Funding sources: None.
Development of chronic inflammatory demyelinating polyneuropathy in a patient receiving infliximab for psoriasis
Article first published online: 13 JAN 2014
© 2013 British Association of Dermatologists
British Journal of Dermatology
Volume 170, Issue 1, pages 206–209, January 2014
How to Cite
Foulkes, A.C., Wheeler, L., Gosal, D., Griffiths, C.E.M. and Warren, R.B. (2014), Development of chronic inflammatory demyelinating polyneuropathy in a patient receiving infliximab for psoriasis. British Journal of Dermatology, 170: 206–209. doi: 10.1111/bjd.12572
Conflicts of interest: A.C.F., L.W., D.G., R.B.W. and C.E.M.G. work in the U.K. National Health Service (NHS). C.E.M.G. has acted as a consultant and/or speaker for Abbott, Centocor, Incyte, Janssen, Leo Pharma, Novartis, Pfizer and Schering-Plough (now MSD), all of which manufacture therapies used in the treatment of psoriasis. R.B.W. has acted as a consultant and/or speaker for Abbott, Janssen, Leo Pharma, Pfizer, Novartis and Schering-Plough (now MSD), all of which manufacture therapies used in the treatment of psoriasis. A.C.F. has received educational support to attend conferences and/or acted as a consultant for Pfizer, Abbott, Janssen, Novartis and Leo Pharma, all of which manufacture therapies used in the treatment of psoriasis.
- Issue published online: 13 JAN 2014
- Article first published online: 13 JAN 2014
- Accepted manuscript online: 5 AUG 2013 03:11AM EST
- Medical Research Council. Grant Number: G1000417/94909
- Medical Evaluation Unit
Dear Editor, A 49-year-old white man was referred to the Manchester Psoriasis Service with a 21-year history of severe chronic plaque psoriasis refractory to therapy with topical agents, phototherapy (TL-01), systemic agents (methotrexate, ciclosporin and fumaderm) and the biologic agents adalimumab and ustekinumab, including with concurrent ciclosporin therapy. Relevant history included alcohol excess. There was no family history of demyelination. Following a flare of psoriasis in June 2011, treatment was changed from ustekinumab (90 mg dosing regimen) with ciclosporin 2 mg kg−1 daily, to infliximab intravenously (5 mg kg−1 at weeks 0, 2 and 6, and thereafter at 8-week intervals). On initiation of infliximab, ciclosporin was discontinued but reintroduced at 2 mg kg−1 daily due to a flare in December 2011. Two weeks later, the patient reported sudden onset of weakness of his right hand and numbness of the fingertips bilaterally. With no objective sensory disturbance and unilateral right upper limb weakness, urgent assessment by a neurologist led to a provisional diagnosis of brachial plexopathy secondary to ciclosporin, which was stopped. Due to the severity of the patient's psoriasis, infliximab therapy was continued. During January 2012 he reported worsening of sensory disturbance in the arms and new weakness in both legs. Neurological examination revealed reduced tone in the right upper limb, right forearm muscle wasting, right hand weakness in an ulnar and median nerve distribution. Reflexes were present in both arms with no sensory loss. The lower limbs had normal tone. Mild bilateral dorsiflexion weakness was noted. Sensation was normal; all reflexes were absent.
Urgent investigations included magnetic resonance imaging of the brain and cervical spine, which was normal. Nerve conduction studies revealed changes compatible with a primary demyelinating neuropathy and met diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). Cerebral spinal fluid findings demonstrated no pleocytosis or oligoclonal bands, protein and glucose were within normal parameters; nerve biopsy was not performed. With a working diagnosis of infliximab-associated CIDP, infliximab therapy was discontinued in February 2012 and ciclosporin reinstituted.
The patient's neurological condition deteriorated 3 months from onset of symptoms with marked global limb weakness with distal bias, sensory ataxia and severe neuropathic pain of the feet. Treatment with intravenous immunoglobulin (IVIg) was commenced [150 g over 5 days (0·4 mg kg−1)], with a second course a month later followed by concomitant oral prednisolone (40 mg daily) after 8 weeks, which resulted in a significant worsening of his condition. Clinical stabilization was achieved with a course of plasma exchange and continued monthly pulses of IVIg. One year after the initial onset of symptoms the patient's distal limb power has improved, he is able to mobilize with a stick but continues to be profoundly sensory ataxic and IVIg dependent. Following withdrawal of infliximab, the patient's psoriasis flared and now requires combination treatment with Fumaderm® (Almirall Hermal, Reinbek, Germany) 240 mg three times daily, acitretin 50 mg daily and ciclosporin 50 mg twice daily.
CIDP is an acquired demyelinating disease of the peripheral nervous system. It typically presents between the ages of 30 and 60 years and is characterized by progressive symmetrical proximal and distal muscle weakness, sensory dysfunction and impaired balance. The course of the disease can be monophasic, relapsing and remitting or progressive. Various diagnostic criteria exist, utilizing findings from clinical, electrophysiological and laboratory testing. Because demyelination in CIDP is multifocal, clinical and pathological manifestations vary. The reported prevalence of 1–7·7 per 100 000 in Northern Europe may be an underestimation due to difficulty in the identification of ‘atypical’ cases.
The exact triggers for CIDP are unknown. A number of disorders are associated with CIDP including organ transplantation, inflammatory bowel disease, diabetes, and malignant melanoma where it has been hypothesized that carbohydrate epitopes shared by myelin sheath and melanoma act as target antigens. The usual therapeutic options for CIDP include oral corticosteroids, IVIg and plasma exchange. The prognosis is variable, some patients responding to cessation of the tumour necrosis factor (TNF) inhibitor, others requiring ongoing treatment with immunosuppressant therapy.
The development of CIDP has been described in 17 patients treated with all TNF inhibitors licensed for use in psoriasis: infliximab, nine;[4-7] etanercept, four;[5-7] and adalimumab, four,[7-10] one of whom received adalimumab for severe psoriasis. Our case is consistent with previous reports (Table 1). There are several hypotheses as to how TNF inhibitors may be implicated in the pathogenesis of CIDP, including: TNF inhibitor therapy leading to autoantibody production via reduced regulatory T-cell activity; or through the removal of the support to peripheral neurons played by constitutive TNF-α. However, the mechanistic link is unclear, as TNF inhibitor therapy has not been discontinued[7, 10] in all such concomitant cases of CIDP, and paradoxically etanercept has been used successfully to treat the condition.
|Case||Author and reference||Case age (years) and sex||Disease||Treatment||Onset of symptoms in relation to treatment||Symptoms||Electrophysiology||Antibody||Treatment||Follow-up/outcome|
|Discontinuation of drug||Immunosuppressant therapy|
|1||Jarand et al.||50 F||RA||Infliximab (3 mg kg−1, total exposure 1000 mg)||Following five doses of infliximab||Diplopia, left hand weakness and numbness||Demyelinating polyneuropathy with conduction block||Not performed||Y||IVIg monthly||35 months; some improvement|
|2||Richez et al.||73 F||RA||Etanercept||17 months||Lower limb weakness, upper and lower limbsdysaesthesia||Mild neurogenic patterns||Antiganglioside GM1 (IgM) +ve||Y||–||6 months; neuropathy improved with improved EMG|
|3||47 M||AS||Infliximab||4 months||Lower limb weakness, distal upper limb dysaesthesia||Motor nerve conduction studies multifocal demyelinating neuropathy with partial conduction block in three nerves||Antiganglioside GM2 (IgM) +ve||Y||–||6 months; mild paraesthesia and abnormal gait|
|4||Solomon et al.||69 M||RA||Adalimumab||2·5 years||Numbness and weakness both hands||Severe axonal sensorimotor polyneuropathy||P/Q-type voltage-gated calcium channel antibody +ve||Y||IVIg then azathioprine and prednisolone||18 months; partial improvement|
|5||Lozeron et al.||50 M||RA||Adalimumab (total exposure 4000 mg)||Unknown; worsening after 2 years||Tingling in both hands and feet||Diagnostic of demyelinating polyneuropathy||N/A||Reduced dosage||Prednisolone||2 years; remaining numbness in toes|
|6||Alshekhlee et al.||45 F||RA||Etanercept||1 week||Lower limb weakness with bilateral foot drop, severe sensory ataxia, areflexia||Evidence of acquired demyelination including multiple conduction blocks||Antiganglioside −ve||Y||IVIg after 2 months and prednisolone 1 mg kg−1; IVIg at 4-month intervals||2 years; improvement in activities of daily living|
|7||49 M||RA||Infliximab||1 year||Numbness in both hands after 1 year, progressing to proximal and distal muscle weakness and areflexia after a further year||Evidence of progressive acquired demyelinating sensory and motor peripheral polyneuropathy||Antiganglioside −ve||Y||IVIg 2 g kg−1 daily for 5 days, then after 6 weeks, then 8 weeks, thereafter every 8 weeks||2 years; some clinical improvement, walking unassisted|
|8||Seror et al.||79 F||RA||Infliximab||30 months||Ataxia, foot drop, areflexia||Nerve conduction study abnormalities showed typical features of CIDP in eight of nine cases. Nerve conduction abnormalities were conduction block or temporal dispersion in six, reduced motor nerve conduction velocity in six, prolonged F-wave latency in three and distal prolonged latency in three||Antiganglioside antibodies were tested in four patients and were found to be present in three||Y||IVIg||Partial improvement, relapse with adalimumab|
|9||49 M||AS||Infliximab||16 months||Paraesthesia of all limbs, areflexia||Y||IVIg||Partial improvement|
|10||36 M||AS||Infliximab||6 weeks||Proximal and distal weakness all limbs with paraesthesia||Y||IVIg||Partial improvement|
|11||39 F||RA||Adalimumab||8 months||Lower limb paraesthesia and ataxia||Y||IVIg||Complete regression|
|12||45 F||RA||Etanercept||17 months||Mild distal weakness lower limbs, distal paraesthesia all limbs||Y||None||Stabilization then delayed improvement|
|13||47 M||AS||Infliximab||5 months||Weakness lower limbs, paraesthesia distal upper limbs, diffuse areflexia||Y||None||Stabilization|
|14||52 M||AS||Etanercept||31 months||Mild lower limb distal paraesthesia||N||None||Stabilization|
|15||55 F||RA||Infliximab||32 months||Paraesthesia all limbs, diffuse areflexia||Y||IVIg and prednisolone||Stabilization|
|16||66 M||IM||Infliximab||4·4 months||Distal paraesthesia lower limbs||Y||IVIg||Complete regression, relapse|
|17||Ahmed et al.||53 F||Psoriasis||Adalimumab||10 months||Proximal and distal upper and lower limb weakness and areflexia||Consistent with severe demyelinating neuropathy||N/A||Y||IVIg and prednisolone||NB: History of GBS 29 years earlier. 12 months; recovery, treatment discontinued|
The British Association of Dermatologists' 2009 guidelines for biologic interventions for psoriasis recommend that if symptoms suggestive of demyelination develop during therapy, treatment be withdrawn and specialist advice sought. Reporting of such events via patient registries such as the British Association of Dermatologists' Biologic Interventions Register is imperative to gain understanding of the role TNF inhibitors may play in the onset of peripheral demyelinating disease.
A.C.F. is an MRC Clinical Training Fellow supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (grant no. G1000417/94909), ICON, GlaxoSmithKline, AstraZeneca and the Medical Evaluation Unit. R.B.W. is an NIHR Senior Clinical Lecturer; C.E.M.G. is an NIHR Senior Investigator.
- 2Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society – first revision. J Peripher Nerv Syst 2010; 15:185–95.
- 3Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic and therapeutic challenges for a treatable condition. Lancet Neurol 2010; 9:402–12., , .