonald’s criteria for time and space distribution, many differential diagnoses are plausible for this presentation, MS with associated uveitis, HLA-B27 associated uveitis and a newly diagnosed MS as two separate entities, and systemic vasculitis induced uveitis and cerebral lesions. Infectious causes and lymphoma, however, are improbable due to the prolonged history and negative laboratory investigations.

A certain type of uveitis, uveitis pars planitis, is considered a manifestation of MS that often precedes or, less often, accompanies the first attacks [17]. The type of uveitis was reassessed accordingly and revealed both anterior and intermediate uveitis which is, along with the prolonged history of uveitis, less compatible with MS and more compatible with HLA-B27 uveitis with or without seronegative arthritis such as ankylosing spondylitis, psoriasis, and inflammatory bowel disease (IBD). During 10 years of uveitis, the patient had no arthritis, gastrointestinal symptoms, skin lesions, or even lower back pain. Moreover, AXR of the pelvis revealed no sclerotic changes.

Despite its obscurity, a relationship between MS and autoimmune diseases was deduced because of the high prevalence of MS in patients with autoimmune diseases as suggested by many reports [1820]. This speculation added to the positive family history of MS renders this patient highly susceptible to MS. Furthermore, the temporal relationship between the first attack and Adalimumab infusion makes Adalimumab induced or provoked MS the most likely diagnosis.

Suspected MS following anti-TNF-α treatment in patients with family history of MS was reported in many cases [14, 18] which recommended that anti-TNF-α should be avoided in such patients and advocated requesting cerebral MRI before treatment initiation in patients with high risk of MS [21, 22].

Several mechanisms have been proposed to interpret the paradox of MS activation in spite of amelioration of systemic inflammation following anti-TNF-α infusion such as the presence of blood brain barrier (BBB). This barrier halts the entry of anti-TNF-α drugs to CNS. Meanwhile, these drugs enhance T cell receptor signaling and the functionality of antigen presenting cells and, consequently, they activate CNS demyelination. This is the essence of lack of entry theory. Presence of BBB was also the culprit in sponge theory wherein TNF-α is supposed to be drawn out of joint synovial fluid following TNF-α antagonism whereas BBB prevents this process in CNS. Thus TNF-α gradient develops across BBB and results in upregulation of TNF-α receptor expression in CNS. Moreover, severely destructed BBB in experimental autoimmune encephalopathy mice models besides the high dose used have been supposed to facilitate anti-TNF-α entry to CNS and permit the subsequent amelioration [23]. Other theories hypothesized that tumor necrosis factor receptor 2 (TNFR2) is a potential regenerator of oligodendrocytes. Hence blocking TNF-α may prevent this natural mechanism and suppress remyelination [24]. Another hypothesis postulated that anti-TNF-α drugs promote interferon γ (INF-γ) expression and this in turn disturbs the balance between INF-β and INF-γ levels which triggers demyelination process [23]. Whether the precise mechanism is uncovering or inducing demyelination is still undetermined.

Although some points argue against MS such as OCBs negativity and the lack of contrast enhancement, MS negative OCBs are a well-established entity that represents 20–30% of MS patients [25]. Moreover, OCBs could be detected later on during the circumstance of MS. No clear data is available regarding frequency of OCBs negativity in anti-TNF-α induced MS since most of the reports of similar cases did not mention the results of OCBs analysis. The lack of enhancement, however, may be explained by the time window between performing MRI and the clinical attacks; such window would have guaranteed the resolution of enhancement if it existed in addition to treatment with Azathioprine, a drug that has been accepted as a disease modifying treatment of MS [26].

Asymptomatic cerebral lesions highly suggestive of MS are widely described in patients with family history of MS under the title of radiographically isolated syndrome (RIS) [27, 28], but explicit clinical attacks turn RIS into clinically isolated syndrome (CIS) or MS. Most of the reported cases depicted several months of using anti-TNF-α agents preceding the development of clinical attacks [13, 16], while in this case development of the first clinical attack took place days following the second dose, a period that suggests a process of uncovering latent MS rather than inducing it. Even though second clinical attack occurred approximately eight months after halting Adalimumab, MRI performed six months later revealed no active disease; consequently no treatment modification was suggested, and if hints of clinical or radiological activity are noticed later on, Rituximab would be the treatment of choice of both uveitis and MS.

4. Conclusion

MS is highly expected in patients with family history of MS and, to a lesser degree, in patients with autoimmune diseases, and physician should consider such risks in patients who are eligible for anti-TNF treatment by detailed history, examination, and close followup as well as performing MRI prior to therapy initiation in highly suspected individuals.


TNF-α:Tumor necrosis factor α
CNS:Central nervous system
MS:Multiple sclerosis
MRI:Magnetic resonance imaging
VEP:Visually evoked potentials
CSF:Cerebrospinal fluid
OCBs:Oligoclonal bands
ESR:Erythrocyte sedimentation rate
CRP:C-reactive protein
ANA:Antinuclear antibodies
RF:Rheumatic factor
ANCA:Antineutrophil cytoplasmic antibodies
HLA:Human leukocyte antigen
IgG:Immunoglobulin G
LDH:Lactate dehydrogenase
IBD:Inflammatory bowel disease
BBB:Blood brain barrier
TNFR2:Tumor necrosis factor receptor 2
RIS:Radiographically isolated syndrome
CIS:Clinically isolated syndrome.

Additional Points

Availability of Data and Materials. All available data are included within the manuscript.


Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Competing Interests

The authors declare that they have no competing interests.

Authors’ Contributions

Rana Alnasser Alsukhni and Ziena Jriekh made substantial contributions to the conception of the manuscript. Yasmin Aboras revised the manuscript critically for important intellectual content. All of the authors have read and approved the final version of the manuscript.


  1. A. Caminero, M. Comabella, and X. Montalban, “Tumor necrosis factor alpha (TNF-α), anti-TNF-α and demyelination revisited: an ongoing story,” Journal of Neuroimmunology, vol. 234, no. 1-2, pp. 1–6, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. M. F. Doran, C. S. Crowson, G. R. Pond, W. M. O'Fallon, and S. E. Gabriel, “Frequency of infection in patients with rheumatoid arthritis compared with controls: A Population-Based Study,” Arthritis and Rheumatism, vol. 46, no. 9, pp. 2287–2293, 2002. View at Publisher · View at Google Scholar · View at Scopus
  3. B. Haraoui and E. Keystone, “Musculoskeletal manifestations and autoimmune diseases related to new biologic agents,” Current Opinion in Rheumatology, vol. 18, no. 1, pp. 96–100, 2006. View at Google Scholar · View at Scopus
  4. M. Ramos-Casals, P. Brito-Zerón, S. Muñoz et al., “Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases,” Medicine, vol. 86, no. 4, pp. 242–251, 2007. View at Publisher · View at Google Scholar · View at Scopus
  5. A. Marchesoni, M. Arreghini, B. Panni, N. Battafarano, and L. Uziel, “Life-threatening reversible bone marrow toxicity in a rheumatoid arthritis patient switched from leflunomide to infliximab,” Rheumatology, vol. 42, no. 1, pp. 193–194, 2003. View at Publisher · View at Google Scholar · View at Scopus
  6. S. Rajakulendran, K. Gadsby, D. Allen, S. O'Reilly, and C. Deighton, “Neutropenia while receiving anti-tumour necrosis factor treatment for rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 65, no. 12, pp. 1678–1679, 2006. View at Publisher · View at Google Scholar · View at Scopus
  7. A. Schoe, N. E. Van Der Laan-Baalbergen, T. W. J. Huizinga, F. C. Breedveld, and J. M. Van Laar, “Pulmonary fibrosis in a patient with rheumatoid arthritis treated with adalimumab,” Arthritis Care and Research, vol. 55, no. 1, pp. 157–159, 2006. View at Publisher · View at Google Scholar · View at Scopus
  8. E. S. Chung, M. Packer, K. H. Lo, A. A. Fasanmade, and J. T. Willerson, “Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial,” Circulation, vol. 107, no. 25, pp. 3133–3140, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. J. Askling, C. M. Fored, E. Baecklund et al., “Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists,” Annals of the Rheumatic Diseases, vol. 64, no. 10, pp. 1414–1420, 2005. View at Publisher · View at Google Scholar · View at Scopus
  10. D. Baker, D. Butler, B. J. Scallon, J. K. O'Neill, J. L. Turk, and M. Feldmann, “Control of established experimental allergic encephalomyelitis by inhibition of tumor necrosis factor (TNF) activity within the central nervous system using monoclonal antibodies and TNF receptor-immunoglobulin fusion proteins,” European Journal of Immunology, vol. 24, no. 9, pp. 2040–2048, 1994. View at Publisher · View at Google Scholar · View at Scopus
  11. K. Selmaj, W. Papierz, A. Glabinski, and T. Kohno, “Prevention of chronic relapsing experimental autoimmune encephalomyelitis by soluble tumor necrosis factor receptor I,” Journal of Neuroimmunology, vol. 56, no. 2, pp. 135–141, 1995. View at Publisher · View at Google Scholar · View at Scopus
  12. B. W. Van Oosten, F. Barkhof, L. Truyen et al., “Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2,” Neurology, vol. 47, no. 6, pp. 1531–1534, 1996. View at Publisher · View at Google Scholar · View at Scopus
  13. N. Mohan, E. T. Edwards, T. R. Cupps et al., “Demyelination occurring during anti-tumor necrosis factor α therapy for inflammatory arthritides,” Arthritis and Rheumatism, vol. 44, no. 12, pp. 2862–2869, 2001. View at Publisher · View at Google Scholar · View at Scopus
  14. E. Andreadou, E. Kemanetzoglou, Ch. Brokalaki et al., “Demyelinating disease following anti-TNFa treatment: a causal or coincidental association? Report of four cases and review of the literature,” Case Reports in Neurological Medicine, vol. 2013, Article ID 671935, 9 pages, 2013. View at Publisher · View at Google Scholar
  15. R. Seror, C. Richez, C. Sordet et al., “Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey,” Rheumatology, vol. 52, no. 5, pp. 868–874, 2013. View at Publisher · View at Google Scholar · View at Scopus
  16. E. Kaltsonoudis, A. K. Zikou, P. V. Voulgari, S. Konitsiotis, M. I. Argyropoulou, and A. A. Drosos, “Neurological adverse events in patients receiving anti-TNF therapy: a prospective imaging and electrophysiological study,” Arthritis Research and Therapy, vol. 16, no. 3, article R125, 2014. View at Publisher · View at Google Scholar · View at Scopus
  17. S. M. Malinowski, J. S. Pulido, N. E. Goeken, C. K. Brown, and J. C. Folk, “The association of HLA-B8, B51, DR2, and multiple sclerosis in pars planitis,” Ophthalmology, vol. 100, no. 8, pp. 1199–1205, 1993. View at Publisher · View at Google Scholar · View at Scopus
  18. É. Toussirot, É. Pertuiset, A. Martin et al., “Association of rheumatoid arthritis with multiple sclerosis: report of 14 cases and discussion of its significance,” Journal of Rheumatology, vol. 33, no. 5, pp. 1027–1029, 2006. View at Google Scholar · View at Scopus
  19. A. Calin, “Is there an association between ankylosing spondylitis and multiple sclerosis?” Annals of the Rheumatic Diseases, vol. 48, no. 12, pp. 971–972, 1989. View at Publisher · View at Google Scholar · View at Scopus
  20. T. Ruiz-Jimeno, A. Carvajal, C. Mata, and E. Aurrecoechea, “Demyelinating disease in a patient with psoriatic arthritis and family history of multiple sclerosis treated with infliximab,” Journal of Rheumatology, vol. 33, no. 7, pp. 1457–1458, 2006. View at Google Scholar · View at Scopus
  21. N. L. Sicotte and R. R. Voskuhl, “Onset of multiple sclerosis associated with anti-TNF therapy,” Neurology, vol. 57, no. 10, pp. 1885–1888, 2001. View at Publisher · View at Google Scholar · View at Scopus
  22. A. Winkelmann, R. Patejdl, S. Wagner, R. Benecke, and U. K. Zettl, “Cerebral MRI lesions and anti-tumor necrosis factor-alpha therapy,” Journal of Neurology, vol. 255, no. 6, supplement 6, pp. 109–114, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. W. H. Robinson, M. C. Genovese, and L. W. Moreland, “Demyelinating and neurologic events reported in association with tumor necrosis factor α antagonism: by what mechanisms could tumor necrosis factor α antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis?” Arthritis and Rheumatism, vol. 44, no. 9, pp. 1977–1983, 2001. View at Google Scholar · View at Scopus
  24. G. Kassiotis and G. Kollias, “Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination,” Journal of Experimental Medicine, vol. 193, no. 4, pp. 427–434, 2001. View at Publisher · View at Google Scholar · View at Scopus
  25. “Multiple sclerosis and other demylination diseases of the central nervous system,” in Bradley's Neurology in Clinical Practice, chapter 380, p. 1318, 6th edition, 2012.
  26. I. Casetta, G. Iuliano, and G. Filippini, “Azathioprine for multiple sclerosis,” Cochrane Database of Systematic Reviews, no. 4, Article ID CD003982, 2007. View at Google Scholar · View at Scopus
  27. N. De Stefano, E. Cocco, M. Lai et al., “Imaging brain damage in first-degree relatives of sporadic and familial multiple sclerosis,” Annals of Neurology, vol. 59, no. 4, pp. 634–639, 2006. View at Publisher · View at Google Scholar · View at Scopus
  28. T. Gabelic, D. P. Ramasamy, B. Weinstock-Guttman et al., “Prevalence of radiologically isolated syndrome and white matter signal abnormalities in healthy relatives of patients with multiple sclerosis,” American Journal of Neuroradiology, vol. 35, no. 1, pp. 106–112, 2014. View at Publisher · View at Google Scholar · View at Scopus