ACHAIKI IATRIKI | 2021; 40(2): 115–120
Review
Angeliki Sapsani1, Maria Kalafateli2
1Faculty of Medicine, School of Health Sciences, University of Patras, Patras, Greece
2Department of Gastroenterology, General Hospital of Patras, Patras, Greece
Received: 05 Jan 2021; Accepted: 02 Mar 2021
Corresponding author: Maria Kalafateli, Kerineias 12, 26441, Patras, Greece, Tel.: +30 6930 720455, E-mail: mariakalaf@hotmail.com
Key words: Crohn’s Disease, natalizumab, progressive multifocal leukoencephalopathy
Abstract
Natalizumab is a humanized IgG4 antibody against a4 integrin, which blocks the a4b7-mediated homing of lymphocytes to the gut. The efficacy of natalizumab for the induction of remission and clinical response in patients with moderate to severe Crohn’s disease has been supported by several studies. However, its association with progressive multifocal leukoencephalopathy (PML), a potentially fatal infection of the central nervous system, resulted in withdrawal and then re-approvement of the drug only under a highly restrictive monitoring program, in order to minimize this risk. This review aims to summarize existing data on the efficacy and safety of natalizumab, with a special reference to PML, in an attempt to determine which patients are in the highest risk of developing this infection and which patients could possibly benefit from natalizumab treatment.
Introduction
Natalizumab (Tysabri; Elan pharmaceuticals and Biogen Idec) is a humanized IgG4 monoclonal antibody against a4 integrin which binds to either b7 or b1 integrin to form a4b7 and a4b1 integrins, respectively. As a result, natalizumab blocks both a4b7 – mucosal addressin cell adhesion molecule 1 (MadCAM-1) interaction that mediates leukocyte homing to the gut, as well as a4b1 – vascular cell adhesion molecule 1(VCAM1) interaction, which is important for the migration of lymphocytes to the central nervous system (CNS) [1,2].
Natalizumab, was first approved by FDA in November 2004, as a quite promising drug for the treatment of relapsing – remitting Multiple Sclerosis (MS). However, its manufacturers withdrew the drug from the market and ceased ongoing clinical trials only 3 months later, as 2 patients with MS and 1 patient with Crohn’s disease (CD) developed progressive multifocal leukoencephalopathy (PML), a potentially fatal opportunistic infection of the central nervous system (CNS) caused by John Cunningham polyomavirus (JCV), resulting in two deaths (including the CD patient) [1-3]. Natalizumab was re-approved in 2006 by the FDA as a second line treatment for relapsing remitting MS, under a highly restrictive monitoring program to better assess and minimize patients’ PML risk, called TOUCH (Tysabri Outreach: Unified Commitment to Health). Later in 2006, natalizumab was also approved for MS by the European Medicines Evaluation Agency (EMEA), although without a similar monitoring program. In 2008, natalizumab was re-approved for the treatment of moderate to severe CD again under the safety monitoring program TOUCH [1,3-5].
Efficacy of natalizumab in cd
In a systematic review, Nelson et al [3] analyzed data from five randomized controlled trials (RCT) [6-10] in order to determine the efficacy and safety of natalizumab for induction of remission in CD. Four out of five RCTs [6-9] compared one, two or three natalizumab infusions (3mg/kg, 6mg/kg, 300mg, respectively) with placebo while one study [10] compared three natalizumab plus infliximab infusions with infliximab plus placebo. The authors concluded that natalizumab was effective for the induction of remission and clinical response in some patients with moderate to severe active disease. More specifically, one infusion of natalizumab was significantly superior to placebo for the induction of remission at 2 and 4 weeks, as 85% and 76% of patients in the natalizumab group compared to 90% (RR 0.94, 95% CI 0.89 to 0.98) and 83% (RR 0.91, 95% CI 0.86 to 0.96) of patients in the placebo group, respectively, failed to enter remission. Furthermore, one infusion was significantly superior to placebo for the induction of clinical response at 4 weeks (49% vs 61%; RR: 0.78, 95% CI: 0.66-0.92). Two infusions were significantly superior for the induction of remission at 6 and 8 weeks (66% vs 76%; RR: 0.85, 95% CI: 0.78-0.93 and 66% vs 77%; RR: 0.85,95% CI: 0.76-0.95, respectively).Three infusions were also significantly superior to placebo for the induction of remission and clinical response at 12 weeks (61% vs 73%; RR: 0.85, 95% CI: 0.78-0.98 and 39% vs 53%; RR: 0.76, 95% CI: 0.67-0.86, respectively).Thus, it seems that the benefit tends to increase with additional infusions of natalizumab. In addition, post hoc subgroup analysis demonstrated significantly greater response in patients with objectively confirmed active inflammation (such as high CRP) or chronically active disease despite the use of conventional therapies (immunosuppressants and anti-TNF agents). In the study which compared combination therapy of natalizumab and infliximab with placebo and infliximab [10], there was no statistically significant difference in remission rates at 10 weeks. However, post hoc subgroup analysis suggested that patients with higher CPR levels achieved higher rates of remission with combination therapy [3]. In a retrospective study, Bellaguarda et al [11] confirmed natalizumab’s efficacy in CD. They reported decreased risk of a subsequent surgery in patients treated with natalizumab compared with patients that did not receive natalizumab, while history of CD, fistulizing disease and perianal disease were associated with an increased risk of surgery in Cox regression analysis.
Adverse effects
As far as adverse effects are concerned [3], natalizumab was generally well tolerated with consequent results in all five aforementioned studies [6-10]. Adverse effects occurred infrequently and there was no statistically significant difference in the proportion of patients who experienced adverse effects or discontinued treatment between the natalizumab group treated with one, two or three infusions (300mg or 3mg/kg or 6mg/kg) and the placebo group. Similarly, there was no significant difference in the rates of serious adverse effects among studies. Common adverse effects included headache, abdominal pain, arthralgia, colitis, nausea, vomiting, pharyngitis, influenza syndrome, hypersensitivity-like reactions and development of antibodies against natalizumab, while serious adverse events included exacerbation of CD and complications of CD such as intestinal obstruction. The anti-natalizumab antibodies were associated with infusion and hypersensitivity-like reactions as well as loss of efficacy. One of the studies [8] suggested that concomitant use of immunosuppressive drugs and corticosteroids might be protective against antibody formation. However, one patient under combined 6-mercaptopurine and natalizumab therapy was diagnosed with B-cell lymphoma. None of the included studies reported tuberculosis or opportunistic infections, but two patients developed a malignancy (basal cell carcinoma and B-cell lymphoma, respectively). The study that compared combination therapy of natalizumab and infliximab with infliximab and placebo [10] demonstrated similar rates of side effects, drug discontinuation and serious side effects across groups at 10 weeks. Common adverse events in this study [10] included headache, worsening of CD, nausea, and nasopharyngitis.
Although, these studies demonstrated quite encouraging results regarding the safety profile of natalizumab, they were not designed to detect serious and rare adverse effects as the maximum duration of follow-up was 12 weeks [3]. As already mentioned, two patients with MS and one patient with CD treated with natalizumab developed PML [1-3,5]. The CD patient that participated in the ENACT-1 trial [8] and was diagnosed with PML, received 3 doses of natalizumab every 4 weeks during the study period (starting from March 2002) followed by 5 further doses of open label natalizumab every 4 weeks (starting from February 2003). Since the diagnosis of CD, the patient had received multiple immunosuppressive treatments including infliximab and azathioprine, the last doses of which were given 20 and 8 months before admission, respectively. The patient was admitted with severe confusion and disorientation in July 2003, one month after the last dose of natalizumab, following a total of 8 doses of the drug. The patient was falsely diagnosed with astrocytoma and was finally reclassified with the diagnosis of PML in 2005. As frozen serum analysis demonstrated, JCV DNA appeared in serum 3 months after the initiation of open-label natalizumab or 2 months before admission. In conclusion, this patient manifested symptoms of PML after 17 months of intermittent treatment with natalizumab, (i.e., 8 doses of natalizumab), a time interval beyond the observational period of studies conducted at the time of natalizumab’s FDA approval [12].
Pml risk
Since PML is the most concerning adverse event and the major reason for which natalizumab does not constitute an appealing option among the available inflammatory bowel disease regimens, an attempt is made in the next section to analyse its pathogenesis and the subgroup of patients with the higher risk to develop PML, in order to assist the prevention of this outcome.
PML is caused by JCV, a polyomavirus that affects almost exclusively severely immunocompromised patients with mainly cell-mediated immune response defects such as HIV infected patients, patients with hematologic malignancies and organ-transplanted patients. JCV is usually acquired during childhood, while seropositivity in the general population ranges from 39% to 91% [5,13,14]. Once the virus enters the host, it can infect the kidneys, the lymphoid tissue and the bone marrow (CD34+, CD19+, CD20+ lymphoid cells) and establish either a persistent or a latent infection. Natalizumab, unlike other immunosuppressive drugs, has two unique features that increase the risk of PML. Firstly, natalizumab forces CD34+ cells, which can differentiate to B – cells, to migrate from the bone marrow to the peripheral circulation. Some of these cells then differentiate to B-cells. Secondly, natalizumab upregulates transcription factors found in CD19+ and CD20+ cells. These transcription factors also bind to JCV DNA transcription sites and promote its replication in latently infected cells. Although some of these cells might be detected by the immune system, JCV infected circulating B-cells as well as free virions, can reach and enter the brain, where JCV causes lytic infection of oligodendrocytes resulting in demyelination foci [13]. Symptoms vary depending on the brain areas involved, ranging from focal neurological deficits to cognitive impairment, often leaving patients with severe and permanent disabilities [13], while mortality rates approach 25% [5].
Following these incidents, the manufacturers in association with the National Institutes of Health (NIH), conducted a retrospective investigation to assess the risk of PML in patients treated with natalizumab. Data from 3116 patients who participated in clinical trials of natalizumab for the treatment of MS (n=1869), CD and rheumatoid arthritis (both n=1247) were evaluated [15]. Clinical history, physical examination and MRI were used to rule out PML. Patients with any abnormal finding consistent with PML were referred to an independent adjudication committee for further evaluation with cerebrospinal fluid testing, and those fulfilling all these criteria, received the diagnosis of PML. Finally, the investigation didn’t reveal any new cases of PML and suggested that the incidence of PML in patients exposed to natalizumab was 1 case per 1000 patients in the population that received a mean of 17.9 monthly doses of natalizumab. However, the exact duration of treatment exposure needed to increase the odds of PML development remains unknown. The median exposure in patients with CD was 7 infusions [15]. So far, three factors are known to increase the risk of PML in natalizumab treated patients: longer duration of treatment, prior use of immunosuppressants and the presence of anti-JCV antibodies [14,16].
More recently, Bloomgren et al analysis [16] on MS patients provided an algorithm based on the three risk factors mentioned above, which could help minimize the risk of PML. What is worth mentioning is that the risk increases with longer duration of treatment with the greatest increase occurring after 2 years of therapy. In addition, no seronegative patient developed PML at the time of the analysis, since no seropositive patient had been tested negative before being diagnosed with PML and the incidence of 0.09 cases per 1000 patients was calculated after a sensitivity analysis was performed, taking into consideration the false negative rate of anti-JCV antibody assay [16]. Today, the introduction of anti-JCV antibody index provides another useful tool, that allows more accurate risk stratification of PML via improving detection of low anti-JCV positive responses, thus minimizing intermittent positivity and false negative results [17]. Ho et al [18] calculated the PML risk in seropositive patients treated with natalizumab, depending on yearly exposure to natalizumab and prior immunosuppressant use and further stratified it with the anti-JCV antibody index. PML risk is considered to be low at anti-JCV antibody index values of 0.9 or less and increases at values of 1.5 or more. For patients with anti-JCV antibody index less than 0.9, the cumulative risk is estimated to reach 1.6 per 1000 patients for a period of 6 years or 72 infusions of natalizumab and remains less than 1 per 1000 patients for a period of 4 years or 48 infusions (0.6 per 1000). For patients with an index more than 0.9 but less than 1.5, the cumulative risk is 8.5 per 1000 patients for a period of 6 years (72 infusions) and remains less than 1 per 1000 patients (0.3 per 1000) for a period of 2 years (24 infusions). As for patients with an index more than 1.5, the cumulative risk for a period of 6 years is 28 per 1000 patients and remains less than 1 per 1000 (0.2 per 1000) only for a period of 1 year of exposure (12 infusions). However, the numerically largest increase in risk is observed after 3 years of exposure in all three index categories. More specifically, for patients with an index less than 0.9, the risk rises from 0.2 for a 3-year exposure period to 0.6 per 1000 patients for a 4-year exposure period. For patients with an index more than 0.9 but less than 1.5 the risk rises from 1.1 to 3.1 per 1000 and for patients with an index more than 1.5 the risk rises from 3.7 to 10.4 per 1000 patients [18]. Thus, the greatest increase in PML risk in this study was observed after 3 years of treatment [18] in contrast to the study by Bloomgren at al [16] where the greatest risk was observed after the first 2 years.
While all data of JCV seroprevalence are derived from MS patients, Bellaguarda et al [11] were the first to assess the prevalence of JCV seropositivity among 191 patients with CD, the effects of natalizumab treatment and the seroconversion rate during treatment. JCV seroprevalence was 67.5%, which is in consistence with the rates reported in the general population and in the large MS populations as well. Among the 22 patients who were seronegative, only 1 patient became seropositive after 22 months of treatment. Prior use of thiopurines was identified as a risk factor for a positive JC serology. In addition, the use of natalizumab was associated with a significantly reduced risk of surgery in both seronegative and seropositive patients, demonstrating its benefit in refractory CD [11]. Applying these results to all CD patients (assuming that they are representative), approximately one third of patients is seronegative and, thus, an appropriate candidate for natalizumab therapy. Taking into consideration the reported incidence of 0.09 cases per 1000 patients by Bloomgren et al [16] and the fact that no patient actually developed PML as well as the fact that seroconversion rates in MS are 2-3% [5], it could be assumed that natalizumab is actually a safe option for seronegative patients. Regarding the seropositive patients with CD, the risk of 1.6 per 1000 after 1 year and 11.1 per 1000 after 2 years of therapy could be deemed low and acceptable for patients suffering from refractory disease. Besides, natalizumab treatment could be discontinued if patients show no response within 3 months, making it extremely unlikely to develop PML [5]. Based on data from MS patients, a proposed algorithm for patients’ selection for natalizumab treatment in CD is presented in Figure 1.
Figure 1. Proposed algorithm for patients’ selection for natalizumab treatment in Crohn’s disease (CD) depending on the number and type of risk factors for progressive multifocal encephalopathy (PML) development.
JCV, John Cunningham virus; Tx, treatment.
As abovementioned, since 2006 for MS and 2008 for CD, natalizumab is prescribed after enrolment in the TOUCH program. The TOUCH program ensures that patients and health care professionals are informed about the risk of PML associated with natalizumab treatment. Only prescribers, infusion centres and pharmacies associated with infusion centres enrolled in the program are allowed to prescribe natalizumab. Risk stratification includes the three factors known to increase risk of PML and already mentioned: prior immunosuppression therapy, number of infusions and duration of treatment, as well as positive JCV serostatus. However, although JCV serostatus is suggested to be checked every 6 months throughout treatment, it’s not mandatory. Thus, this recommendation is not always applied in practice, which could compromise patients’ safety, especially when no symptom is present (13.3% are asymptomatic as reported from Biogen Database by August 2016 [19]). In addition, TOUCH provides information about concurrent use of antineoplastic, immunosuppressant and immunomodulatory drugs and suggests monitoring of patients for other opportunistic infections [4].
As of June 2017, 731 cases of PML were reported, 24% of which were fatal with an incidence of 4.21 per 1000 patients. The majority of cases are associated with prior immunosuppression, as it is shown from Biogen data collection by February 2017 [20].
Follow-up of patients under treatment with natalizumab
Despite the careful selection of candidates for natalizumab treatment, the risk of PML cannot be eliminated and, thus, natalizumab users should be under close monitoring. This includes regular anti- JCV antibody and neurological examination, as well as MRI screening [21].
More specifically, all seronegative patients receiving natalizumab should be re-tested for anti-JCV antibodies every 6 months [21,22] considering that seroconversion of previously negative patients can occur as treatment duration increases (approximately 2% per year) [23].
Subsequently, a neurological examination should be performed every 3 months or if new symptoms appear [22]. PML progresses over days to weeks and is presented with cortical symptoms and signs, behavioral and neuropsychological alteration, retrochiasmal visual deficits, seizures or hemiparesis. High awareness and proper education of physicians, patients and their families, is needed to early identify these features [23].
Furthermore, all patients should have a baseline brain MRI scan before treatment initiation as screening test. Then, MRI imaging should be repeated at regular intervals depending on the evaluated individual risk for PML development [21,22]. Yearly screening is acceptable for low-risk patients (patients without any risk factor); however, patients in higher risk should be screened on a 3-to-6-month basis, including patients with three risk factors, or seropositive patients with high anti JCV antibody index (≥1.5), without prior immunosuppressant use but treatment duration longer than 2 years [21,22]. MRI should also be performed whenever a patient presents with new-onset neurological symptoms [22]. PML on MRI is depicted as multifocal, asymmetric, subcortical white matter lesions, with little surrounding edema or mass effect [23]. Hyperintense signals in subcortical white matter on FLAIR (fluid-attenuated inversion recovery) sequence has higher sensitivity for detection of PML [23,24].
If PML is suspected based on clinical and MRI findings, a lumbar puncture with evaluation of cerebrospinal fluid (CSF) for the detection of JCV DNA should be undertaken to confirm the diagnosis. The therapeutic drug monitoring department at Biogen Idec should be informed and the CSF sample should be sent in a certified laboratory for JCV DNA testing [22]. The drug should be discontinued immediately when PML is suspected. Clinicians should be aware that there is no currently FDA-approved treatment for PML [24].
Conclusion
To summarise, even though current therapies for CD have achieved revolutionary rates of induction of remission in moderate to severe CD, there are still many patients that fail to enter remission or just don’t tolerate first-line and second-line treatments. Thus, there is an increasing need for further options with safe and effective drugs. Natalizumab is an effective drug for some patients with moderate to severe CD. However, its association with PML and the introduction of vedolizumab, a drug with similar mechanism of action but without PML risk, prevents its further use in inflammatory bowel disease. Nevertheless, natalizumab should not be excluded as an option given the relatively high rates of loss of response to anti-TNF agents and the formation of antibodies against these regimens [5]. In addition to that, if we compare RCTs assessing the efficacy of vedolizumab with those assessing the efficacy of natalizumab, always considering the challenges and errors coming up from such an attempt, natalizumab appears to have higher response rates than vedolizumab which could be either due to trials premature end-points or to the lack of systemic activity of vedolizumab which limits its efficacy [5]. In conclusion, natalizumab should be prescribed in selected patients following a careful consideration of the PML risk. Although natalizumab doesn’t consist an appealing option nowadays, it should not be precluded from our list yet, given its high rates of efficacy in patients with refractory disease.
Conflict of interest disclosure
None to declare.
Declaration of funding source
None to declare.
Author contributions
Sapsani A: collection, analysis and interpretation of data, drafting the manuscript; Kalafateli M: design of the study, interpretation of data, drafting and revising the manuscript.
References
1. Guagnozzi D, Caprilli R. Natalizumab in the treatment of Crohn’s Disease. Biologics. 2008;2(2):275-84.
2. Lamb CA, O’Byrne S, Keir ME et al. Gut-Selective Integrin-Targeted Therapies for Inflammatory Bowel Disease. J Crohns Colitis. 2018;12(2):S653-68.
3. Nelson SM, Nguyen TM, McDonald JW. Natalizumab for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2018;2018(8):CD006097.
4. Avasarala J. The TOUCH program and natalizumab: Fundamental flaw in patient protection. F1000Res. 2015;4:1450.
5. Scott F, Osterman M. Natalizumab for Crohn’s Disease: Down but Not out. Clin GastroenterolHepatol. 2015;13(11):1926-8.
6. Gordon FH, Clement WYL, Hamilton MI, et al. A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn’s disease. Gastroenterology. 2001;121:268-74.
7. Gosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn’s disease. N Eng J Med. 2003;348:24-32.
8. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353(18):1912-25.
9. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn’s disease:results of the ENCORE trial. Gastroenterology. 2007;132(5):1672-83.
10. Sands BE, Kozarek R, Spainhour J et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis. 2007;13(1):2-11.
11. Bellaguarda E, Keyashian K, Pekow J et al. Prevalence of Antibodies Against JC Virus in Serum of Patients With Refractory Crohn’s Disease and Effects of Natalizumab Therapy. ClinGastroenterolHepatol. 2015;13(11):1919-25.
12. Van Assche G, Van Ranst M, Sciot R et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s Disease. N Engl J Med. 2005;353:362-8.
13.Major EO, Yoursy TA, Clifford DB. Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned. Lancet Neurol. 2018;17(5):467-80.
14.Saruta M, Papadakis K. Lymphocyte Homing Antagonists in the Treatment of Inflammatory Bowel Diseases. Gastroenterol Clin N Am. 2014;43:581-601.
15.Yoursy TA, Major EO, Ryschkewitsch C et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl Med 2006;354(9):924-33.
16.Bloomgren G, Richman S, Hotermans C et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870-80.
17.Biogen. Medical information website, https://medinfo.biogen.com/medinfo (March 2020).
18.Ho PR, Koendgen H, Campbell N et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-33.
19.Mason L, Carrillo-Infante C, Richman S. Outcomes of asymptomatic progressive multifocal leukoencephalopathy (PML) in natalizumab-treated multiple sclerosis (MS) patients. Presented at: 4th Congress of the European Academy of Neurology (EAN). Jun 16th – 19th; Lisbon, Portugal. EPR3110.
20.Biogen. Medical information website, https://medinfo.biogen.com/medinfo (Release Date: February 11, 2019).
21.European Medicines Agency. Tysabri: European Public Assessment Report – Product Information (18/06/2009). Available from: https://www.ema.europa.eu/
22.Fernández O, García-Merino J, Arroyo R et al. Spanish consensus on the use of natalizumab (Tysabri®)-2013. Neurología. 2015;30(5):302-14
23.Fernández O.Best practice in the use of natalizumab in multiple sclerosis. Ther Adv Neurol Disord. 2013 Mar; 6(2): 69-79.
24.Biogen – Touch Prescribing Program. Helpful information for evaluation of new neurological symptoms in patients receiving TYSABRI. (Release Date: 07/2020). Available from: https://www.touchprogram.com/TTP/