www.sps.nhs.uk Authored June 2019

Risk of progressive multifocal leukoencephalopathy (PML) with biological agents in autoimmune disorders: Review of spontaneous confirmed cases (June 2019)

Progressive multifocal leukoencephalopathy (PML) is a rare but life-threatening demyelinating disease that has been reported in association with a number of rheumatological diseases and immunosuppressive biological therapies. Ongoing vigilance of PML is crucial as early diagnosis and withdrawal of immunosuppressive therapy may improve outcomes.

This article outlines the available spontaneous adverse drug event data for PML in association with a number of biological immunosuppressive agents.

Sheetal Ladva, Medicines Information Pharmacist, London & SE Region

The first stop for professional medicines advice

Introduction Progressive multifocal leukoencephalopathy (PML) is a rare but life-threatening demyelinating disease that occurs predominantly in immunosuppressed patients. It is caused by activation of the John Cunningham virus (JC) which leads to infection and destruction of myelin-producing oligodendrocytes. In survivors, it can lead to devastating neurological complications for which there is no proven effective therapy.1

In the past, PML has been associated with patients infected with human immunodeficiency virus (HIV) and other immunosuppressed populations e.g. those with malignancies and organ transplants. More recently it has been reported in association with a variety of rheumatological diseases e.g. systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and with a number of immunosuppressive therapies e.g. natalizumab, efalizumab, mycophenoilate mofetil and rituximab. Given the fatal nature of the disease and lack of therapeutic options, ongoing vigilance of PML is crucial as early diagnosis and withdrawal of immunosuppressive therapy may improve outcomes.1

This article outlines the available data on PML in association with a number of biological immunosuppressive agents identified following a literature search (March 2018), spontaneous reporting to regulatory agencies and unpublished data from manufacturers (table 1). A further two tables are available in the Appendix; table 2, which describes selected case reports of PML with rituximab in various autoimmune diseases and table 3 which outlines PML cases reported through the US FDA and European EudraVigilance databases of adverse drug reaction reports. Due to the limitations in database searching, this is not an exhaustive review of all cases of PML and other articles may have been published in this area.

Epidemiological data Data on the incidence of PML are limited to a few epidemiological studies.

A study that examined trends in PML mortality in the US (1979-1994) reported a 20-fold increase in PML mortality from a stable baseline rate of less than 0.2 per million persons annually before 1984 to approximately 3.3 per million persons in 1994. The increase was attributable to HIV-infection which was recorded on 2,267 (89.0%) of 2.546 death records from 1991 through 1994.2

A US database analysis (1998-2005), which included 297,797,180 hospital discharges, identified 9675 cases of PML. Of these 7934 (82%) were attributable to HIV, 813 (8.4%) to haematological malignancies, 274 (2.8%) to solid cancers, 43 (0.44%) to SLE, 24 (0.25%) to RA, and 25 (0.26%) to other connective tissue diseases. For autoimmune diseases, this equated to the following rates of PML per 100,000 discharges coded after exclusion of concomitant HIV, cancer, and organ transplantation: SLE (4 in 100,000), RA (0.4 in 100,000), and other connective tissue diseases (2 in 100,000).3

Another US database study (2000-2009) described the incidence of PML in 2,030,578 patients with select rheumatological diseases (RA, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, inflammatory bowel disease, and ankylosing spondylitis). Among these patients, there were 53 patients that were hospitalised with a diagnosis of PML, corresponding to an incidence of 2.6 cases/100,000 patients. Among the 53 patients, only 11 (21%) of the PML cases had either HIV or cancer diagnoses. The rate of PML in the patients without HIV or cancer diagnosis was 0.2 cases/100,000 patients with those select rheumatologic diseases.4

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A similar US database study (2000-2008) estimated the incidence of PML in adult non-HIV patients with selected diseases, including 138,469 patients with autoimmune diseases. The incidence rates per 100,000 patient-years were as follows: RA (0; 95%CI: 0-2.2), SLE (2.4; 95%CI: 0.1-13.2), autoimmune vasculitis (10.8; 95%CI: 0.3-60.4), multiple sclerosis (0; 95%CI: 0-5.2), and Sjogren’s disease (0; 95%CI: 0-21.8).5

A Swedish study (1999 to 2009) estimated the incidence rate of PML in patients with RA compared with the general population. The estimated incidence rate of PML per 100,000 patient-years in the overall RA population was 1 (95% CI: 0.3-0.5; 4 cases of PML in 66,278 patients), and 0.3 for the general population (95% CI: 0.1-0.6; 5 cases of PML in 286,949 patients) although difference was not statistically significant. Among the RA patient cohort, the incidence rate of PML in patients who were naive to biologic therapy was 0.8 (95% CI: 0.2-0.5; 3 cases of PML in 65,548 patients) and 2.3 for those that had been exposed to biologic therapy (95% CI: 0.1-1; 1 case of PML in 8,426 patients).6

A systematic literature review of reports in English of PML in patients with rheumatic diseases worldwide identified 46 cases of proven PML in patients with rheumatic diseases (SLE [n=30], idiopathic inflammatory myopathy [n=6], granulomatosis with polyangiitis [GPA; n=4], RA [n=3], Sjogren’s syndrome and CD4 lymphopenia [n=1 scleroderma and amyloidosis [n=1], and destructive polyarthritis with a positive antinuclear antibody, positive Jo1 antibody and CD4 lymphopenia [n=1]).7

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Table 1: Cases of PML identified through literature search, MHRA yellow card data and unpublished data from manufacturer

Drug (manufacturer)

Published case reports of PML Reports of PML via MHRA Yellow card data

Unpublished data (from manufacturer)

Comments

Abatacept (Bristol Myers Squibb)

nil nil 2 ‘possible’ PML cases reported but no further info provided.8

Adalimumab (Abbvie)

Case 1: 71 yr old patient identified from WHO ADR database; 7 month median latency from starting to PML diagnosis; no further clinical details available.9

Case 2: 66 yr old Caucasian woman with long-standing RA treated with adalimumab for 2 years. No previous history of steroids/other biological immunosuppressant use; HIV- negative and no evidence of sarcoidosis, MS, diabetes or malignancy. When symptomatic, changed to MTX; follow up unknown.10

2 reports No relevant data provided.

Belimumab (GSK)

Case 1: 40 yr old female with 16 yr history of mild SLE and HIV-negative. Prior treatment with steroids and HCQ. After 10 infusions of belimumab, and concomitant MMF and steroids, developed progressive neurologic decline, treated with high-dose steroids and CYC but continued to decline. PML diagnosed but patient died several weeks after all immunosuppression stopped.11

Case 2: 58 yr old woman with SLE. Prior treatments include HCQ, MMF and prednisolone. Belimumab started due to active SLE with a good clinical response for 6 months. Then presented with a 3-week history of fatigue, apathy, and aphasia during which time PML diagnosed and all immunosuppression stopped. One year later, patient recovered but with moderate aphasia and executive function deficits still persist.12

8 cases reported through FDA adverse event reporting system. Individual case details not available but all

nil As of 8/3/2018, estimated rate of probable or confirmed PML from clinical trials and post-marketing reports with belimumab is 5 per 82,766 patient-years or 6.04 per 100,000 patient-years (95% CI; 1.96, 14.10).14

A comment in response to the first case report, notes that no direct link can be drawn between belimumab administration and PML occurrence, since SLE patients are at higher risk of infections and may display an altered basal CD19 expression. They suggest that a preliminary count of CD19 lymphocytes should be performed before the introduction of biological treatment.15

A systematic review (2016) suggests that while PML is a very rare disease in SLE patients, there is an increased risk compared to the general population, potentially due to immunosuppression, other contributing factors in their underlying disease, treatments

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were female, mean age 50.1yrs, receiving for rheumatological condition with no concomitant biological, PML reported in mean of 4.25months after first dose and 2 patients died.13

prescribed to manage disease, or a combination of these factors.16

Brodalumab (Leo Laboratories)

nil No monograph available

No relevant data provided.

Certolizumab (UCB Pharma)

nil nil One case reported through FDA Adverse Event Reporting System (between January 2003 and June 2016) but no further details available.17

Dupilumab (Genzyme)

nil nil No relevant data identified

Etanercept (Pfizer)

Case 1: 23 yr old Native American female with 6 yr history of SLE and erosive polyarthritis. Treated for 4 years with prednisone and HCQ. Etanercept with steroids started because of inadequate response with HCQ and continued for 4 years. Etanercept discontinued after PML diagnosis and patient died.18

Case 2: 74 yr old Japanese female with RA. Prescribed steroids and various DMARDs (auranofin, penicillamine, 4- acetylaminophenylacetic acid, MTX, leflunomide, CYC) Etanercept administered and PML diagnosed 8 months later (MRI positive but JC virus negative) and undergoing rehabilitation.19

1 report Other case reports of PML have been reported but not included because of unconfirmed status.20

Golimumab (Merck Sharpe and Dohme)

2 cases reported through the FDA adverse event reporting system but case details not available.13

nil Nil additional data.

Guselkumab (Janssen-Cilag)

nil nil No PML cases reported to EMA.21

Infliximab (Merck Sharpe and Dohme)

Case 1: 69 yr old female with RA. Initially treated with 8 years of MTX, and courses of leflunomide, etanercept and adalimumab over 2 yrs. At presentation, been treated with 5 yrs of infliximab and MTX.22 Case 2: 72 yr old Caucasian male with erosive RA previously treated with steroids, HCQ and MTX. 3 yrs

8 reports; 1 fatal

Nil additional data. 2 further cases in pts with cartilage-hair hypoplasia (genetic condition)29,30

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later HCL discontinued due to toxicity and subsequently treated with infliximab, MTX and steroids for ∼3 years. PML diagnosis 2 years later and MTX and infliximab discontinued. 23 Case 3: 52 yr old patient identified from WHO ADR database; 16 month median latency from starting to PML diagnosis; no further clinical details available.24 Case 4: Reported during prospective cohort study of 511 Belgian patients with RA; no further details available.25,26

Case 5: 16 yr old male identified from a chart review of paediatric patients with IBD. PML onset after 3 months of infliximab and AZA. Within 6 months of discontinuing infliximab, symptoms resolved and brain MRI returned to normal.27

Case 6: A retrospective review of Swedish national data (1988-2013) identified one PML case from a total of 281. No further details were provided other than the patient had received treatment at least 6 months before onset of PML.28

Ixekizumab (Eli-Lilly)

nil nil Based on safety database up to the 5/12/2018, PML is mentioned as very rare <0.01%; no further details provided.31

Rituximab (Roche)

Analysis of an international study (n=129,000 treated with rituximab, 4 whom developed PML) and inclusion of 5th patient estimated risk of rituximab-associated PML at 1: 25,000.32

For patients with SLE, risk estimated at 1: 4000 which probably reflects higher risk of PML associated with lupus. 33

63 reports; 23 fatal

As of November 2017, manufacturer notes the following cases of confirmed PML in patients treated worldwide: -14 cases in approximately 420,101 patients treated for RA.35,36 - 3 cases in patients treated for GPA/MPA.35,36

- 221 and 117 cases in patients treated NHL and CLL, respectively.37

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A retrospective Swedish review which calculated the national incidence of PML in Sweden (1998 and 2013) reported 26 cases of PML with previous biological agents (15 patients with haematological malignancy and 11 with autoimmune disease) including rituximab (n = 15), natalizumab (n = 8), alemtuzumab (n = 2), ofatumumab (n = 1), and infliximab (n = 1).34

Due to the numerous cases of PML reported with rituximab, only a selection of case reports (in pts with RA, GPA, SLE) have been described in further detail - see Appendix 1.

As of November 2016, 13 cases in patients with SLE OR SLE-like connective tissue disease.36

Sarilumab (Genzyme)

nil nil No relevant data identified.

Secukinumab (Novartis)

nil nil In post-marketing experience up to 25/12/2018, and search of published medical literature, no cases of PML have been reported. Manufacturer notes that PML is not identified as an important identified or potential risk in the secukinumab risk management plan.38

Tocilizumab (Roche)

2 cases reported through the FDA adverse event reporting system but case details not available.13

nil No PML cases identified in search of published medical literature.39

Ustekinumab (Janssen-Cilag)

nil 1 report 1 case reported through the EMA; no details provided and not known if same as the MHRA-reported case.40

Vedolizumab (Takeda)

An analysis suggests that risk of PML with vedolizumab is small, and unlikely to be > 6.75 cases/100,000 (based on no published case reports to date).1

Case 1: Previously undiagnosed HIV+ patient (age unknown) with 20 year history of Crohn’s Disease and multiple years of immunosuppressive therapies including current use of vedolizumab and azathioprine.

nil As of May 2018, global post-marketing exposure to vedolizumab totals more than 208,000 patient-yrs and prior to this report there have been no reported cases of PML with vedolizumab. The manufacturer therefore concludes that risk-benefit

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Vedolizumab stopped and HIV treatment started. Most probable cause is HIV status (CD4 count 300) and prolonged immunosuppressant use.41

profile of vedolizumab remains unchanged.42

Key: CYC, cyclophosphamide;; GPA, Granulomatosis with polyangiitis; HCQ, hydroxychloroquine; IBD, inflammatory bowel disease; MMF mycophenolate mofetil, MS multiple sclerosis; MTX, methotrexate; PML, progressive multifocal leukoencephalopathy; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus Limitations of data

• Due to limitations inherent in database searching, this is not an exhaustive review of all cases of PML and other articles may have beenpublished in this area. Spontaneous reports should be interpreted with great caution to quantify and compare safety profiles across productsover time. The observed variability in reporting patterns and heterogeneity of PML cases presents challenges to such comparisons. Pleasenote that accumulated case reports cannot be used to calculate incidence or estimates of drug risk for the following reasons:

o the number of reports received may not be reflective of the actual number of cases that have occurred,o the actual number of patients receiving the product at any time point is not known, ando a causal relationship between the product and these cases has not been established.

• Duplicate cases have been removed, where possible, by screening cases by age, gender, date of event, and other criteria, such asconcomitant drugs and reaction terms.

• PML cases have been confirmed by JC virus in cerebral spinal fluid or brain MRI; unconfirmed diagnoses have been excluded. In confirmedPML cases, treatment of PML has not been described.

• Cases from a haematology/malignancy/neurology/transplantation perspective have been excluded.• A separate search of US and European adverse event databases has been conducted – see Appendix 2.

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4. Bharat A et al. Incidence and risk factors for progressive multifocal leukoencephalopathy among patients with selected rheumatic diseases.Arthritis Care Res (Hoboken) 2012; 64:612-615.

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1429–30.11. Fredericks CA et al. A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab. Lupus 2014; 23/7: 711-

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74 20. Pfizer data on file: Personal communication 2/4/19

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21. Jannsen-Cilag data on file: Personal communication 1/4/1922. Sammut L et al. Progressive multifocal leukoencephalopathy associated with infliximab Journal of the Royal College of Physicians of

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565-57125. Durez P et al. A dose adjustment in patients with rheumatoid arthritis not optimally responding to a standard dose of infliximab of 3 mg/kg

every 8 weeks can be effective: a Belgian prospective study. Rheumatol. 2005; 44/4:465-468.26. Durez P et al. Safety of combination of methotrexate (MTX) and infliximab (IFX) in a large Belgian observational patient cohort with refractory

rheumatoid arthritis. Arthritis Rheum. 2002; 46(9 Suppl.): S536. [unable to access]27. Kolho KL et al. Severe adverse reactions to infliximab therapy are common in young children with inflammatory bowel disease. Acta

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35. Iacobaeus E et al. The national incidence of PML in Sweden, 1988-2013. Neurology 2018; 90/6:e498-e506.36. Berger et al. Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event. Journal of NeuroVirology

2018; 24/3: 323-33137. Roche data on file. Personal communication 5/4/1938. Novartis data on file. Personal communication 29/4/1939. Roche data on file. Personal communication 8/4/1940. Jannsen-Cilag data on file: Personal communication 1/4/1941. Card T et al. What Is the Risk of Progressive Multifocal Leukoencephalopathy in Patients with Ulcerative Colitis or Crohn's Disease Treated

with Vedolizumab? Inflammatory Bowel Diseases 2018; 24/5: 953-95942. Takeda data on file. Personal communication 18/3/1943. Harris HE. Progressive multifocal leucoencephalopathy in a patient with systemic lupus erythematosus treated with rituximab. Rheumatology,

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Appendix

Table 2 – Selected case reports of PML with rituximab in various autoimmune diseases (table adapted from Berger et al36)

Patient characteristics

Duration of disease

Relevant medical history Relevant drug history Total number of rituximab courses/doses*

Outcome

50 yr old F36 RA – 14 yrs

Radiation (history of malignancy), Sjögren syndrome with lymphopenia, undetectable complement and CD4, lymphadenopathy.

Prior non biologics: MTX, steroids, HCQ, etodolac Prior biologics: Infliximab Concomitant drugs: MTX, steroids

No: 4 courses Latency: 5 years from 1st dose and 18 months from last dose

Fatal

62 yr old F36 RA – 20 yrs

Leukopenia Prior non biologics: Leflunomide, sulfasalazine, gold, HCQ, steroids Prior biologics: Adalimumab, etanercept, anakinra Concomitant drugs: MTX

No: ~4 courses Latency: ~18 months from 1st dose and ~ 3 months from last dose

Recovering

60 yr old F36 RA – 5 yrs

SLE Prior non biologics: Azathioprine, MTX, CYC, HCQ Prior biologics: None Concomitant drugs: Steroids, MMF

No: 9 courses Latency: ~56 months from 1st dose and ~ 6 months from last dose

Fatal

83 yr old F36 RA – 7 yrs

None reported Prior non biologics: MTX, steroids Prior biologics: Denosumab Concomitant drugs: MTX, steroids

No: unspecified Latency: ~57 months from 1st dose and ~ 8 months from last dose

Fatal

70 yr old F36 GPA – duration not specified

Immunoglobulin deficiency, breast cancer, diabetes mellitus and vasculitis with chronic stage III renal insufficiency and HIV - negative.

Prior non biologics: MTX, steroids, CYC, epirubicin, fluorouracil Prior biologics: none reported Concomitant drugs: AZA

No: unspecified Latency: 11 months from 1st dose and ~4 months from last dose, symptoms prior to start of rituximab

~ 1 year after PML diagnosis, general improvement but cognitive deficits present and JCV detected in CSF.

62 yr old M36 GPA – 8 yrs

HIV-negative; no other conditions reported.

Prior non biologics: CYC, AZA, steroids Prior biologics: none reported Concomitant drugs: none reported

No: unspecified Latency: ~24 months from 1st dose and ~6 months from last dose

~ 3 months after PML diagnosis,

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condition improved.

45 yr old F43 SLE – 23 yrs

Neutropenia with subsequent pneumonia, herpes zoster reactivation on 3 occasions and haemorrhagic cystitis. HIV- negative

Prior non biologics: steroids, AZA, CYC Prior biologics: none reported Concomitant drugs: none reported

No: 9 doses Latency: unknown

Fatal

36 yr old Japanese M44

SLE and neuropsychiatric SLE; duration not reported

6 months before PML onset, SLE complicated with haemophagocytic lymphohistiocytosis.

Prior non biologics: steroids, Prior biologics: none reported Concomitant drugs: steroids, cyclosporine, CYC, MMF (introduced 4 months before PML onset)

No: 4 courses Latency: unknown; final dose of rituximab 5 months before PML onset.

Some improvement of PML but severe residual disabilities.

37 year old F45

refractory polymyositis

thoracic myopathy and lymphopenia

Prior non biologics: steroids, MTX, AZA, MMF, cyclosporine, IVIG Prior biologics: none reported Concomitant drugs: steroids

No: 5 doses Latency: unknown; final dose of rituximab 2 months before PML onset.

Fatal

Key: ANA, antinuclear antibody; CYC, cyclophosphamide; F, female; GPA, Granulomatosis with polyangiitis; HCQ, hydroxychloroquine; M, male; MMF, mycophenolate mofetil; MTX, methotrexate; PML, progressive multifocal leukoencephalopathy; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus

* Per rituximab license for RA; one treatment course consists of 2 × 1000 mg IV infusions separated by 2 weeks, with treatment courses repeatedevery 24 weeks based on clinical evaluation, but no sooner than every 16 weeks

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Table 3: PML cases reported through the FDA Adverse Events Reporting System (FAERS) and EudraVigilance (European database of suspected adverse drug reaction reports

Generic drug

Number of PML cases reported to FAERS

Number of PML cases reported to EudraVigilance

Abatacept Monograph not listed/not reported 5; of which 2 fatal, 1 recovered, 1 recovering, 1 unknown Adalimumab 35; 8 fatal 22; of which 4 fatal, 2 not recovered, 2 recovering, 14 unknown Belimumab 29; 5 fatal 13; of which 2 fatal, 2 not recovered, 1 recovered; 2 recovering, 6 unknown Brodalumab Monograph not listed/not reported No reports Certolizumab

Monograph not listed/not reported 1; outcome unknown

Dupilumab Monograph not listed/not reported No reports Etanercept 59; 17 fatal 28; of which 4 fatal, 15 not recovered, 1 recovering, 8 unknown Golimumab 6; 0 fatal 1; not recovered Guselkumab Monograph not listed/not reported Monograph not listed Infliximab 75; 22 fatal 41; of which 9 fatal, 11 not recovered, 3 recovering, 18 unknown

Ixekizumab 1; 0 fatal 1; outcome unknown Rituximab 1,339; 664 fatal 824; of which 332 fatal, 190 not recovered, 5 not specified, 12 recovered, 13 recovered with sequalae, 42

recovering, 230 unknown Sarilumab Monograph not listed/not reported No reports Secukinumab

2; 0 fatal 1; outcome unknown

Tocilizumab 13; 0 fatal 4; of which 1 not recovered, 3 unknown Ustekinumab

Monograph not listed/not reported 1; outcome unknown

Vedolizumab

5; 0 fatal 3; of which 1 not recovered, 2 unknown

See FAERS and EudraVigilance website for limitations to their data - Searches conducted 15/5/19

US FAERS data Reports from 1969 to 31/3/19. Total number of PML cases 4,653; total number of fatalities 1, 621

European EudraVigilance data Reports up to May 2019. Database includes reports from healthcare professional and members of the public with outcome data

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