Appendix - jnnp.bmj.com

Appendix

Tables e1a-d. Diagnostic and drug codes for the identification of the multiple sclerosis

population, DMT exposures, and study outcomes

Table e-1a Multiple sclerosis and demyelinating disease related codes and drug

identification numbers of the disease-modifying therapies‡

Key: ‡The DMTs listed represented all those available (approved) for use in MS by Health Canada at some point

during the study

ICD-91 ICD-10 Drug

identification

number

Multiple sclerosis

Multiple sclerosis 340 G35 Demyelinating disease

Optic neuritis 377.3 H46 Acute transverse myelitis 323.82

341.2 G37.3

Acute disseminated encephalomyelitis

323 G36.9

Demyelinating disease of CNS unspecified

341.9 G37.8

Other acute disseminated

demyelination

G36

Neuromyelitis optica 341.0 G36.0

Disease-modifying therapy Betaseron® (IFNB-1b) 02169649 Extavia® (IFNB-1b) 02337819

Avonex (IFNB-1a) 02237770 02269201

Rebif (IFNB-1a) 02281708 02277492 02237317

02237319 02237320 02318253

02318261 Copaxone (glatiramer acetate) 02233014

02245619 Tysabri (natalizumab) 02286386 Gilenya (fingolimod) 02365480

Tecfidera (dimethyl fumarate)

02404508

Aubagio (teriflunomide) 02416328 Lemtrada (alemtuzumab) 02418320

Table e-1b ICD-9-CM and ICD-10-CA codes for identification of infection-related

physician claims and hospital admissions

Infection ICD-9 ICD-10

Intestinal infectious diseases 001.xx – 009.xx A00.xx -A09.xx Tuberculosis 010.xx – 018.xx A15.xx -A19.xx

Zoonotic bacterial diseases 020.xx – 027.xx A20.xx -A28.xx Other bacterial disease (eg. leprosy, diseases due to other mycobacteria, diphtheria, whooping cough,

septicemia)

030.xx – 041.xx A30.xx -A49.xx

Human immunodeficiency virus 042.xx B20.xx

Poliomyelitis and other non-arthropod-borne viral disease of central nervous system

045.xx – 049.xx A80.xx -A81.xx, A85.xx -A89.xx

Viral diseases accompanied by exanthem (eg.

smallpox; cowpox and paravaccinia, chickenpox, herpes zoster, herpes simplex, measles, rubella)

050.xx -059.xx

B00.xx -B09.xx

Arthropod-borne viral diseases 060.xx – 066.xx A83.xx -A85.xx, A90.xx -A99.xx

Other disease due to viruses and chlamydiae 070.xx – 079.xx B15.xx -B19.xx,

A70.xx -A74.xx, A82.xx, B25.xx

-B34.xx, B07.xx Rickettsioses and other arthropod-borne disease 080.xx – 088.xx A75.xx -A79.xx,

B50.xx -B57.xx

Syphilis and other venereal diseases 090.xx – 099.xx A50.xx -A64.xx Other spirochetal diseases 100.xx – 104.xx A65.xx -A69.xx Mycoses 110.xx – 118.xx B35.xx -B49.xx

Helminthiasis 120.xx – 129.xx B65.xx -B83.xx Other infections and parasitic diseases 130.xx – 136.xx B58.xx -B64.xx,

B85.xx -B89.xx Late effects of infectious and parasitic diseases 137.xx – 139.xx B90.xx -B94.xx

Bacterial meningitis 320.xx G00.xx, G01.xx, G04.2x

Meningitis due to other organisms 321.xx B45.1x, G02.xx,

Meningitis of unspecified cause 322.xx G03.0x G03.8x, G03.1x, G03.9x

Intracranial and intraspinal abscess 324.xx G06.xx Late effects of intracranial abscess or pyogenic infection

326.xx G09.xx

Blepharitis 373.0x H01.0x Infective dermatitis of eyelid of types resulting in

deformity

373.4x H01.8x

Other infective dermatitis of eyelid 373.5x H01.8x Parasitic infection of eyelid 373.6x B89.xx

Acute inflammation of orbit 376.0x H05.0x


physician claims and hospital admissions (continued)


Infective otitis externa 380.1x H60.0x, H60.1x, H60.2x, H60.3x,

H62.4x Suppurative and unspecified otitis media 382.xx H66.xx

Acute mastoiditis 383.0x H70.0x Acute nasopharyngitis (common cold) 460.xx J00.xx Acute sinusitis 461.xx J01.xx

Acute pharyngitis 462.xx J02.xx Acute tonsillitis 463.xx J03.xx

Acute laryngitis and tracheitis 464.xx J04.xx, J05.xx Acute upper respiratory tract infection of multiple or unspecified sites

465.xx J06.xx

Acute bronchitis and bronchiolitis 466.xx J20.xx, J21.xx Chronic sinusitis 473.xx J32.xx

Chronic disease of tonsils and adenoids 474.xx J35.xx Chronic laryngitis and laryngotracheitis 476.xx J37.xx Viral pneumonia 480.xx J12.xx

Pneumococcal pneumonia 481.xx J13.xx, J18.1x Other bacterial pneumonia 482.xx J15x, J14x

Pneumonia due to other specified organism 483.xx J16.xx Pneumonia in infectious diseases classified elsewhere 484.xx J17.xx Bronchopneumonia, organism unspecified 485.xx J18.0x

Pneumonia, organism unspecified 486.xx J18.xx Influenza 487.xx J11.xx, J10.xx,

J09.xx Bronchitis, not specified as acute or chronic 490.xx J40.xx Infections of the kidney 590.xx N10.xx, N11. xx,

N12.xx,, N15.1x, N28.84, N28.85,

N28.86, N16.xx Cystitis 595.xx N30.xx Urethritis not sexually transmitted 597.xx N34.xx

Urinary tract infection, site not specified 599.0x N39.0x Inflammatory disease of prostate (prostatitis) 601.xx N41.xx

Carbuncle and furuncle 680.xx L02.xx Cellulitis and abscess of finger and toe 681.xx L03.xx Other cellulitis and abscess 682.xx L03.xx

Acute lymphadenitis 683.xx L04.xx Impetigo 684.xx L01.xx

Other local infections of skin and subcutaneous tissue 686.xx L08.xx, L88.xx, L98.0x,

Septic arthritis 711.0x M00.xx, M01.xx


physician claims and hospital admissions (continued)

Key: ICD-9-CM=International Classification of Diseases, Ninth Revision, Clinical Modification; ICD-10-CA=

International Classification of Diseases, Tenth Revision, Canada. ICD10 was only used to identify infection -related

hospitalizations.


Osteomyelitis periostitis and other infections involving bone

730.xx M86.xx, M46.2x M46.3x, M89.6x

Bacteremia 790.7x R78.81 Viremia 790.8x B34.9x

http://www.icd10data.com/ICD10CM/Codes/R00-R99/R70-R79/R78-/R78.81

Table e-1c ICD-9-CM and ICD-10-CA codes for identification of the five most common

infection groups


International Classification of Diseases, Tenth Revision, Canada. ICD-10 was only used to identify infection-related

hospitalizations. Groups were created based on prior literature (as shown) or by combining related ICD sub-chapters

(e.g. as for infections of the skin and subcutaneous tissue)

Source references 1. Mueller EL, Walkovich KJ, Mody R, Gebremariam A and Davis MM. Hospital discharges for fever and

neutropenia in pediatric cancer patients: United States, 2009. BMC Cancer. 2015; 15: 388.

2. Nelson RE, Xie Y, DuVall SL, et al. Multiple Sclerosis and Risk of Infection-Related Hospitalization and

Death in US Veterans. Int J MS Care. 2015; 17: 221-30.

3. Chang LY, Lai CC, Chen CJ, et al. Recent trends in prescribing antibiotics for acute tonsillitis in pediatric

ambulatory care in Taiwan, 2000-2009: A nationwide population-based study. J Microbiol Immunol Infect.

2015: 1-7.

4. Wang EE, Einarson TR, Kellner JD and Conly JM. Antibiotic prescribing for Canadian preschool children:

evidence of overprescribing for viral respiratory infections. Clin Infect Dis. 1999; 29: 155-60.

Infection type ICD-9 ICD-10

Upper respiratory tract infections1 460.xx-465.xx J00.xx- J06.xx Infections of urinary system2 595.xx; 590.xx; 597.xx;

599.0x

N10.xx, N11.xx, N12.xx,,

N15.1x, N16.xx. N28.84, N28.85, N28.86, N30.xx, N34.xx, N39.0x,

Bronchitis and bronchiolitis3 466.xx; 490.xx J20.xx, J21.xx, J40.xx Infections of the skin and subcutaneous

tissue

680.xx-686.xx L01.xx-L08.xx, L88.xx,

L98.0x Pneumonia4 480.xx – 486.xx J12.xx- J18.xx

Table e-1d The first and second generation disease modifying drugs for MS approved in

Canada by the end of 2013

Health Canada

Approval data

Generation Date of first

prescription filled

in the current study

Betaseron (IFNB-1b) July 1995 first July 1996

Extavia (IFNB-1b) January 2010 first N/A

Avonex (IFNB-1a) April 1998 first October 1998

Rebif (IFNB-1a) February 1998 first June 1998

Copaxone (glatiramer acetate)

October 1997 first February 1998

Tysabri (natalizumab) October 2006 second March 2007

Gilenya (fingolimod) March 2011 second July 2011

Tecfidera (dimethyl fumarate)

April 2013 second June 2013

Aubagio (teriflunomide)

November 2013 second N/A

Lemtrada

(alemtuzumab)

December 2013 second N/A

Key: N/A = not applicable; no individual filled a prescription for this DMT during the study

All approval dates were obtained from Health Canada (available at: www.hc-sc.gc.ca)

Table e-1e ICD-9-CM and ICD-10-CA codes for identification of comorbidities in the

multiple sclerosis population


International Classification of Diseases, Tenth Revision, Canada. Comorbidities were identified using health

administrative data (≥1 hospital admission or ≥2 physician claims for the relevant diagnostic code) based on data in

the 5 years prior to the index date (for pre-index date comorbidities) as well as over the entire study period. Once a

comorbidity was identified, an individual was considered affected from the date of the first relevant claim and

thereafter. ICD-10 was only used to identify hospitalizations.

Comorbidity ICD-9 ICD-10

Diabetes 250.xx E10.xx -E14.xx Malignancies 140.xx-209.xx

235.xx-239.xx

C00.xx-C96.xx

D37.xx-D49.xx Rheumatoid arthritis 714.xx M05.xx -M06.xx

Psoriasis 696.0x, 696.1x L40.xx, M07.0x-

M07.3x Inflammatory bowel disease 555.xx, 556.xx K50.xx, K51.xx Chronic lung disease

493.xx, 491.xx,

492.xx, 496.xx

J45.xx, J46.xx,

J40.xx, J42.xx, J43.xx, J44.xx

Table e-2 Characteristics of the multiple sclerosis study population at the index date by subsequent disease -modifying treatment

exposure

Characteristics Unexposed ≥1 DMT Any beta-

interferon

Glatiramer

acetate

Natalizumab

Any oral

DMT†

1st and 2nd

generation

combined

1st generation 1st generation 2nd generation 2nd generation

N=5077 N=1716 N=1386 N=656 N=100 N=98

Age (yrs), mean (SD) 47.8 (13.5) 38.2 (9.4) 38.0 (9.4) 37.7 (9.2) 34.5 (9.6) 35.3 (9.1)

Women, N (%) 3712 (73.1) 1287 (75.0) 1039 (75.0) 500 (76.2) 71 (71.0) 76 (77.6)

Index year, N (%)

1996-2001 1777 (35.0) 642 (37.4) 569 (41.1) 189 (28.8) 23 (23.0) 12 (12.2)

2002-2007 1859 (36.6) 659 (38.4) 541 (39.0) 278 (42.4) 60 (60.0) 38 (38.8)

2008-2013 1441 (28.4) 415 (24.2) 276 (19.9) 189 (28.8) 17 (17.0) 48 (49.0)

SES, N (%)

1 (lowest income quintile) 891 (17.5) 308 (17.9) 253 (18.3) 126 (19.2) 19 (19.0) 13 (13.3)

2 984 (19.4) 319 (18.6) 257 (18.5) 118 (18.0) 18 (18.0) 18 (18.4)

3 1052 (20.7) 359 (20.9) 296 (21.4) 142 (21.6) 19 (19.0) 19 (19.4)

4 1097 (21.6) 371 (21.6) 288 (20.8) 144 (22.0) 27 (27.0) 22 (22.4)

5 (highest income quintile) 1028 (20.2) 357 (20.8) 290 (20.9) 126 (19.2) 17 (17.0) 26 (26.5)

Unknown 25 (0.5) <6 <6 <6 <6 <6

Table e-2 Characteristics of the multiple sclerosis study population at the index date by subsequent disease -modifying treatment

exposure (continued)

†The oral DMTs included fingolimod and dimethyl fumarate. No person filled a prescription for teriflunomide, alemtuzumab, or the generic beta-interferon-1b (extavia ®)

during the study period. As some persons filled a prescription for more than one DMT during the study period, the sum of the subgroups exceeds the total number of people

ever exposed (n=1716). ‡Comorbidities identified during the 5 years prior to index date (diabetes, malignancies, chronic lung disease, inflammatory bowel disease,

rheumatoid arthritis and psoriasis); all were included to generate the ‘number of comorbidities.’ Due to privacy regulations, and as required by the data custodians (stewards),

cells with less than 6 cases were not be reported.

Characteristics Unexposed ≥1 DMT Any beta-

interferon Glatiramer

acetate

Natalizumab

Any oral

DMT†

1st and 2nd

generation

combined

1st generation 1st generation 2nd generation 2nd generation

N=5077 N=1716 N=1386 N=656 N=100 N=98

Diabetes 310 (6.1) 54 (3.1) 46 (3.3) 26 (4.0) <6 <6

Malignancies 408 (8.0) 67 (3.9) 54 (3.9) 26 (4.0) <6 <6

Chronic lung diseases 497 (9.8) 131 (7.6) 106 (7.6) 59 (9.0) 7 (7) <6

Inflammatory bowel disease 56 (1.1) 16 (0.9) 10 (0.7) 7 (1.1) <6 <6

Rheumatoid arthritis 140 (2.8) 20 (1.2) 16 (1.2) 8 (1.2) <6 <6

Psoriasis 15 (0.3) 7 (0.4) 7 (0.5) <6 <6 <6

Number of comorbidities‡, N

(%)

None 3857 (76.0) 1449 (84.4) 1170 (84.4) 542 (82.6) 84 (84.0) 89 (90.8)

1 1035 (20.4) 242 (14.1) 195 (14.1) 99 (15.1) 16 (16.0) 9 (9.2)

2 or more 185 (3.6) 25 (1.5) 21 (1.5) 15 (2.3) 0 0

Table e-3 Adjusted hazard ratios of physician claims for specific infections by multiple sclerosis disease modifying treatment

Infection Model DMT exposure status Infection-related

physician claims

Person-years Crude rate

per 1000 PY (95%CI)

aHR (95%CI)

Upper respiratory

tract infection

Unexposed 9926 51,703.5 192.0 (188.2-195.8) reference

1 Any DMT 1416 6832.6 207.2 (196.6-218.3) 0.96 (0.88-1.05)

2 Any 1st generation DMT 1334 6577.0 202.8 (192.1-214.0) 0.94 (0.85-1.03)

2 Any 2nd generation DMT 82 255.6 320.8 (255.2-398.2) 1.58 (1.18-2.10)

3 Beta-interferon 1011 5019.2 201.4 (189.2-214.2) 0.92 (0.83-1.02)

3 Glatiramer acetate 323 1557.7 207.4 (185.4-231.3) 1.00 (0.85-1.17)

3 Natalizumab 64 177.6 360.4 (277.5-460.2) 1.77 (1.26-2.49)

Any 1st generation DMT 1334 6577.0 202.8 (192.1-214.0) reference


Infections of the

urinary system

Unexposed 6494 51640.9 125.8 (122.7-128.9) reference

1 Any DMT 849 7222.6 117.5 (109.8-125.7) 1.09 (0.96-1.23)



3 Beta-interferon 604 5259.4 114.8 (105.9-124.4) 1.06 (0.92-1.23)


3 Natalizumab 25 192.9 129.6 (83.9-191.3) 1.21 (0.79-1.86)



Table e-3 Adjusted hazard ratios of physician claims for specific infections by multiple sclerosis disease modifying treatment (continued)


physician claims


per 1000 PY (95%CI)

aHR (95%CI)

Infections of the

skin and

subcutaneous

tissue


1 Any DMT 510 7418.5 68.7 (62.9-75.0) 1.03 (0.91-1.17)



3 Beta-interferon 390 5383.5 72.4 (65.4-80.0) 1.09 (0.94-1.26)


3 Natalizumab 13 214.0 60.7 (32.3-103.9) 0.92 (0.49-1.72)



Bronchitis and

bronchiolitis


1 Any DMT 494 7344.6 67.3 (61.5-73.5) 0.93 (0.81-1.06)



3 Beta-interferon 360 5351.9 67.3 (60.5-74.6) 0.92 (0.78-1.07)


3 Natalizumab 19 198.0 96.0 (57.8-150.0) 1.45 (0.89-2.36)



Table e-3 Adjusted hazard ratios of physician claims for specific infections by multiple sclerosis disease modifying treatment (continued)

Key: aHR=adjusted Hazard Ratio; CI= Confidence Interval; DMT= disease modifying treatment; PY=person -years. Models were adjusted for sex, age (continuous), index

year (continuous), SES (quintiles), number of comorbidities (none, 1, ≥2). Due to privacy regulations, and as required by the data custodians (stewards), cells with less than 6 cases were not be reported, nor were the corresponding crude rates. Oral DMTs were assessed only as part of the second generation drugs, i.e not as a separate class, due to the limited number of eve nts.


physician claims


per 1000 PY (95%CI)

aHR (95%CI)

Pneumonia

Unexposed 1362 51677.2 26.4 (25.0-27.8) Reference

1 Any DMT 92 7670.4 12.0 (9.7-14.7) 0.75 (0.59-0.95)



3 Beta-interferon 66 5570.6 11.8 (9.2-15.1) 0.74 (0.56-0.98)


3 Natalizumab <6 214.7 - 1.29 (0.47-3.54)

Any 1st generation DMT 85 7372.8 11.5 (9.2-14.3) Reference

2 Any 2nd generation DMT 7 297.6 23.5 (9.5-48.5) 2.33(1.06-5.12)

Table e-4 Adjusted hazard ratios of infection-related physician claims by multiple sclerosis disease modifying treatment stratified by sex

and age at the index date

Stratified

by sex and

age

Model DMT exposure status Infection-related

physician claims


per 1000 PY

(95%CI)

aHR (95%CI)

Men Unexposed 6,724 12,554.0 535.6 (522.9-548.6) reference

1 Any DMT 681 1517.5 448.8 (415.7-483.8) 0.91 (0.77-1.08)

Women Unexposed 27,225 37,757.9 721.0 (712.5-729.7) reference

1 Any DMT 3,142 4548.2 690.8 (666.9-715.4) 1.00 (0.94-1.08)

Age ≤44 Unexposed 17,479 2,6291.4 664.8 (655.0-674.8) reference

1 Any DMT 2946 4611.3 638.9 (616.0-662.4) 0.99 (0.92-1.07)

Age 45+ Unexposed 16,470 2,4020.5 685.7 (675.2-696.2) reference

1 Any DMT 877 1454.4 603.0 (563.7-644.3) 0.92 (0.81-1.06)










and age at the index date (continued)

Stratified by

sex and age


physician claims


per 1000 PY

(95%CI)

aHR (95%CI)



Women Unexposed 27,225 37,757.9 721.0 (712.5-729.7) Reference


Age ≤44 Unexposed 17,479 2,6291.4 664.8 (655.0-674.8) Reference


Age 45+ Unexposed 16,470 2,4020.5 685.7 (675.2-696.2) Reference



3 Beta-interferon 420 1037.3 404.9 (367.1-445.5) 0.81 (0.68-0.98)


3 Beta-interferon 2302 3441.4 668.9 (641.9-696.8) 0.97 (0.89-1.05)


3 Beta-interferon 2080 3347.9 621.3 (594.9-648.6) 0.95 (0.88-1.04)


3 Beta-interferon 642 1130.8 567.7 (524.7-613.4) 0.88 (0.75-1.02)

Table e-4 Adjusted hazard ratios of infection-related physician claims by multiple sclerosis disease modifying treatment stratified by

sex and age at the index date (continued)

Stratified by

sex and age


physician claims


per 1000 PY

(95%CI)

aHR (95%CI)









Men Unexposed 6,724 12,554.0 535.6 (522.9-548.6) Reference

3 Natalizumab 54 51.1 1056.8 (793.9-1378.8) 2.17 (1.15-4.10)


3 Natalizumab 99 106.8 927.0 (753.4-1128.6) 1.41 (1.08-1.85)


3 Natalizumab 128 135.6 944.0 (787.5-1122.4) 1.63 (1.18-2.26)


3 Natalizumab 25 22.3 1121.1 (725.5-1654.9) 1.48 (0.90-2.41)


and age at the index date (continued)

Key: aHR=adjusted Hazard Ratio; CI= Confidence Interval; DMT= disease modifying treatment; PY= person -years. Models were adjusted for sex (except for the sex-specific

models), age (continuous, except for the age-specific models), index year (continuous), SES (quintiles), and number of comorbidities (none, 1, ≥2). Due to privacy

regulations, and as required by the data custodians (stewards), cells with less than 6 cases were not be reported , nor were the corresponding crude rates. Oral DMTs were

assessed only as part of the second generation drugs, i.e not as a separate class, due to the limited number of events.

Stratified by

sex and age


physician claims


per 1000 PY

(95%CI)

aHR (95%CI)

Men Any 1st generation DMT 617 1452.6 424.8 (391.9-459.6) reference


Women Any 1st generation DMT 3007 4389.0 685.1 (660.9-710.1) reference


Age ≤44 Any 1st generation DMT 2777 4421.5 628.1 (604.9-651.9) reference


Age 45+ Any 1st generation DMT 847 1420.2 596.4 (556.9-638.0) reference


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