Neuropharmacology & Neurotherapeutics
Gene therapy of cerebrovascular disease
Aug. 24, 2021
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Infliximab is a monoclonal antibody for the treatment of autoimmune diseases. Originally a mouse antibody, it was later developed into a human (humanized) antibody. Because it is a combination of mouse and human antibody, it is called a chimeric monoclonal antibody. The chimeric antibody was designed to reduce immunogenicity and improve pharmacokinetics in humans (19). Infliximab has been approved by the United States Food and Drug Administration for the treatment of psoriasis, Crohn disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, sarcoidosis, and ulcerative colitis.
Infliximab, administered by intravenous injection, binds specifically to human tumor necrosis factor alpha and neutralizes its biological activity. Tumor necrosis factor alpha is a proinflammatory cytokine produced by many cell types (blood monocytes, macrophages, mast cells, and endothelial cells) that play a key role in the pathogenesis of multiple autoimmune disorders.
Pharmacodynamics. Elevated concentrations of tumor necrosis factor alpha have been found in involved tissues and body fluids of patients with autoimmune diseases. Treatment with infliximab reduces infiltration of inflammatory cells into inflamed areas. Most of the clinical pharmacology has been studied in Crohn disease, rheumatoid arthritis, and spondyloarthritis as it is widely used as a treatment for these diseases. However, several forms of vasculitis appear responsive to tumor necrosis factor antagonists, which include Behçet disease, Churg-Strauss vasculitis, polyarteritis nodosa, and giant cell arteritis among others. Wegener granulomatosis and sarcoidosis have been shown to improve with infliximab.
Biological activities attributed to tumor necrosis factor alpha include: induction of proinflammatory cytokines, such as interleukins 1 and 6; enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes; activation of neutrophil and eosinophil functional activity; and induction of acute phase reactants and other liver proteins. The relationship of these biological response markers to the mechanisms by which infliximab exerts its clinical effects is unknown.
Antidepressant response to infliximab in patients with increased baseline inflammation, as reflected by a plasma C-reactive protein concentration, involves inhibition of genes related to innate immune activation with alterations in glucose and lipid metabolism (22).
Pharmacokinetics. In adults, single intravenous infusions of infliximab 3 mg/kg to 20 mg/kg show a linear relationship between the dose administered and the maximum serum concentration. The volume of distribution at steady state is independent of dose and indicates that infliximab is distributed primarily within the vascular compartment. The median terminal half-life of infliximab is 7.7 to 9.5 days.
Following an initial dose of infliximab, repeated infusions at 2 and 6 weeks result in predictable concentration-time profiles following each treatment. No systemic accumulation of infliximab occurs on continued repeated treatment with 3 mg/kg or 10 mg/kg at 4- or 8-week intervals. Development of antibodies to infliximab increases infliximab clearance. At 8 weeks after a maintenance dose of 3 to 10 mg/kg of infliximab, median infliximab serum concentrations range from approximately 0.5 to 6 mcg/mL.
Clinical trials have been conducted for all the approved conditions, which are mainly systemic disorders but may have neurologic complications. Only a few clinical trials of neurologic disorders treated with infliximab have been published.
A randomized controlled trial evaluated the long-term efficacy of infliximab in patients with acute or subacute sciatica secondary to herniated disc (20). One-year follow-up showed that 67% of patients in the infliximab group reported no pain compared with 63% in the control group. Although the long-term results of this randomized trial do not support the use of infliximab compared with placebo for lumbar radicular pain in patients with disc herniation-induced sciatica, further study appears to be warranted in a subgroup of patients with L4-L5 or L3-L4 herniations.
In a multicenter, open-label, investigator-driven study, the European Ankylosing Spondylitis Infliximab Cohort (EASIC), most patients were successfully treated with infliximab for 5 years whereas discontinuation and reintroduction of therapy was less satisfactory due to the frequent occurrence of hypersensitivity reactions (14). A multicenter, prospective, open-label, single-arm phase 3 study of infliximab therapy for intestinal, neurologic, and vascular involvement in Behcet disease reported improvement of clinical symptoms in all the systems involved (16). Safety and pharmacokinetics of infliximab in Behcet disease was comparable with that in patients with rheumatoid arthritis or Crohn disease. A retrospective multicenter study of patients diagnosed as suffering from CNS sarcoidosis, including some previously refractory to other immunosuppressive treatments, showed favorable responses to treatment with infliximab as assessed by imaging as well as clinical examination (12). In a retrospective study, the infliximab biosimilar was as effective and safe for treating neurosarcoidosis as the original preparation (26).
Indications are listed below according to the disease.
Rheumatoid arthritis. Infliximab, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. The results of a prospective nonrandomized study showed that the use of accelerated infliximab infusion in rheumatic patients is safe, with high satisfaction among patients and health care providers (09).
Crohn disease. Infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn disease who have had an inadequate response to conventional therapy.
Ankylosing spondylitis. Infliximab is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
Psoriatic arthritis. Infliximab is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
Plaque psoriasis. Infliximab is indicated for the treatment of adult patients with chronic severe plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. Infliximab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.
Ulcerative colitis. Infliximab is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use.
(1) Infliximab is used for the treatment of Behçet disease based on the rationale that it blocks TNF-alpha involved in the pathogenesis of the disease. A case of life-threatening vasculo-Behçet disease was reported with remission for 3 years with use of infliximab and recurrence after withdrawal, but with response on reintroduction of the drug (21). Neuro-Behçet disease has been treated with infliximab, and it effectively prevents further relapses and stabilizes the symptoms of patients who are being treated with single or multiple immunosuppressant drugs (32).
(2) Sciatica due to intervertebral disc herniation.
(3) Cogan syndrome.
(4) Treatment of central nervous system involvement associated with primary Sjögren syndrome. Clinical trials have not shown efficacy of infliximab in Sjögren syndrome (25).
(5) For sarcoidosis of the nervous system that is refractory to treatment using steroids combined with various immunosuppressive drugs (27). A retrospective long-term study on patients with severe and resistant sarcoidosis involving the central nervous system showed remission in 11 out of 12 cases following treatment with infliximab (06). Infectious complications were frequent and occurred mainly in male patients with longer duration of steroids and immunosuppressant use prior to infliximab. Paradoxically, several case reports in the literature describe the development of sarcoidosis as an adverse effect of treatment with infliximab (08).
(6) A randomized, controlled trial has shown that infliximab does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers (24).
(7) Infliximab combined with methylprednisolone has been shown to be effective for recovery following acute spinal cord injury in experimental animals (07).
(8) Autoimmune sensorineural hearing loss associated with rheumatoid arthritis (11).
(9) In an open study, injection of infliximab into sacroiliac joints of patients with non-radiographic axial spondyloarthritis who had failed to respond to non-steroidal anti-inflammatory drugs resulted in significant decrease in back pain as well as stiffness, lowering of C-reactive protein levels, and improvement of MRI parameters of disease activity (31).
(10) Treatment of aseptic neutrophilic myositis, an inflammatory skin condition with rare infiltration into the muscle (13).
(11) A systematic review of controlled trials showed that infliximab is ineffective in reducing depressive symptoms according to the Hamilton Scale for Depression if the patients already have increased inflammatory genes, including tumor necrosis factor and C-reactive protein (03).
(12) Recent large retrospective studies from the United States and France established that infliximab appears to be efficacious for neurologic manifestations of sarcoidosis when other treatments are inadequate (23).
Infliximab at doses greater than 5 mg/kg should not be administered to patients with moderate to severe heart failure as it may be associated with an increased incidence of death and hospitalization due to worsening heart failure.
Infliximab should not be re-administered to patients who have experienced a severe hypersensitivity reaction to infliximab. Additionally, infliximab should not be administered to patients with known hypersensitivity to inactive components of the product or to any murine proteins.
Goals and duration of treatment vary according to the condition treated as stated in the indications.
The recommended dose of infliximab for rheumatoid arthritis is 3 mg/kg given as an intravenous infusion followed with additional similar doses at 2 and 6 weeks after the first infusion and then every 8 weeks thereafter. Infliximab should be given in combination with methotrexate. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks bearing in mind that risk of serious infections is increased at higher doses.
It is not known if there are differences in clearance or volume of distribution of infliximab in patients with marked impairment of hepatic or renal function.
Anesthesia. Effect in combination with anesthesia is not known.
Pregnancy. Infliximab does not actively cross the placenta during the first trimester of pregnancy, but some transfer during the late second and third trimesters leads to detectable levels in the infant's serum for several months after birth (10). Immunological effects of this are unknown, but live vaccination should be avoided until infliximab is undetectable in the serum. Infliximab is not transferred from mother to child by excretion through breast milk (18). Therefore, mothers receiving infliximab may be allowed to breastfeed their babies.
Pediatric. Precautions in children vary according to the disease. For example, infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn disease who have had an inadequate response to conventional therapy. There are special boxed warnings about pediatric patients regarding dosage and adverse reactions.
Geriatric. In clinical trials, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. Because incidence of infections is higher in the elderly population in general, caution should be used in treating the elderly.
There are no clinically significant interactions reported in the literature.
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tumor necrosis factor alpha-blocking agents. The most commonly reported opportunistic infections were tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis. Patients have frequently presented with disseminated rather than localized disease and are often taking concomitant immunosuppressants such as methotrexate or corticosteroids with infliximab. Treatment with infliximab should not be initiated in patients with an active infection, including clinically important localized infections. The risks and benefits of treatment should be considered prior to initiating therapy in patients:
• with chronic or recurrent infection.
• who have been exposed to tuberculosis.
• who have resided or traveled in areas of endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis.
• with underlying conditions that may predispose them to infection.
Neurologic complications. Infliximab and other agents that inhibit tumor necrosis factor alpha have been associated with various neurologic complications, which include seizures and new onset or exacerbation of clinical symptoms or radiographic evidence of central nervous system demyelinating disorders (including multiple sclerosis and CNS manifestations of systemic vasculitis) and peripheral demyelinating disorders (including Guillain-Barré syndrome). In a case report, infliximab treatment was associated with CNS inflammatory demyelinating activity that was histopathologically indistinguishable from multiple sclerosis (17). Aseptic meningitis is an uncommon side effect of infliximab with 5 case reports in the literature (29).
One case report and review of literature shows 15 patients in whom the symptoms of optic neuritis developed following tumor necrosis factor alpha antagonist therapy: 9 patients experienced complete resolution and 2 patients had partial resolution whereas 4 patients continued to have symptoms (30). The possibility of anterior optic neuropathy, in addition to retrobulbar optic neuritis, should be considered in patients who experience sudden-onset visual loss while being treated with infliximab (05). Patients being treated with a tumor necrosis factor alpha antagonist should be closely monitored for the development of ophthalmologic or neurologic signs and symptoms; if optic neuritis is diagnosed, medication should be discontinued, and steroid treatment should be started.
A patient with severe rheumatoid arthritis who was successfully treated with infliximab suffered diverse neurologic complications: brachial plexitis, asymptomatic thoracic myelitis with extensive lesions in MRI study, and herpes zoster lumbar plexitis (01). In rare cases, multifocal motor neuropathy with conduction block has been reported as an adverse effect of infliximab (04). In a patient with ankylosing spondylitis treated with infliximab, multifocal demyelinating axonal neuropathy has been reported as an adverse effect, which resolved after treatment with intravenous immunoglobulin (02). A patient with Crohn disease developed parkinsonism after starting treatment with infliximab and gradual but continual improvement of the resting tremor occurred after withdrawal of infliximab (15).
A review of adverse effects of infliximab indicates that demyelinating disorders might persist despite discontinuation of treatment, suggesting that the drug could trigger the demyelinating process, which further evolves independently (28). Prescribers should exercise caution in considering the use of infliximab in patients with preexisting or recent onset of demyelinating or seizure disorders. Discontinuation of infliximab should be considered in patients who develop significant central nervous system adverse reactions.
K K Jain MD
Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.See Profile
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