Journal of Dermatological Treatment

ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: http://www.tandfonline.com/loi/ijdt20

Demyelinating disorders secondary to TNFinhibitor therapy for the treatment of psoriasis: A review Tian Hao Zhu, Mio Nakamura, Michael Abrouk, Benjamin Farahnik, John Koo & Tina Bhutani To cite this article: Tian Hao Zhu, Mio Nakamura, Michael Abrouk, Benjamin Farahnik, John Koo & Tina Bhutani (2016): Demyelinating disorders secondary to TNF-inhibitor therapy for the treatment of psoriasis: A review, Journal of Dermatological Treatment, DOI: 10.3109/09546634.2015.1136385 To link to this article: http://dx.doi.org/10.3109/09546634.2015.1136385

Published online: 02 Feb 2016.

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Date: 07 February 2016, At: 21:13

http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, Early Online: 1–8 ! 2016 Taylor & Francis. DOI: 10.3109/09546634.2015.1136385

REVIEW ARTICLE

Demyelinating disorders secondary to TNF-inhibitor therapy for the treatment of psoriasis: A review Tian Hao Zhu1, Mio Nakamura2, Michael Abrouk3, Benjamin Farahnik4, John Koo2, and Tina Bhutani2

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1

University of Southern California Keck School of Medicine, Los Angeles, CA, USA, 2Department of Dermatology, Psoriasis and Skin Treatment Center, University of California San Francisco, San Francisco, CA, USA, 3University of California Irvine School of Medicine, Irvine, CA, USA, and 4 University of Vermont College of Medicine, Burlington, VT, USA Abstract

Keywords

Background: Tumor necrosis factor-a inhibitors (TNFi) are the most widely used systemic treatments for patients with psoriasis and psoriatic arthritis. There currently exists a U.S. Food and Drug Administration issued warning label on all TNFi for ‘‘rare cases of new onset or exacerbation of central nervous system demyelinating disorders.’’ The aim of this review was to update the incidence of TNFi-induced demyelinating diseases. Methods: Pubmed database was searched for safety data regarding demyelinating disease secondary to TNFi therapy prescribed for psoriasis. Results: In clinical trials: 6990 patients had received treatment with etanercept with one reported case of multiple sclerosis; 5204 patients were treated with adalimumab with no cases identified and 2322 patients were treated with infliximab with one case of demyelinating polyneuropathy. Outside of clinical trials: 19 individual cases of demyelinating disorders from TNFi treatment have been reported. Conclusion: Although there is potential for TNF blockade to lead to demyelination of the central and peripheral nervous systems, the results of the present review suggest that demyelinating diseases associated with TNFi are extremely rare. TNFi are not recommended for use in patients with a personal history of demyelinating disease. However, with clinical vigilance and individualized treatment regimen, TNFi may be safe for use in other patients.

Psoriasis, tumor necrosis factor-inhibitor, adalimumab, etanercept, infliximab, demyelinating disorder, adverse event

Introduction Tumor necrosis factor-a inhibitors (TNFi) are among the most commonly prescribed systemic treatments for immune-mediated inflammatory diseases. Since their approval by the U.S. Food and Drug Administration (FDA), TNFi have significantly advanced the treatment of psoriasis. They have been shown to reduce symptoms, allow long-term control of the disease and improve physical function for adult patients with moderate to severe plaque psoriasis (1,2). However, despite their efficacy in treating psoriatic disease, concerns still exist today regarding safety and tolerability. The most recognized warnings and precautions have included serious infections related to reactivation of latent tuberculosis, malignancy, and cardiovascular disease (2–4). Although less commonly documented, TNF-blocking agents have also been associated with neurological complications. The FDA has included a warning label regarding ‘‘rare cases of new onset or exacerbation of central nervous system demyelinating disease’’ (2–4). However, this association is not well understood.

Correspondence: Tian Hao Zhu, 515 Spruce Street, San Francisco, CA 94118, USA. Tel: +1-415-476-3396. Fax: +1-415-502-4126. E-mail: [email protected]

History Received 12 November 2015 Revised 19 December 2015 Accepted 20 December 2015 Published online 29 January 2016

There are currently three TNFi approved for use in the treatment of psoriasis. They include the fusion protein etanercept (enbrel) and monoclonal antibodies adalimumab (humira) and infliximab (remicade). This article attempts to review the incidence of TNFi-induced demyelinating diseases reported in phase III and IV trials as well as those reported in case reports or case series. Potential mechanisms explaining their relation will be explored. Finally, the authors will attempt to understand the clinical perspective of demyelinating diseases as a potential side effect of TNFi therapy.

Methods Pubmed database was searched from 1965 to August 2015 for phase III and IV clinical trials, case reports and case series. Each of the following terms [‘‘neurological adverse event,’’ ‘‘risks,’’ ‘‘side effects,’’ ‘‘demyelinating disorder,’’] was combined with the word ‘‘psoriasis’’ and the list of TNFi and their trade names – etanercept (enbrel), adalimumab (humira) and infliximab (remicade). Only events that occurred during TNFi treatment for psoriasis or psoriasis with psoriatic arthritis were considered. Demyelinating disorders were defined as acquired inflammatory conditions of the central or peripheral nervous system characterized by myelin sheath damage and included the diagnosis of multiple sclerosis (MS), optic neuritis (ON), Guillain–Barre´

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T. H. Zhu et al.

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syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), bilateral phrenic neuropathy and ‘‘demyelinating polyneuropathy’’ (demyelinating disease not otherwise specified).

Results Etanercept (enbrel)

weekly or weekly injections of 25 or 50 mg. A total of 6990 patients were involved in these studies and only one case of MS was reported in an individual who was treated with etanercept 25 mg twice weekly for 24 weeks. A phase III trial with a 96-week follow-up period investigating etanercept therapy in a pediatric population did not identify any demyelinating events (13,15).

Phase III clinical trials

Phase IV clinical trials

There were a total of 15 phase III randomized controlled psoriasis trials and extension studies with safety information following etanercept therapy (5–19). The studies are listed in Table 1(A), which summarizes the dosing regimen, duration of treatment, the total number of subjects and number of reported cases of the demyelinating disease. The dosing schedule included twice

There have been four post-marketing surveillance studies with three reported incidents of demyelinating diseases to date. Papp et al. (2012) summarized 4-year safety data from a post-hoc analysis of a cohort of 506 Canadian patients and found no cases of demyelinating disorders (20). In an open-label phase IV study (EDUCATE) following patients with psoriasis and PsA, Gottlieb

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Table 1. Reports of demyelinating disorders in phase III clinical trials and extension studies on TNFi’s for the treatment of psoriasis.

References (name of the study)

Dosing regimen (weeks)

Duration (weeks)

Reported cases of the demyelinating disease

A. Etanercept (Enbrel) Mease et al. 2000* Leonardi et al. 2003 Gottlieb et al. 2003 Mease et al. 2004* Costanzo et al. 2005 Papp et al. 2005 De Felice et al. 2006* Moore et al. 2007 Paller et al. 2008 van de Kerkhof et al. 2008 Paller et al. 2010 Sterry et al. 2010 (PRESTA)* Leonardi et al. 2010 Ortonne et al. 2013 Lebwohl et al. 2013

BIW QW, BIW BIW BIW BIW BIW BIW BIW QW QW QW QW, BIW QW, BIW QW, BIW QW, BIW

12 24 24 24 24 24 12 12 48 24 96 24 48 24 24 Total

0/19* 0/652 0/112 1/101* 0/44 0/583 0/71* 0/2546 0/211 0/142 0/181 0/752* 0/912 0/72 0/592 1/6990

B. Adalimumab (Humira) Gordon et al. 2006 Menter et al. 2008 (REVEAL) Mease et al. 2009 (ADEPT)* Bissonnette et al. 2010 Thac¸i et al. 2010 (BELIEVE) Asahina et al. 2010 (M04-688) Gladman et al. 2010 (ACCLAIM)* Strober et al. 2011 Leonardi et al. 2011 (REACH) Gordon et al. 2011 (REVEAL) Papp et al. 2012 (PRIDE) Leonardi et al. 2012

0**, 1, then EOW or QW 0**, 1, then EOW EOW EOW then QW 0**, 1, then EOW 0**, 1, then EOW EOW 0**, 1, then EOW 0**, 1, then EOW EOW 0**, 1, then EOW QW or EOW

60 52 48 24 16 24 12 16 28 156 24 312 Total

0/147 0/1212 0/128* 0/85 0/730 0/169 0/68* 0/82 0/72 0/840 0/203 0/1468 0/5204

C. Infliximab (Remicade) Chaudhari et al. 2001 Gottlieb et al. 2004 Reich et al. 2005 (EXPRESS) Smith et al. 2006 Antoni et al. 2008 (IMPACT)* Torii et al. 2010* Torii et al. 2011* Barker et al. 2011 (RESTORE1) Bissonnette et al. 2011 Baranauskaite et al. 2012 (RESPOND)* Gottlieb et al. 2011 (PSUNRISE) Yang et al. 2012 Reich et al. 2013 (RESTORE2)

0, 2, 6 0, 2, 6 0, 2, 6 0, 2, 6 Q8W 0, 2, 6 0, 2, 6 0, 2, 6 0, 2, 6 0, 2, 6 0, 2, 6 0, 2, 6 Q8W

6 26 50 50 52 62 50 26 22 14 26 26 124 Total

0/33 0/249 0/378 0/23 0/46* 0/37* 0/37* 0/653 0/24 0/57* 1/215 0/129 0/441 1/2322

then Q8W then Q8W then then then then then then then

Q8W Q8W Q8W Q8W Q8W Q8W Q8W

TNFi, tumor necrosis factor inhibitor; PsA, psoriatic arthritis; QW, once a week; BIW, twice a week; Q8W, every 8 weeks. *Study involved patients treated with TNFi for psoriasis and psoriatic arthritis. **Adalimumab 80 mg loading dose at week 0.

43 F

23 M

47 F

40 M

45 M

40 M

47 M

32 M

Mahil et al. 2012**

C. Infliximab (Remicade) Cisternas et al. 2002

Ruiz-Jimeno et al. 2006

Lozeron et al. 2009

Lozeron et al. 2009***

Eguren et al. 2009

Eguren et al. 2009

Bebe et al. 2012

Unknown

Unknown

Unknown

Unknown

Unknown

None

GBS

None

None

42 M

None

Solomon et al. 2011**

36 F

B. Adalimumab (Humira) Berthelot et al. 2005*

Unknown

GBS

61 F

Solomon et al. 2011

Unknown

53 F

34 M

Nozaki et al. 2011

Unknown

Ahmed et al. 2011

40 M

Lozeron et al. 2009

Unknown

None Unknown

18 F

A. Etanercept (Enbrel) Sukal et al. 2006

PH

Chung et al. 2006 55 M Alexopoulou et al. 2009 65 F

Age/sex

References

Unknown

Unknown

Unknown

Unknown

Unknown

MS

Unknown

None

Unknown

Unknown

None Unknown

None

Unknown

Unknown

Unknown

Unknown

FH

2 week

14 weeks

32 weeks

7 months

72 weeks

8 months

3 months

11 months

4 months

10 months

4 months 2 months

2 months

6 years

Several months 2 years

1 year

Lower limb paresthesia and weakness Myalgia and extremity weakness

Progressive extremity weakness

Foot drop and extremity paresthesia Clawhand and muscle weakness

Extremity and respiratory weakness Vision loss, facial paresthesia, paraparesis

Lower limb numbness and spasticity

Vision loss

Extremity hyperesthesia and gait clumsiness

Paresthesia, foot drop, lower extremity weakness Vision loss Dyspnea, tachypnea

Chest dysesthesia, leg numbness, imbalance, UTI

Extremity numbness and blurry vision Paresthesia in fingers and feet Unknown

Duration of TNFi uses prior to onset of neurological Presenting signs symptoms and symptoms

Table 2. Case reports of demyelinating disease with TNFi therapy for psoriasis.

Demyelinating polyneuropathy Demyelinating polyneuropathy

Demyelinating polyneuropathy Demyelinating polyneuropathy Demyelinating polyneuropathy

Multiple sclerosis

Guillain–Barre´ Syndrome

Demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy Optic neuritis

Optic neuritis Bilateral phrenic neuropathy

Demyelinating polyneuropathy

Demyelinating polyneuropathy Demyelinating polyneuropathy Multiple sclerosis

Multiple sclerosis

Demyelinating disease

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None

None

IVIG + Plasmapheresis IVIG

IVIG

IVIG + Steroids

IVIG

None

Steroids

IV corticosteroids Supplemental O2+Supportive care IVIG + Steroids

None

Interferon

None

None

None

Treatment

Complete resolution (continued )

Complete resolution at 4 months

Complete resolution at 6 months

Complete resolution at 3 months

Complete resolution at 5 months

Progressive multiple sclerosis at 7 months

Complete resolution at 3 weeks

Partial visual improvement at 8 months Complete resolution at 6 months

Complete resolution at 19 months

Complete resolution at 1 year Complete resolution at 2 months

Complete resolution at 4 weeks

Progressive multiple sclerosis at 3 years

Complete resolution at 11 months Not resolved

Complete resolution at 7 months

Outcomes

DOI: 10.3109/09546634.2015.1136385

Psoriasis and TNFi associated demyelinating disorders 3

IVIG

IVIG

None Foulkes et al. 2014**** 49 M

None

2 week

Lower limb paresthesia and gait Demyelinating clumsiness polyneuropathy Extremity sensory disturbance and Chronic inflammatory muscle weakness demyelinating polyneuropathy Unknown Naruse et al. 2013

64 M

Unknown

1 month

Demyelinating disease FH References

Age/sex

PH

Duration of TNFi uses prior to onset of neurological Presenting signs symptoms and symptoms

Table 2. Continued

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FH, family history of demyelinating disease; GBS, Guillain–Barre´ syndrome, IV-intravenous; IVIG, intravenous immunoglobulin; MS, multiple sclerosis; PH, personal history of demyelinating disease; PsA, psoriatic arthritis; TNFi, tumor necrosis factor inhibitor; UTI, urinary tract infection. *Patient received etanercept and infliximab prior to starting adalimumab. **Patient received etanercept prior to starting adalimumab. ***Patient received etanercept prior to starting infliximab. ****Patient received adalimumab prior to starting infliximab.

Partial resolution at 1 year

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Treatment

Complete resolution at 1 week

T. H. Zhu et al.

Outcomes

4

et al. (2006) did not identify any patients with demyelinating symptoms out of 1122 treated in the 24-week observational period (21). A similar study by Gladman et al. (2011) involved 110 Canadian patients with psoriasis and PsA who received weekly etanercept 50 mg for up to 2 years also reported no incidence of demyelinating disease (22). However, recent data from the OBSERVE registry with 2510 patients in dermatology clinics surveyed in the US and Canada identified three cases of new onset CNS demyelinating diseases 0.1% (95% CI: 0.0–0.3%) at its 5year conclusion stage (23). Case reports/series There were a total of four cases of etanercept associated demyelinating disorders reported in case reports and case series (Table 2A) (24–27). Subjects included males and females ages 18–61. The average duration of drug therapy before symptom onset was 3 years with a range of several months to 6 years. The reported neuropathies included demyelinating polyneuropathy (n ¼ 2) and MS (n ¼ 2). Half of the patients’ neurologic symptoms resolved completely following cessation of etanercept without further intervention. One patient’s symptoms remained unchanged while another patient with MS experienced worsening of symptoms despite treatment with interferon. Adalimumab (humira) Phase III clinical trials A total of 12 phase III randomized clinical trials and extension studies were identified with safety data pertaining to demyelinating disorders following treatment of psoriasis (28–39). The 12 studies are summarized in Table 1(B). Most studies used the standard loading dose of adalimumab 80 mg at weeks 0, followed by 40 mg at week 1 and every other week thereafter. A minority of the studies used weekly dosing (28,31,39) or did not specifically report a loading dose (30,31,34,37,39). Study duration ranged from 12 weeks to 6 years (312 weeks). Overall, there have been a total of 5204 patients who have received treatment with adalimumab with no reported cases of demyelinating disorders. Phase IV clinical trials In a 5-year analysis of an ongoing 10-year observational registry (ESPRIT) evaluating long-term efficacy and safety of adalimumab in routine clinical practice, patients with moderate-to-severe psoriasis on adalimumab were followed through routine questionnaires, as well as patient and physician assessments. In this post-marketing study, 6059 patients have been monitored with no reported cases of demyelinating disease to date (40). Case reports/series There have been six cases of demyelinating diseases reported in case reports and case series associated with adalimumab (Table 2B) (27,41–45). There were two male and four female patients between the ages of 36 and 65. The duration of adalimumab therapy to the onset of neurological event ranged from 2 to 11 months with an average of 5.5 months. Reported diseases included two cases of ON (27,42) and demyelinating polyneuropathy (41,45) and one case each of CIDP (44) and bilateral phrenic neuropathy (43). Following the neurological event, adalimumab therapy was discontinued in all cases. Upon initiation of supportive care, intravenous steroids or intravenous immunoglobulin (IVIG), 5/6 patients achieved full recovery while one patient attained partial resolution.

DOI: 10.3109/09546634.2015.1136385

Infliximab (remicade) Phase III clinical trials Thirteen phase III randomized clinical trials and extension studies were found with safety data regarding infliximab therapy for psoriasis (46–58). These studies are summarized in Table 1(C). All studies used the standard dosing of infliximab 5 mg/kg at weeks 0, 2, 6, then every 8 weeks thereafter (if applicable) for a duration of 6–124 weeks. Two studies had additional dosing groups, one using 10 mg/kg (46) and the other 3 mg/kg (47). Out of the total number of 2322 patients, there was only one case of demyelinating polyneuropathy.

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Phase IV clinical trials A phase IV multicenter study reported no cases of demyelinating disease out of 660 patients taking infliximab over a 2-year observational period (59). Additionally, in the ongoing worldwide Psoriasis Longitudinal Assessment and Registry with data from over 2.54 observational years from 2261 patients taking infliximab, there have been no demyelinating diseases reported to date (60). Case reports/series There are nine case reports of infliximab-associated demyelinating disorders to date (Table 2C) (25,61–66). Subjects included males and females between the ages of 23 and 64 and the onset of symptoms occurred at an average of 15 weeks after initiation of therapy. There were six cases of demyelinating polyneuropathy (25,63–65) and one case each of CIDP (66), MS (62) and GBS (61). Seven of the nine cases required IVIG and/or corticosteroids. Withdrawal of infliximab led to symptom resolution in all but one case of progressive-relapsing-type MS (62) and one case of CIDP (66). These two patients exhibited persistent symptoms requiring long-term immunoglobulin and/or corticosteroid therapy.

Discussion There currently exists a warning label issued by the FDA on all TNFi for ‘‘rare cases of new onset or exacerbation of central nervous system demyelinating disorders.’’ The label originated from a phase II study on lenercept, a TNFi which was being tested as a potential new treatment for MS. Contrary to expectation, a statistically significant increase in the proportion of subjects experiencing exacerbations of MS was observed with lenercept, as well as a shortening of time-to-flare (67). Neurologic deficits were also significantly worse in subjects receiving lenercept than those receiving placebo (67). Due to similar mechanisms of action of etanercept, adalimumab, and infliximab, these TNFi have been labeled with the same warnings today. TNF-a has long been characterized as an important proinflammatory cytokine in the disease process of psoriasis and PsA (68). Downregulation of TNF-a has been shown to limit pathologic inflammation and improve psoriatic plaques. However, immunologic studies have documented a potential mechanism by which TNF-a blockade can lead to the development of neuropathological disorders (1,69,70). It has been shown that MS-like disease was reproducible in TNF-a knockout mice. Upon rechallenge with recombinant TNF-a the MS syndrome improved significantly, suggesting the protective effect of TNF-a on the CNS (71,72). Recently, TNF-a has also been shown to play a critical role as a regulator of autoreactive T cells by suppressing T-cell reactivity to self-antigens (70). When TNF-a levels are diminished or neutralized, tolerance to self-antigens is weakened, which permits autoreactive T-cells to bind self-antigens on myelin sheaths (1).

Psoriasis and TNFi associated demyelinating disorders

5

This leads to interferon-g production and subsequent demyelination (1,69). Thus, long-term TNF-a antagonist administration may potentially increase the risk of developing autoimmune demyelinating neuropathy. Another hypothesis is that immune complexes can form from anti-drug autoantibodies during TNF blockade that become deposited in the walls of blood vessels. This then activates complement and triggers a type-III hypersensitivity reaction leading to vasculitis-induced nerve ischemia and disruption of axonal signaling (1). Furthermore, anti-TNFa induced neurological disorders are multi-faceted and consist of not only T-cell but also B-cell mediated autoimmune attack, which can target the peripheral myelin sheath (1). It appears that TNF antagonist disturbs the equilibrium of the immune system, exposing peripheral and central nervous system compartment to tissue damage by both autoreactive T and B cells. While there are potential immunologic hypotheses of how TNF-a blockade leads to demyelination of the central and peripheral nervous systems, the results of the present review suggest that demyelinating diseases associated with TNFi are very rare. Out of a total of 14 516 clinical trial patients on etanercept, adalimumab, and infliximab, there were only two cases of demyelinating diseases reported in phase III trials. This includes a subject who had completed five infusions of infliximab for psoriasis and presented with peripheral paresthesia, which selfresolved without any changes in medication dosing (56). The other case involves a subject who received etanercept for psoriasis and PsA and developed MS at the end of the 24-week blinded study with complete clinical improvement after discontinuation of therapy (8). There were three total cases of the demyelinating disease in phase IV trials for etanercept, and none identified for adalimumab or infliximab. Although only five cases have occurred in clinical trials, there have been 19 cases of TNFi associated demyelinating diseases presented as case reports or case series. The most common syndromes included demyelinating polyneuropathy (n ¼ 10), MS (n ¼ 3), ON (n ¼ 2), CIDP (n ¼ 2), GBS (n ¼ 1) and bilateral phrenic neuropathy (n ¼ 1). Recurring symptoms were those of paresthesia, numbness, muscle weakness, limb ataxia, gait instability, decreased sensation, vision changes and incontinence. Diagnosis of these cases was reliable as clinical suspicion was confirmed with MRI or nerve conduction studies. There appears to be no specific uniform dose at which symptom onset was observed, but some patients treated with infliximab or etanercept in total cumulative doses over 2000 mg experienced prolonged symptoms suggesting a dose-severity relationship. Upon drug cessation, and in some cases additional pharmacologic treatment, most patients recovered without further sequelae. Such temporal association constitutes positive dechallenge (disappearance of an adverse event after withdrawal of the medication) and may imply causation. Nevertheless, there exists the possibility that these findings are unrelated to the drug of study. Using MS as a model of comparison, there are approximately 250 000–350 000 patients with MS in the United States with an estimated incidence of 4–6 cases per 100 000 persons (0.005%) (41,70). When combining the results of phase III clinical trials reviewed here, there was one individual out of 14 516 patients (0.007%) who developed MS on TNFi therapy, which is the similar rate of occurrence as in the general population. This may be an unrelated development of a de novo case or unmasking of MS in an individual predisposed to developing MS. The current FDA guidelines recommend patients with personal history of central nervous system demyelinating disorders such as MS and/or peripheral nerve illness avoid TNF antagonist agents (73). From the literature reviewed here, there was one case of

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T. H. Zhu et al.

GBS which was reactivated in an individual with past history of GBS-like illness. The patient was in full remission for 4 years but subsequently developed GBS (61). Although anecdotal, there have been no studies to determine risks versus benefits in this group of patients. Until more information is available, it is important for clinicians to inquire about the personal history of demyelinating disorders in all patients who are candidates for TNFi therapy. On the contrary, it is difficult to determine if a positive family history of demyelinating disease is a strict contraindication to TNFi therapy as the majority of cases (Table 2) failed to report any known family history. From the five cases that did include data on family history, only one patient had reported a sister with MS while the rest were negative (62). In the reconciliation of this issue, a recent study by Mansouri et al. (2015) has suggested that the number needed to treat is, at least, an order of magnitude smaller than the number needed to harm in patients with a firstdegree relative with MS (74). This implies that use of TNFi in patients with family history of the demyelinating disease may still be safe. Nevertheless, a diligent effort should be made to screen patients for familial risk factors related to disorders of demyelination and to consider all treatment options available before ruling out TNFi as a potential therapy in such patients. For practicing dermatologists, one should have a sense of vigilance for the development of new or unusual neurological symptoms for all patients on TNFi therapy. If symptoms suggestive of neuropathy develop, treatment should be stopped and patients should be evaluated for possible referral to a neurologist. Although neurological disorders can be debilitating with severe functional impairment, improvement and return to baseline functioning are the most frequent outcome after stopping treatment, and therefore, withdrawal should be considered the first step in the management of suspected drug-induced neuropathy (1). Some patients may require additional treatment with IVIG or corticosteroids. On the other hand, there have been patients who experienced complete clinical improvement of all neurological symptoms without having to withdraw or alter the dose of antiTNF treatment (25). Some important limitations to this review should be considered. First, clinical trials often have strict exclusion criteria that would have prevented patients with demyelination risk factors (e.g. family history or personal history) from participating in the study. Screening patients for such risk factors prior to starting TNFi therapy is standard practice, so it may not be surprising that such few cases of the demyelinating disease were reported in phase III and IV trials. Therefore, it may be difficult to ascertain the true risk of demyelination with TNFi therapy as the data may not be all inclusive. Second several patients (Table 2) were reported to have taken two or more TNFi prior to the onset of demyelinating disease. Determining the culprit TNFi agent was difficult and while we assigned the TNFi of interest based on temporal proximity it could also have been likely that demyelination was due to the other TNFi. Lastly, whether the use of two or more TNFi carries a greater risk of demyelination than one TNFi is yet to be determined as few cases have reported rechallenge of the medication following TNFi withdrawal.

Conclusion In summary, demyelinating disease is a very rare occurrence with TNFi therapy. Although some temporal associations and disease presentations suggest causation, the overall incidence may also be drug-independent. Most importantly, the symptoms are reversible and the number needed to treat is smaller in comparison to the number needed to harm in most cases. Further studies are necessary to better understand the impact of dosing and duration of therapy on the development of demyelinating diseases. In

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addition, the implication of restarting patients on TNFi following a neurologic event and whether a low dose or alternate TNFi is appropriate remains unclear. Overall, TNFi should be avoided in patients with personal history of demyelinating disease, but with clinical vigilance and individualized treatment regimen, TNFi may be safe in the general population, including those with firstdegree relatives with the demyelinating disease.

Declaration of interest Dr. Koo is an advisor/consultant/speakers bureau for AbbVie, Janssen, LEO, Photomedex, Amgen, AstraZeneca, Merck, Sun Pharmaceutical Industries, Novartis and Pfizer. Mr. Zhu, Dr. Nakamura, Mr. Abrouk, Mr. Farahnik and Dr. Bhutani have no conflicts of interest to declare.

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Demyelinating disorders secondary to TNF-inhibitor therapy for the treatment of psoriasis: A review.

Tumor necrosis factor-α inhibitors (TNFi) are the most widely used systemic treatments for patients with psoriasis and psoriatic arthritis. There curr...
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