Immunomodulatory drugs tend to have more precisely targeted effects on one or a few components of the immune system compared to immunosuppressive drugs, which produce a broader and less specific suppression of the immune response. Nevertheless, specific inhibition of single components may have unanticipated consequences.
Natalizumab is a monoclonal antibody against α
4β 1-integrin, an adhesion molecule on the surface of white blood cells (except neutrophil granulocytes), which has been used as second-line treatment in multiple sclerosis. In 2005, it was withdrawn from the market because of three cases of natalizumab-associated progressive multifocal leukoencephalopathy, but was reintroduced the following year. The case history below is an example of progressive multifocal leukoencephalopathy during natalizumab treatment in multiple sclerosis.
Patient 2. A woman in her fifties with relapsing-remitting multiple sclerosis had been on natalizumab (Tysabri) for several years when discrete changes were seen on MRI. She had had no signs of disease activity for several years. JCV antibodies had been detected in her serum two years previously, but the index was not available at this time. Natalizumab was discontinued, but the patient slowly developed unsteadiness and double vision, and an MRI scan two months later showed a marked increase in pathology (Fig. 2a). This included an inhomogeneous hyperintense lesion in the right cerebellar peduncle that was difficult to distinguish from multiple sclerosis-associated pathology. A PCR assay for JCV DNA revealed 1 173 copies/ml in the cerebrospinal fluid.
Figure 2 a) The T2-weighted image shows an inhomogeneous hyperintense lesion in the right cerebellar peduncle that cannot easily be distinguished from a multiple sclerosis-associated lesion. b) An MRI scan three weeks later showed contrast-enhancing lesions consistent with progressive multifocal leukoencephalopathy with a strong immune response (IRIS)
Plasmapheresis was performed, but the symptoms progressed. An MRI scan three weeks later showed contrast-enhancing lesions consistent with immune reconstitution inflammatory syndrome (Fig. 2b). The patient received high-dose methylprednisolone (Solu-medrol), with subsequent remission. She recovered from the progressive multifocal leukoencephalopathy, but developed sequelae.
As per March 2017, the manufacturer had reported 711 natalizumab-associated cases of progressive multifocal leukoencephalopathy – 708 patients were being treated for multiple sclerosis and three for Crohn's disease
(8) and CD8-positive T lymphocytes (9) are thought to have key roles in the pathogenesis of multiple sclerosis. Binding of natalizumab to α 4β 1-integrin blocks interaction of α 4β 1-integrin with its ligand VCAM-1 (vascular cell adhesion protein) on endothelial cells, and prevents autoreactive T lymphocytes from crossing the blood-brain barrier. Other 'normal' lymphocytes are also excluded from the brain, resulting in reduced immunosurveillance of the central nervous system, with an accompanying risk of opportunistic infections.
Multiple sclerosis per se does not seem to be a risk factor for progressive multifocal leukoencephalopathy, but vigilance is required during treatment because all of the latest disease-modifying agents directly or indirectly affect T cell-associated immune responses
(8), and have the potential to cause progressive multifocal leukoencephalopathy (10). Natalizumab, however, is a special case and is therefore subject to specific monitoring; an algorithm has also been developed for stratifying the risk of progressive multifocal leukoencephalopathy prior to and during natalizumab treatment (11).
The overall disease risk upon use of natalizumab is estimated to be just over 4/1 000 treated patients
(7). However, the risk increases with treatment duration, especially if this extends beyond two years, and also in cases of previous immunosuppressive therapy, and with increasing levels of anti-JCV antibodies. In this context, prior immunosuppressive therapy means in practice (in Norway) mitoxantrone, a treatment that has now more or less been abandoned.
However, we believe it is important to be aware that any drug that causes prolonged lymphocytopenia also increases the risk of progressive multifocal leukoencephalopathy – including long after discontinuation. For patients with two years of natalizumab use, no prior immunosuppressive therapy with mitoxantrone, and a JCV index in the range 0.9–1.5, the risk is approximately 6/1 000 treated patients. If the JCV index is > 1.5, the estimated risk is 17/1 000 treated patients
Other drugs used in multiple sclerosis have also given rise to progressive multifocal leukoencephalopathy. Several cases have been reported during treatment with fingolimod and dimethyl fumarate
(13), both of which may give rise to prolonged lymphocytopenia. Teriflunomide, an active metabolite of leflunomide, has not been associated with the disease to date, but several cases have been linked to leflunomide treatment of rheumatological disease (14).
Daclizumab has recently been approved for use in relapsing-remitting multiple sclerosis. The antibody blocks the IL-2 receptor on activated T cells. There have been no reports to date of progressive multifocal leukoencephalopathy in association with this drug
(15). Cladribine is used to treat hairy cell leukaemia, and has proven effective in multiple sclerosis (16). Unfortunately, use of cladribine has also recently been associated with progressive multifocal leukoencephalopathy (10).
Of the rheumatic diseases, systemic lupus erythematosus predisposes to progressive multifocal leukoencephalopathy, probably independently of immunotherapy
(17). The disease can affect the central nervous system, giving rise to both focal and diffuse symptoms, as well as MRI findings that may resemble those of progressive multifocal leukoencephalopathy, potentially leading to underdiagnosis of the latter.
In an American study, only four cases of progressive multifocal leukoencephalopathy were identified per 100 000 discharged patients with systemic lupus erythematosus
(17). However, this was ten times the number of cases seen in patients with rheumatoid arthritis and 20 times the number in the general population. In 2006, two cases of progressive multifocal leukoencephalopathy were reported in patients with systemic lupus erythematosus who were treated with the monoclonal antibody rituximab.
Rituximab targets the B-cell marker CD20 and leads to a reduction in the number of B cells in the blood. It has proved to be effective in leukaemia and in a range of autoimmune diseases. Several cases of progressive multifocal leukoencephalopathy have been associated with this drug, but none so far in patients with multiple sclerosis.
There have been no cases either in association with ocrelizumab, a new monoclonal antibody against the B-cell marker CD20, which has also shown robust efficacy in multiple sclerosis
(18). Efalizumab, another monoclonal antibody that inhibits T-cell adhesion and diapedesis from the circulation, was withdrawn in 2009 after three cases of progressive multifocal leukoencephalopathy in patients treated for psoriasis (19).