Neurological Complications of Biologic Therapy in Psoriasis: A Review

Mark Bechtel, MD; Catherine Sanders, MS; Ann Bechtel, RN, BSN
The Ohio State University College of Medicine, Columbus, Ohio

Disclosure: Dr. Bechtel is a speaker for Amgen, Centocor, Genentech, and Abbott. Ms. Sanders and Ms. Bechtel report no relevant conflicts of interest.

Biologic agents have been a significant advancement in the management of psoriasis. Along with significant clinical improvement, there have been concerns for emerging side effects with the use of biologics. Reports have emerged showing the association between efalizumab and the development of progressive multifocal leukoencephalopathy and other demyelinating disorders. Tumor necrosis factor-alpha inhibitors have been associated with various demyelinating disorders. As such, it is imperative for dermatologists to be well informed regarding how to notify patients about the risks of biologic treatment. Dermatologists must be able to identify the signs and symptoms of neurological complications and recognize when to refer patients to neurologists for diagnostic workup, disease confirmation, and any necessary treatment. This review is a compilation of evidence showing the association between biologic therapy and neurological complications, as well as an overview of the clinical presentation and diagnosis of such diseases.
(J Clin Aesthetic Dermatol. 2009;2(11):27–32.)

Biologic agents in the treatment of psoriasis and other medical diseases have represented major advances in the therapeutic management of these disorders with improved quality of life. Unfortunately, some of the biologic agents have been associated either directly or indirectly with neurological complications. In particular, efalizumab has been associated with progressive multifocal leukoencephalopathy (PML) and other demyelinating disorders and the tumor necrosis factor-alpha (TNF-a) inhibitors have been associated with peripheral and central demyelinating disorders. It is important for dermatologists and other healthcare providers to be aware of the neurological complications of biologic agents, how they present, and the appropriate workup to confirm the diagnosis.

Progressive Multifocal Leukoencephalopathy
Definition. PML is a progressive disorder associated with the John Cunningham virus (JC virus) that is characterized by scattered demyelination of the brain, sparing the spinal cord and optic nerve.1 The JC virus resides in the latent form in up to 80 percent of healthy adults and typically causes PML only in immunocompromised patients.[1] Hematological malignancies, transplant recipients, and chronic inflammatory diseases have been associated with PML.[1] Patients with human immunodeficiency virus (HIV) are especially vulnerable to PML.

Clinical presentation. In the studies of the clinical manifestations of PML, which have been mostly retrospective, a wide spectrum of presentations has been described.[2] A 2003 multicenter, retrospective study of 118 patients with acquired immunodeficiency syndrome (AIDS) and PML treated with highly active antiretroviral treatment (HAART) showed that the most common symptoms comprise limb weakness (69.5%), gait disorder (64.4%), speech disorder (46.6%), visual impairment (20.3%), sensory loss (18.6%), and seizures (12.7%). Other frequent signs included paresis (66.9%), speech alterations (50.8%), lack of coordination (44.1%), and cranial nerve palsies (31.4%).[3] Seizures are not classic in PML and are usually associated with lesions adjacent to the hemispheric cortex as demonstrated in a study of 89 patients with PML.[4] The study found that 16 of the 89 patients with PML had seizures and that 81.15 percent of those with seizures had HIV.

Fecal and urinary incontinence as well as memory problems were noted in 20 percent of patients with PML who were HIV positive.[5] The cognitive difficulties of PML include dementia, confusion, and change in personality.[1] PML should be suspected in any patient on biologics with acute onset of visual deficits, mental impairment, dementia, personality changes, confusion, and motor weakness.

Association with biologics. There have been three cases of PML reported in patients on efalizumab for the management of psoriasis in the postmarketing setting.[6] The first two cases occurred in elderly patients who were on efalizumab for more than three years. The first case was a 70-year-old man who received efalizumab for more than four years for chronic plaque psoriasis. He was not on immunosuppressive therapy and had no history of immunosuppressive disorders.[7] The second case was a 73-year-old woman who received efalizumab for three years and nine months. She was on a short course of methotrexate three years prior to the onset of her neurological symptoms and had no history of immunosuppressive disorders.[8] Both patients had a fatal outcome.

A third case was reported in February 2009 and involved a 47-year-old man who received efalizumab for three years and two months for chronic plaque psoriasis.[6] He was not on any other immunosuppressive therapy and had no immunosuppressive disorders. In all three cases, the patients had been on efalizumab for more than three years for chronic plaque psoriasis. The diagnosis was confirmed in these patients by detection of JC viral DNA in the cerebrospinal fluid (CSF), neurological symptoms, and magnetic resonance imaging (MRI) studies. A 62-year-old man treated with efalizumab for more than three years for psoriasis developed a progressive neurological disorder.[6] He was not on concomitant immunosuppressive drugs and died before further diagnostic studies were completed. Efalizumab appears to increase the risk of PML, especially with exposure of more than three years or increased age.

PML was reported in 57 patients following rituximab therapy in HIV-negative patients.[9] A case of leuko-encephalopathy was reported in a patient with refractory rheumatoid arthritis treated with entanercept, but the diagnosis was not confirmed by detection of the JC virus DNA in the CSF.10 A nonbiologic drug utilized by dermatologists, mycophenolate mofetil (MMF), has been associated with PML. In one review, the incidence density of PML in MMF transplant patients was 14.4 cases/100,000 person-years.

One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed during clinical trials with ustekinumab. The subject received 12 doses of ustekinumab over two years and presented with headaches, seizures, and confusion. After ustekinumab was withdrawn, the patient fully recovered. RPLS is not caused by demyelination or a known infectious agent, but fatal outcomes have been reported. Patients with RPLS may manifest with headaches, seizures, confusion, and visual disturbances.[12]

Diagnosis. The diagnosis of PML is suggested by clinical features, MRI findings, and CSF polymerase chain reaction (PCR) for JC virus DNA. The ill-defined diffuse lesions of PML tend to be located in the subcortical white matter and the posterior fossa (cerebellum).[13] The CSF of PML patients is often normal, with a mild increase in protein and immunoglobulin G (IgG). Less than 25 percent of patients with PML have been shown to have pleocytosis (mononuclear) with <25cells/µL. When paired with MRI lesions and clinical setting, positive CSF PCR for JC virus DNA has been important diagnostically, although the sensitivity of CSF PCR decreases in patients with HIV treated with HAART. Biopsy may be necessary if CSF PCR is negative; however, the presence of the JC virus antigen or genomic material is only diagnostic with pathological change because of the high prevalence of the virus in the population.[1]

Demyelinating Disorders
All the TNF-a inhibitors and efalizumab have been associated with rare cases of new or exacerbated symptoms of demyelinating disorders. These reports have included multiple sclerosis (MS), optic neuritis, seizures, and central nervous system manifestations of systemic vasculitis. Of interest, TNF-a levels detected in the CSF are strongly correlated with MS activity.[14] Therapeutic attempts to treat MS with TNF-a inhibitors, however, were associated with more frequent and severe exacerbations.[15] The exact role TNF-a inhibitors play in the development of demyelinating disorders is unclear. The blood-brain barrier most likely prevents the entry of TNF-a antagonists into the CSF; however, TNF-a antagonists can increase the number and activity of autoreactive T cells. This could enhance autoimmune responses and explain how TNF-a antagonists exacerbate MS disease activity.[16] All the TNF-a biologic agents used in the treatment of psoriasis urge caution in the treatment of patients with pre-existing or recent onset of central nervous system demyelinating disorders. Siblings of patients with MS carry a significantly higher risk of predisposition for developing MS. A pretreatment family history for demyelinating disorders should be carefully ascertained prior to therapy and patients informed of potential risk.[17]

Optic neuritis. Definition. Optic neuritis (ON) is defined as the abrupt loss of vision resulting from optic nerve demyelination.[18] It is thought that major histocompatibility complex (MHC) class II antigens are associated with ON, leading some to believe that there is a genetic predisposition for specific immune responses.[19] The Optic Neuritis Treatment Trial (ONTT) found that patients who had optic neuritis had a 10-year cumulative probability of 38 percent  for developing clinically definite MS.[20] Typically, ON episodes are more frequent at high latitudes and in spring and summer, although such a generalization is not always the case.[19]

Clinical presentation. Patients with ON typically present with subacute (hours to days) unilateral vision loss and pain with eye movement.[21] Symptoms include alterations of color vision, contrast, and depth perception, as well as fleeting flashes of light, Uhthoff’s phenomenon (visual deterioration following heat or exercise), visual blurring, and flight of colors.[19] Signs on physical examination comprise an afferent papillary defect, central scotomas, and diminished visual acuity and color vision.[21] Ocular fundoscopic examination may be normal (retrobulbar neuritis) or show signs of swelling; optic disc pallor (optic atrophy) gradually develops over the following months.[20,21]

Association with biologics. ON has been reported with the use of anti-TNF-a therapy[22] as well as with the use of infliximab.[23] There have been previous case reports associating ON with the use of etanercept.[24,25] Recently, a case of ON was reported with adalimumab.26 ON should be suspected with any patient on biologics who presents with an abrupt loss of vision.

Diagnosis. Diagnosis of ON is clinical, although an MRI is commonly ordered to evaluate each patient for signs of progression to MS.[21] Additional tests include antinuclear antibodies (connective tissue disease), FTA-ABS (syphilis), and CXR (sarcoidosis).[21]

Multiple sclerosis. Definition. MS is defined by a triad of inflammation, demyelination, and gliosis. Genetics appear to contribute to the development of MS, given that Caucasians have a higher risk of developing the disease when compared to Africans or Asians. It is likely that there are different causative genes in each individual. Interestingly, it is also thought that a person’s environment influences the development of MS, as there is increased prevalence of the disease at higher latitudes. Migration studies suggest that some MS-related exposure occurs during childhood, and that early migration from a low- to high-risk area increases the risk of MS. Of note, there has been some evidence that remote Epstein-Barr virus (EBV) infection plays a role in the development of MS.[27]

Clinical presentation. MS presents either acutely or insidiously and is characterized by an either relapsing-remitting or progressive course.[27] The most common initial manifestations of MS include sensory loss (37% of cases), ON, weakness, paresthesias, and diplopia.[27] Later in the course of MS, cerebellar findings, such as ataxia, dysmetria, and intention tremors, become more pronounced.[21] In addition to paresthesias, patients may also complain of numbness, a sensory level, or “bandlike” of tightness around the torso.[27] Less commonly, patients describe episodes of vertigo, paroxysmal attacks, bladder disturbances, pain, dementia, visual loss, facial palsy, impotence, myokymia epilepsy, and falling.[27] Some patients affected with MS report symptoms characteristic of Uhthoff’s phenomenon or that neck flexion leads to electric-like sensations running down the spine (Lhermitte’s sign).[21]

Association with biologics. There have been reports of patients presenting with manifestations of MS while on inflixamab and etanercept therapy.[28,29] In addition to classical manifestations of MS, patients may manifest transverse myelitis.[30] In a case series of 20 patients developing new onset demyelination during anti-TNF-a therapy for arthritis, 17 patients were receiving etanercept and two were receiving infliximab.[31]

The most common presenting symptom was paresthesia (13/20 patients), suggestive of MS. Visual disturbance secondary to ON was the second most common manifestation. Most patients experienced a complete or partial resolution of symptoms upon discontinuation of anti-TNF therapy. MS has also been reported with the administration of adalimumab.[32] MS should be suspected in any patient on TNF-a therapy who develops paresthesias, weakness, blurring, or loss of vision. TNF-a therapy should be avoided in patients with pre-existing demyelinating disorders or a strong family history of MS.

Diagnosis. The 2001 McDonald diagnostic criteria remain useful for practicing physicians.33 Clinically definite MS requires two or more symptomatic episodes (symptoms for >24 hours separated by 1 month or more) and two or more pathological signs from anatomically noncontiguous white matter tracts in the CNS. The diagnosis consists of a neurological examination sign, and a second sign that may be documented by abnormal paraclinical tests, such as MRI (MRI is the most sensitive test for MS) or evoked potential (EP).[27] The CSF of patients with MS may show, among other findings, oligoclonal IgG bands (not in serum) and increased IgG.[21]

Transverse myelitis. Definition. Acute transverse myelitis (TM) is a focal inflammatory disorder of the spinal cord that leads to sensory, motor, and autonomic dysfunction.[34] Among the many causes of TM are inflammatory, immune-mediated, and demyelinating etiologies. Demyelinating myelopathy may occur as a sequela to MS. Immune-mediated inflammatory TM has been associated with systemic lupus erythematosus (SLE) (often with antiphospholipid antibodies), Sjögren’s syndrome, mixed connective tissue disease, Behcet’s syndrome, and vasculitis with perinuclear antineutrophilic cytoplasmic antibodies (p-ANCA). Sarcoidosis is another important etiological consideration. Postinfectious myelitis can follow a vaccine or result from a presumed autoimmune response to infection (EBV, cytomegalovirus [CMV], mycoplasma, influenza, measles, varicella, rubeola, and mumps). Similarly, multiple viral and bacterial etiological infectious agents have been reported with cases of acute infectious myelitis (including, but not limited to, herpes zoster, herpes syndrome virus [HSV] types 1 and 2, EBV, CMV, rabies virus, Listeria monocytogenes, Borrelia burgdorferi, and Treponema pallidum).[35]

Clinical presentation. In the classical presentation of TM, back pain (frequently thoracic) and lower extremity weakness progress over hours to weeks. Some patients may present with acute segmental back or radicular pain, followed by rapid ascending paresthesias and weakness. It is not uncommon for patients to complain of a sensation of “band-like” tightness.[36] A 2008 retrospective nine-year study found that of TM signs and symptoms at presentation, 100 percent  were sensory, 47.6 percent motor, and 19.0 percent autonomic.[37] Urinary dysfunction, a common symptom in the early phase of TM, is a known sequela.[38] Fecal retention and incontinence have also been reported and decreased sphincter tone may be found on examination.[36]

Association with biologics. TM has been associated with etanercept. This can occur with other neurological manifestations suggestive of MS.[30]TM should be suspected in a patient on a biologic who presents with back pain (frequently thoracic), lower extremity weakness, urinary and fecal incontinence, and a “band-like” tightness across the back.

Diagnosis. A 2002 report by the Transverse Myelitis Consortium Working Group proposed diagnostic criteria for TM.[34] Diagnosis of TM requires evidence of spinal cord inflammation determined by gadolinium enhanced MRI, CSF pleocytosis, or elevated CSF IgG index. If no inflammation is seen at symptom onset, repeat MRI and lumbar puncture should be repeated within 2 to 7 days. To differentiate idiopathic TM from TM with underlying disease, history should include inquiries about rashes, fever, oral or genital ulcers, sicca symptoms, shortness of breath, and inflammatory arthritis; physical examination should focus on finding signs of adenopathy, rash, decreased lacrimation, livedo reticularis, erythema nodosum, Raynaud’s phenomenon, keratitis, conjunctivitis, and ulcers.[34,39,40] Tests to be performed by referring physician (neurologist).

Guillain-Barre syndrome. Definition. Guillain-Barre syndrome (GBS) is an acute, autoimmune polyradiculoneuropathy characterized by a rapidly evolving symmetrical limb weakness, mild sensory signs, and either areflexia or diminished muscle stretch reflexes, and autoimmune findings.[21] GBS is typically preceded by a viral infection, and has been associated with Campylobacter jejuni enteritis, Epstein-Barr virus, CMV, and HIV.[21] Circumstantial evidence suggests that GBS results when the immune system responds to infectious agents or vaccines and a molecular mimicry system then misdirects to host nerve tissue and produces antiganglioside antibodies (most frequently to GM1).[41]

Clinical presentation. The acute areflexic motor paralysis of GBS may first present as “rubbery legs,” with tingling dysesthesias in the extremities and ascending paralysis evolving over hours to days.[41] In the early stages of GBS, about half of all patients have been found to complain of pain in the neck, shoulder, back, or spine.[41] Two to four weeks of progressive neck weakness may present before respiratory compromise.[21] Cranial neuropathy can occur in patients with GBS, and facial palsy can result.[42] Early loss of bowel or bladder function suggests an alternative diagnosis, such as the commonly confused TM.[39]

Association with biologics. GBS has been associated with efalizumab therapy and is listed in the efalizumab package insert as an adverse reaction.[43] GBS also has been associated with infliximab.[44] Any patient on biologic therapy should be suspected of having GBS with progressive symmetrical limb weakness.

Diagnosis. Required diagnostic criteria for GBS include progressive weakness of two or more limbs secondary to neuropathy, areflexia, and a disease course of less than four weeks.[41] The characteristic CSF finding of albuminocytologic dissociation (<50cells/mm3) and electrophysiological evidence of slowing of nerve conduction and partial/complete conduction block in motor fibers may be unremarkable within the first week of onset.[21] A retrospective study showed that an absent H-reflex (97% of cases) was the most sensitive electrodiagnostic finding suggesting early GBS, although a combination of findings needed for definitive diagnosis was often not seen until five days after onset of symptoms.[45]

Chronic inflammatory demyelinating polyneuropathy. Definition. Although the chronic course of chronic inflammatory demyelinating polyneuropathy (CIDP) results in a higher prevalence than GBS, both diseases are characterized by elevated CSF protein levels and evidence of acquired demyelination. Given that CIDP responds to glucocorticoids, it has been suggested that CIDP is immune-mediated. The myelin protein Po has been implicated as a possible autoantigen in some patients. About 25 percent of patients who have clinical features of CIDP also have monoclonal gammopathy of undetermined significance (MGUS).[41]

Clinical presentation. The onset of CIDP is oftentimes gradual and occasionally subacute, and the course can be chronic progressive and in others relapsing remitting. Acute onset CIDP may be present when GBS deteriorates over nine weeks following onset or relapses three times or more.[41] Weakness is typically present for at least two months, and antecedent infections and respiratory symptoms are not as likely in CIDP patients as compared to GBS patients.[21] Weakness of the extremities is often, but not always, symmetric, and motor and/or sensory (i.e., ataxia) symptoms may be present. Ten percent of patients with CIDP have tremors that may signify subacute worsening or improvement. Only a small number of patients have cranial nerve findings (i.e., external ophthalmoplegia).[41]

Association with biologics. CIDP has been associated with the use of etanercept.[46] There have also been reported cases of GBS or CIDP variant of peripheral demyelination with the use of infliximab.[47] Any patient on biologics should be suspected of having CIDP with progressive symmetrical limb weakness that follows a chronic course.

Diagnosis. The diagnosis of CIDP is based on clinical, CSF, and electrophysiological findings. The CSF is often acellular with an elevated protein level. There are multiple principal features characteristic on electrodiagnostic studies, but the presence of a conduction block is a sign of acquired demyelinating process. Serum protein electrophoresis with immunofixation would search for monoclonal gammopathy.[41]

Biologic therapy represents a recent trend in the treatment of psoriasis, but as reports emerge showing an association between these drugs and neurological complications, it becomes imperative for dermatologists to stay abreast regarding the potential risks of such therapy. Currently, caution is urged in all TNF-a agents in patients with pre-existing or recent onset of CNS demyelinating disorders. Although efalizumab recently has been removed from market, it is important for dermatologists to remember that patients may still be at risk for developing neurological complications. Given the serious implications of diseases, such as PML and central and peripheral demyelinating disorders, it is important to ask patients specifically whether they have been experiencing neurological symptoms. Dermatologists must know how to inform patients about medication risks, as such discussions will allow those seeking treatment to make educated decisions regarding their disease management as well as potentially increase patient awareness of any neurological complications if any were to develop. Early recognition of the clinical manifestations of neurological complications in patients treated with biologic therapy enables dermatologists to appropriately refer patients to neurologists for diagnostic workup, disease confirmation, and any necessary treatment.

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