Modern Rheumatology

ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20

Peripheral neuropathies during biologic therapies Masato Yagita, Toshiaki Hamano, Saori Hatachi & Masaaki Fujita To cite this article: Masato Yagita, Toshiaki Hamano, Saori Hatachi & Masaaki Fujita (2013): Peripheral neuropathies during biologic therapies, Modern Rheumatology To link to this article: http://dx.doi.org/10.3109/14397595.2013.859770

Published online: 09 Dec 2013.

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Date: 23 September 2015, At: 06:34

http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2013; Early Online: 1–6 © 2013 Japan College of Rheumatology DOI: 10.3109/14397595.2013.859770

CASE REPORT

Peripheral neuropathies during biologic therapies Masato Yagita1, Toshiaki Hamano2, Saori Hatachi1, and Masaaki Fujita3 1Department of Clinical Immunology and Rheumatology, The Tazuke-Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan, 2Department of Neurology, Kansai Electric Power Hospital, Osaka, Japan, and 3Department of Dermatology, University of California Davis School of

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Medicine, Sacramento, CA, USA Abstract

Keywords

Peripheral neuropathies should be recognized as the adverse effects of biological agents, especially anti-TNF agents. However, no solid clinical databases for biological agent-associated peripheral neuropathies (BAPN) have been established in Japan. Here we report two cases of peripheral neuropathy associated with anti-TNF agents. One was peroneal motor neuropathy. The other case was chronic inflammatory demyelinating polyradiculoneuropathy. In addition, we summarize the previous reports on BAPN and discuss their prevalence rate, pathogenesis and management.

Biological agents, Peripheral neuropathy

Introduction The application of biological agents has brought a paradigm shift in the treatment of autoimmune rheumatic diseases including rheumatoid arthritis (RA) [1]. Although the benefit of the biological agents has been emphasized, the accumulating data also revealed the various risks, such as serious infections and cardiac failure, in therapies using these agents [2,3]. Neurological disorders are also elicited by biological agents, and most reported cases are associated with anti-TNF therapy [infliximab (IFX), etanercept (ETN) and adalimumab (ADA)] [3,4]. A meta-analysis of post-marketing studies revealed that the prevalence of TNF-α antagonist-associated neurological diseases was 0.01–0.1% (102/365000 for IFX, 17/150000 for ETN, and 10/10050 for ADA) [3,4]. Demyelinating central nervous system (CNS) disorders have been reported as the major neurological disorders elicited by biological agents, and conversely, relatively fewer peripheral neuropathies have been reported [5]. According to a 2010 database from the Biological Agents in Autoimmune Diseases (BIOGEAS) registry of the Spanish Society of Internal Medicine, over 140 cases with demyelinating CNS disorders (optic neuritis and multiple sclerosis) were found, and peripheral neuropathies were observed in 40 cases [5]. These peripheral neuropathies included acute or chronic demyelinating neuropathies and vasculitic neuropathies. However, no solid clinical databases for biological agentassociated peripheral neuropathies (BAPN) have been established in Japan, and there has been no consensus or guideline on how to manage these neurological disorders once they occur. Here we report two cases of peripheral neuropathy during therapies using biological agents in RA. In addition, we summarize the previous reports regarding BAPN including those in the Correspondence to: Masato Yagita, MD, Department of Clinical Immunology and Rheumatology, The Tazuke-Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgi-machi, Kita-Ku, Osaka 5308480, Japan. Tel: ⫹(81)-6-6312-1221. Fax: ⫹(81)-6-6312-8867. E-mail: [email protected]

History Received 4 September 2013 Accepted 23 October 2013 Published online 9 December 2013

Japanese literature and discuss their prevalence rate, pathogenesis and management.

Results Development of peripheral neuropathies during treatment with biological agents A total 261 RA patients have been treated with biological agents from April 12, 2005, until now at our institution. One hundred and fourteen of these 261 patients were administered over two biological agents (2–4 agents). IFX, ETN, ADA, tocilizumab (TCZ) and abatacept were administered to 123, 105, 65, 53 and 23 patients, respectively. Among these patients, two cases with peripheral neuropathies were observed. One was a case of peroneal motor neuropathy observed during IFX therapy, and the other case was chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) during the administration of ETN after ineffective IFX therapy. Case reports Case 1 A 45-year-old man with RA was initially treated with salazosulfapyridine (500 mg/day) and methotrexate (MTX, 6 mg/week), and IFX (3 mg/kg) was added because of the poor disease control of RA (DAS28-CRP: 5.4). After administration of IFX, his RA disease had been in remission. However, he developed a sudden onset of left foot drop after the 10th infusion of IFX. The interval between the last infusion of IFX and the development of foot drop was 33 days. There were no episodes of mechanical compression of the peroneal nerve (such as prolonged leg crossing or squatting). He had been in a healthy condition with a good nutritional status. And there were no episodes of diarrhea or preceding infections. No familial history of hereditary neurological diseases was found either. Neurological examination revealed apparent muscle weakness of the left tibialis anterior, peroneus longus and extensor hallucis longus (Medical Research Council Scale [MRC] for Muscle

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2

M. Yagita et al.

Strength: 0/5 for foot flexion). Sensory function and tendon reflexes were normal. No lesions compressing the nerve were detected on MRI of lumbar spines and lower limbs. Although the amplitude of compound motor action potentials (CMAPs) and motor conduction velocity of the left peroneal nerve were within normal limits in motor nerve conduction study (NCS), needle electromyography showed reduced numbers of motor units in the left peroneus longus and fibrillation potentials and positive sharp waves in the left tibialis anterior. These results suggested acute denervation of the left peroneal nerve caused by axonopathy. A study of cerebrospinal fluid revealed normal results. There were no abnormal findings in blood cell counts, urinalysis and general biochemistry. The blood sugar level was within the normal limit. Liver and thyroid function were normal, and serological tests for hepatitis B virus, hepatitis C virus and syphilis were negative. The serological Epstein–Barr virus titer and cytomegalovirus titer were normal. There were no monoclonal bands in serum electrophoresis. C-reactive protein was slightly positive (0.33 mg/dl, normal: ⬍ 0.3 mg/dl). Autoantibody to galactose-deficient IgG was slightly positive (11.5 AU/ml, normal range ⬍ 6.0 AU/ml). Matrix metalloproteinase-3 was within normal limits. Although anti-nuclear antibody (ANA) was slightly positive (x80, homogeneous and speckled pattern), the serum complement level was within normal limits (C3:118 mg/dl; C4:26mg/dl; CH50:42 U/ml). Anti-double strand DNA antibody, myeloperoxidase (MPO)-/ Proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCA) were negative. C1q-binding immune complex was not examined. Anti-ganglioside antibodies could not be tested. Because no other causes of neuropathy could be found, IFX was discontinued. MTX (6–8 mg/week) and a low dose of tacrolimus (1.5 mg/day) were administrated for the disease control of RA. The nerve palsy gradually improved, and administration of steroid or immunoglobulin therapy was not performed. The nerve palsy completely resolved 7 months later on discontinuation of IFX. Case 2 A 33-year-old woman with RA developed bilateral weakness of the upper limbs after two months’ therapy with ETN. She had a 13-year medical history of seropositive RA and was being treated with MTX (8 mg/week) and prednisolone (2 mg/day) at the time of referral. Because of poor disease control of RA (DAS28-CRP: 3.6), administration of IFX (3 mg/kg) was started. IFX was initially effective, and administration of prednisolone could be stopped. However, she had an allergic skin reaction to IFX at its 4th administration. Moreover, it became apparent that IFX was ineffective, and ETN was substituted for IFX. Six weeks after the administration of ETN, she developed weakness in both proximal and distal muscles of the bilateral upper limbs (MRC for Muscle Strength: 3/5). She also experienced dysesthesia of the bilateral hands and the medial side of the right lower limb. Tendon reflexes were bilaterally diminished. Although she complained of dysesthesia in both hands, sensory perception to all modalities was normal. No lesions compressing the nerves were detected on MRI of cervical and lumbar spines, and lower limbs. Motor NCS of the upper limbs revealed a reduced CMAP amplitude and conduction blocks in the bilateral ulnar nerves and left median nerve. F-waves could not be elicited in the left ulnar nerve. These results suggested the possibility of acquired demyelination. Sensory NCS of the bilateral median and ulnar nerves revealed normal results. Motor NCS of the lower limbs could not be performed. Her past medical history was unremarkable except for RA. She had been in a state of good nutrition. No episodes of diarrhea or preceding infections were noticed. No familial history of hereditary neurological diseases was found either.

Mod Rheumatol, 2013; Early Online: 1–6

A study of cerebrospinal fluid revealed normal results. There were no abnormal findings in blood cell counts, urinalysis and general biochemistry. The blood sugar level was within the normal limit. Liver and thyroid function were normal, and serological tests for hepatitis B virus, hepatitis C virus, syphilis and human immunodeficiency virus were negative. There were no monoclonal bands in serum electrophoresis. C-reactive protein was below 0.3 mg/dl. The activity of RA was well controlled, and IgG type rheumatoid factor was within normal limits. Although ANA was slightly positive (x80, homogeneous and speckled pattern), antiDNA antibody and anti-Sm antibodies were both negative, and the serum complements were within normal levels. MPO- and PR3ANCA were also negative. Anti-ganglioside GM2 antibody (IgM subtype) and anti-GalNAc-GD1a antibody (IgM subtype) were positive. Anti-ganglioside GM1 antibodies (both IgG and IgM subtypes), which may be positive in patients with multifocal motor neuropathy [6], were negative. Anti-ganglioside GQ1b, which is reported to be positive in 80–90% of patients with Guillain–Barré syndrome (GBS) [7], was also negative. Anti-hu antibody (one of the paraneoplastic syndrome antibodies), anti-myelin associated glycoprotein antibody, and aquaporin-4 antibody were negative. Judging from the results of NCS and neurology examinations, this patient is a definite case of CIDP according to the criteria for CIDP [8]. The presence of anti-ganglioside antibodies suggested that immune mechanisms were involved in its pathogenesis. Although steroid or intravenous immunoglobulin therapy was considered, these therapies were not performed because the patient did not want them and the neuropathies partially resolved on discontinuation of ETN. However, the neuropathies deteriorated 10 months later, and the patient presented with distal paresthesia of both hands and the lateral side of the right lower limb. Motor NCS revealed a reduced conduction velocity and prolonged F-wave latencies in the bilateral median and radial nerves. The same changes on motor NCS were noticed in the right peroneal nerve. Prolonged F-wave latencies were also found in the right tibial nerve. Sensory NCS of the bilateral median, radial and peroneal nerves revealed normal results. This paresthesia has been treated with administration of clonazepam or pregabalin and is partially improved at the present time. She is still unwilling to be treated with steroids or immunoglobulins. The relationship between peripheral neuropathies and administration of biological agents The relationship between neuropathies and administered biological agents was estimated by the Naranjo adverse drug reaction probability score (definite, over 9; probable, 5–8; possible, 1–4; and doubtful, below 0) [9]. The Naranjo scores of both cases were 7, indicating that the neuropathies of these cases were probable adverse drug reactions. The causal relationship between neuropathies and biological agents was further evaluated in both cases by additional two evaluation systems (Miller’s criteria [10] and the WHO–UMC system [11]). In Miller’s criteria, a possible causal relationship between an exposure to drugs and clinical symptoms was considered to exist when at least four of the eight attribution elements and at least three of the five primary elements were present [10]. In both cases, at least six attribution elements and four primary elements were present. We further performed the causality assessment by the WHO–UMC system [11]. In this system, the relationship in both cases was also judged to be probable/likely. Thus, the neuropathies of these cases were confirmed to be the adverse effects of biological agents by three evaluation systems.

Discussion In this report, we presented two cases with peripheral neuropathies during the treatment of RA with biological agents. One case was

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DOI 10.3109/14397595.2013.859770

peroneal motor neuropathy during IFX treatment, and the other case was CIDP observed during treatment with ETN following IFX therapy. In Case 2, IFX and ETN were both administered, and it is difficult to determine which drug was causal in the development of neuropathy. We surveyed the previous reports of BAPN. As shown in Table 1, 60 published cases with BAPN were found during treatment of arthritis including RA [3,6,7,12–37]. The types of BAPN can be mostly classified into two categories, demyelinating neuropathies [Guillain–Barré syndrome (GBS), Miller Fisher syndrome (MFS, a variant of GBS), multifocal motor neuropathy with conduction block (MMNCB), CIDP, Lewis–Sumner syndrome (LSS, a clinical asymmetrical variant of CIDP), and other forms of demyelinating neuropathies] and axonopathies (axonal sensory or sensorimotor neuropathy). Mononeuritis (simplex or multiplex) is pathologically categorized into axonopathy in most cases; however, demyelination is also observed in some cases. As shown in Table 1, demyelinating neuropathies comprised the majority (47/60 cases), and axonopathies were found in eight cases. Mononeuritis was observed in four cases. All reported cases were associated with anti-TNF therapy (IFX in 38 cases, ADA in 13, ETN in 10). Duration of therapy with biological agents prior to onset of neuropathy was variable (ranging from 8 h to 5 years), and in 31 of the 60 cases (52%, data not shown), BAPN occurred within 6 months or less. We examined the reported cases of BAPN in the Japanese literature. As shown in Table 2, only seven cases of BAPN in addition to our two cases were found [38–44]. These include one case with GBS induced by ADA [38], two cases with CIDP [ref 39 and Case 2 in this report], one case with IFX-induced multifocal motor neuropathy (MMN) [40], one case with IFX-induced sensory neuropathy [41], two cases with axonal polyneuropathy (one with ETN and the other with IFX) [42,43], one case with TCZ-related vasculitis [44], and one case with peroneal motor neuropathy (axonal neuropathy) induced by IFX (Case 1 in this report). We also surveyed the reports on post-marketing surveillance (PMS) for the development of BAPN in our country. The occurrence of demylinating disease was 0/7091 cases for ETN [45]. Adverse neurological disorders associated with IFX or TCZ were reported in PMS. However, it was not clear whether these neurological disorders were demylinating diseases or not [46,47]. There was no description on BAPN in the published PMS of ADA [48]. Thus, further prospective studies including PMS surveillance are apparently needed to understand the real risk of BAPN in Japan. The precise pathogenesis of BAPN remains unclear. As it is known that an increase in TNF-α might be involved in the pathogenesis of demyelinating neurological diseases [49], the development of BAPN during anti-TNF therapy is quite paradoxical [5]. However, TNF-α also has an immunoregulatory function and plays important roles in the functional regulation of antigenpresenting cells and in the apoptosis of autoreactive T cells [5,49]. Bosch et al. reported in their review that administration of antiTNF antagonists might break the balance between inflammation and anti-inflammation and paradoxically increase the anti-myelin immune response through activated T lymphocytes [5]. As various antibodies are found against different myelin components such as gangliosides or glycolipids, Stübgen suggested that the neuropathies might be caused by drug-induced non-specific immune dysregulation, not by an immune attack against a specific crossreacting epitope shared by a drug [49]. The neuropathy of Case 2 might be caused by this drug-induced non-specific immune dysregulation. It remains unknown whether anti-TNF agents can directly induce anti-ganglioside antibodies. It has been also suggested that anti-TNF inhibitor/TNF-α immune complexes may be deposited in small capillaries and induce vasculitis [33]. The damage of endocapillaries due to vasculitis may result in ischemia of nerves.

Peripheral neuropathies during biologic therapies 3 In Case 1 of this report, IFX may be involved in the pathogenesis of peroneal motor neuropathy. As RA activity was well controlled at the development of neuropathy, a neutralizing human antichimeric antibody (HACA) may not be positive and IFX-HACA immune complex may not be formed, either. However, it remains to be possible that another antibodies to IFX (just binding, but not neutralizing) might be produced and form immune complexes leading to the neuropathy. Alternatively, as TNF-α has been suggested to provide signal support for peripheral neurons [49], IFX might inhibit signal support for axons leading to the axonopathy. Judging from the relatively rapid development of the neuropathy, we suppose that the ischemic events due to vasculitis or the inhibition of signal support for axons might be the suggested mechanism of this Case 1. The presence of vasculitis was identified by nerve biopsy in two out of seven cases in the Japanese literature (Table 2). It cannot be excluded that vasculitis might be involved in the development of BAPN even in our two cases. TCZ-associated vasculitis was also reported (Table 2). Although nerve biopsy is invasive and has not been favored, it might be helpful in understanding the underlying pathogenic mechanism of BAPN and for the therapeutic decision of whether administration of steroid or immunoglobulin therapy is needed. There have been no clear-cut guidelines on the management of BAPN. The clinical course of BAPN is unpredictable. As shown in Table 1, biological agents were stopped in 57 of the 60 BAPN cases. In general, a good prognosis for BAPN after cessation of BA was reported [21]. However, around three-quarters of cases with BAPN required immunosuppressive therapies in our survey (Table 1). The responses of BAPN to immunosuppressive therapy were not perfect, and complete remission was limited to around 30% of cases (Table 1). The Japanese BAPN cases shown in Table 2 were mostly in serious stages and/or were complicated with vasculitis or other autoimmune diseases and needed methyl prednisolone pulse therapy and/or IVIG therapy. In Case 2 of this study, the deterioration of neuropathy was observed after partial improvement with the cessation of ETN. Although the precise reason for this deterioration remains unclear, it could be interpreted that the cessation of ETN was not enough for the neuropathy control once triggered. In this case, steroid or intravenous immunoglobulin therapy could not be performed for the prevention against the deterioration. In our survey, the relapse of neuropathy was also observed in three BAPN cases (Table 1). Surprisingly, Lozeron et al. reported two cases with mild demylinating neuropathies in which biological agents were not withdrawn after the development of neuropathies because of rheumatologic disease control or stabilized neurological symptoms (Table 1) [24]. In one case with demyelinating sensory motor polyneuropathy with conduction block IFX was switched to ETN because of RA control after the occurrence of neuropathy. And the neuropathy was treated with IVIG, steroid and azathioprine. The neurological symptoms of the patient improved with steroid therapy but recurred after the stop of steroid. In the other case with demyelinating sensory polyneuropathy, the dose of ADA was reduced without immunosuppressive treatment against the neuropathy because of stabilized neurological symptoms (Table 1) [24]. Thus, the neuropathy could not be controlled in one case [24]. We should carefully evaluate whether the neurological disorders of these cases were related to biological agents and the continuation of the biological agents was the proper decision. Overall, the standard therapy for BAPN is the drug withdrawal, and immunosuppressive therapies are needed when the disease activity cannot be controlled. We also suggest that the continuation of biological agents after the development of neuropathies is thought to be risky.

Demyelination Demyelination Demyelination Axonopahies Axonopahies Axonopahies Axonopahies Axonopahies Axonopahies NR Axonopahies NR NR NR

Demyelination, 47; axonopathies, 8; NR, 5

Total

60

1 1 1 1 1 2 1 1 1 1 1 2 1 1

1 1 3

2

1

1

1 2 1 2 2 1 1

8

1 1 1

1 1 2 1

9

IFX, ETN, ADA

AS ⫹ Psoriasis

IFX IFX IFX, ETN IFX IFX IFX, 2 IFX, ADA ADA ADA IFX ADA IFX, 2 ADA ADA

ETN ETN IFX, 3

IFX, 38; ETN, 13; RA, 38; RA ⫹ Crohn, 1; ADA, 13 RA ⫹ colitis, 1; Psoriasis, 12; Psoriasis ⫹ Chrohn, 1; Psoriasis ⫹ AS,1; AS, 8; AS ⫹ UC, 1

AS RA ⫹ colitis Psoriasis Psoriasis RA RA, 2 RA ⫹ Crohn Psoriasis AS RA RA RA, 2 Psoriasis Psoriasis

Psoriasis Psoriasis RA, 3

IFX, 2

IFX

Crohn ⫹ Psoriasis

Psoriasis, 2

ADA IFX, 1; ETN, 1 ADA IFX, 1; ETN, 1 IFX, 2 IFX ADA

RA RA 2 RA RA, 1; AS, 1 RA, 2 RA RA

IFX, 5; ETN, 2;ADA, 1

IFX ADM IFX

AS ⫹ UC RA RA RA, 4; AS, 4

IFX ETN IFX, 1; ETN, 1 IFX

IFX, 5; ETN, 3;ADA, 1

RA RA Psoriasis, 1;AS, 1 Psoriasis

RA, 8; Psoriasis, 1

Used biological agents

57

1 1 1 1 1 2 1 1 1 1 1 2 1 1

1 1 3

2

1

1 2 1 2 2 1 Dose reduction of ADA Switched to ETN

7

1 1 1

1 1 2 1

9

Outcome

Partial Improved Stabilization Complete Partial Complete, 2 No improvement No improvement Complete Complete Complete Complete, 1; partial, 1 Complete Complete

No improvement Markedly improved Complete, 2; partial, 1

Complete, spontaneous relapse Complete, 1;partial, 1

Partial

Complete Partial Partial, 2 Complete rechallenge (successful) Complete Partial Partial rechallenge (recurrence) Complete, 1; partial, 4; stabilization, 3 Partial Partial, 2 Improved Complete, 1;partial, 1 Complete, 1;partial, 1 Partial Partial

Complete, 2; partial, 6; non improvement, 1; relapse, 2 rechallenge, 1 (successful)

Complete, 21; partial/ IVIG, 35; none, 16; CS, improved, 31; 11; PE, 4; CPA, 3; AZA, stabilization, 4; no 5; mPSL pulse, 4; NR, 1 improvement, 4; relapse 3

None None IVIG, PE IVIG CS (intravenous) IVIG, 1; Gabapentin, 1 None None None mPSL pulse, CPA CS, CyA mPSL pulse, 2; CPA, 1 None None

None None IVIG, 3

IVIG, 1; None, 1

IVIG

IVIG, CS, AZA

IVIG, CS, AZA IVIG, 2; CS, 1 IVIG, CS IVIG, 1; none, 1 IVIG, 2; CPA, 1; AZA,2 IVIG None

IVIG, 5; CS, 2; none, 3

IVIG, CS (intravenous) CS, AZA, gabapentin IVIG, mPSL pulse

none PE IVIG 2 IVIG

IVIG, 8; CS, 1; PE, 2; NR, 1

Discontinuation of BA: No. of cases Treatment for neuropathy

RA, rheumatoid arthritis; AS, ankylosing spondyloarthritis; UC, ulcerative colitis; ADA, adalimumab; IFX, infliximab; ETN, etanercept; CS, corticosteroid; mPSL, methyl prednisolone; IVIG, intravenous immunoglobulins; AZA, azathioprine; CPA, cyclophosphamide; CyA, cyclosporin; PE, plasma exchange; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; GBS, Guillain–Barré syndrome; MMNCB, multifocal motor neuropathy with conduction block; LSS, Lewis–Sumner syndrome; MFS, Miller Fisher syndrome; S, sensory; M, mortor; NR, not reported.

MMNCB Motor neuropathy with CB Motor neuropathy with CB Axonal M polyneuropathy Axonal S/M polyneuropathy Axonal S polyneuropathy Axonal S polyneuropathy Axonal S neuropathy Axonal S neuropahy Mononeuritis multiplex Mononeuritis multiplex Mononeuritis Phrenic neuropathy S/M neuropathy

Demyelination Demyelination Demyelination

Nozaki [3] Hanaoka [26] Rodriguez-Escalera [6], Tektonidou [27], Cocito [28] Paolazzi [29] Singer [30] Lozeron [24] Argyriou [31] Jarand [23] Jarand [23], Tektonidou [27] Solomon [18] Nozaki [3] Kiltz [32] Jarrett [33] Makol [34] Richette [35] Alexopoulou [36] Berthelot [37]

Demyelination

Lozeron [24]

CIDP CIDP CIDP CIDP like LSS Demyelinating S/M polyneuropathy Demyelinating S polynueropathy

Demyelination

Demyelination Demyelination Demyelination Demyelination Demyelination Demyelination Demyelination

Solomon [18] Alshekhlee [19] Hamon [20] Richez [21] Hooper [22] Jarand [23] Lozeron [24]

CIDP

Eguren [25]

Demyelination

Seror [14]

GBS MFS MFS

Demyelination

Demyelination Demyelination Demyelination

Bouchra [16] Kurmann [17] Shin [7]

GBS GBS GBS GBS

Lozeron [24]

Demyelination Demyelination Demyelination Demyelination

Silburn [12] Mohan [13] Seror [14] Cisternas [15]

GBS

Demyelinating S/M polynueropathy with CB Demyelinating S/M polynueropathy with CB Demyelinating M neuropathy, Demyelinating S/M neuropathy Demyelinating neuropathy Demyelinating S mononeuropathy MMNCB

Demyelination

Shin [7]

Underlying diseases, No. of cases

Number of cases

Type of neuropathy

First author [ref]

M. Yagita et al.

Table 1. Published cases with peripheral neuropathies during the treatment using biological agents (BA).

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4 Mod Rheumatol, 2013; Early Online: 1–6

Peripheral neuropathies during biologic therapies 5

⫹ ⫹ ⫺ ⫺ ⫺ Anti-GM1 (IgM)

axonopathy Unknown Axonopathy CIDP 4–5 M 1 day 15.5 M IFX: 4.5 M ETN: 6 weeks IFX TCZ IFX IFX ETN Ohashi [43] Sugiura [44] Our case 1 Our case 2 6 7 8 9

Psoriatic arthritis RA RA RA

Axonopathy 3 weeks ETN Ishigaki [42] 5

RA

Anti-GM2 (IgM) Anti-GalNAc-GD1a (IgM)

⫺ Polymyositis

Vasculitis Vasculitis ⫺ ⫺

⫹ ⫺

Anti-GM1 (IgM) Anti-GA1(IgM) Anti-GalC(IgM) Sensory neuropathy 1M IFX Psoriasis Nishimura [41] 4

RA, rheumatoid arthritis; ADA, adalimumab; IFX, infliximab; ETN, etanercept; TCZ, tocilizumab; mPSL, methyl prednisolone; IVIG, intravenous immunoglobulins; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; GBS, Guillain–Barré syndrome; MMN, multifocal motor neuropathy.

Partial Partial Complete Partial

Unknown

mPSL pulse IVIG IVIG mPSL pulse Observation Observation

IVIG

IVIG IVIG – ⫺ – ⫺ Anti-GM1 (IgM) CIDP MMN 5M 3–4 M IFX IFX Abe [39] RA Fukushima [40] RA 2 3

Other complications – Anti-ganglioside antibodies (Ig-subtype) Type of neuropathy GBS Used biologic Duration of agents treatment ADA 4 months (M) Underlying disease RA Number of first author cases [ref] 1 Morimatu [38]

Table 2. Published cases with peripheral neuropathies during the treatment using biological agents in the Japanese literature.

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vasculitis at Treatment for Nerve biopsy nerve biopsy neuropathy mPSL pulse ⫹ ⫹

Improvement Partial to marked Improvement complete Marked improvement Marked improvement

DOI 10.3109/14397595.2013.859770

In conclusion, peripheral neuropathies are relatively rare adverse effects of biological agents. It seems necessary to establish a solid database, such as a database of prospective post-marketing studies, to understand the real risk of BAPN and improve the outcome of BAPN.

Acknowledgements We thank Dr. Moritoh Inouchi, Department of neurology, The Tazuke-Kofukai Medical Research Institute, Kitano Hospital (Osaka) for valuable comments on neurological evaluations.

Funding This study was supported in part by research grants from Mitsubishi Tanabe Pharmaceutical Company (Osaka, Japan), from Teijin Pharma Limited (Osaka, Japan), and from AstraZeneca K.K. (Osaka, Japan).

Conflict of interest None.

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Peripheral neuropathies during biologic therapies.

Peripheral neuropathies should be recognized as the adverse effects of biological agents, especially anti-TNF agents. However, no solid clinical datab...
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