Supplementary Table 1. Longitudinal studies reporting absenteism in relation to treatment with TNF inhibitors in patients with Crohn’s disease

AuthorYear Study

Study, population Exposure Time point of assessment Assessment of outcome

Results

Lichtenstein 2004ACCENT I

N=573 Long-term dosing or single dose IFX

0-54 weeks Questionnaire Unemployment rate at baseline 38%. In patients who were unemployed at baseline, 31% were employed at 54 weeks if remission was achieved (35-40%), compared to 16% of those not in remission.

Lichtiger 2010,CHOICE

N=673 patients who failed IFX treatment17% IFX primary non-responders 83% IFX primary responders

Adalilumab every 2 weeks

4, 8, 12, 24 weeks WPAI:CD Mean change from baseline in absenteeism was -8.3, -6.5, -7.5, -7.2

Feagan, 2010PRECISE

Responders at week 4 n=425 (64%)Active treatment n=215Placebo n=210

Certolizumab every 4 weeks

06, 16, 26 weeks Work Productivity and ActivityImpairment for CD questionnaireWork Productivity and ActivityImpairment for CD questionnaireWPAI:CD

Score of absenteism was 10% lower from induction to 26 weeks in treated patients compared to placebo

Feagan, 2011WELCOME

N=334 (62%)responders at week 6

Certolixumab every 2 or 4 weeks

0-26 weeks WPAI:CD Absenteism dropped from 25% to 6% and from 23% to 11%

Panaccione2011ACCESS

N=304IFX experienced n=160Anti-TNF naive n=144

Adalilumab every 2 weeks

0-6 months WPAI:CD Mean change in absenteeism:12 weeks: −8.8 points for the anti-TNF-naive group4 weeks −7.2 points, 8 weeks −9.2 points, 24 weeks −7.6 points for the

1

infliximab-experienced group.At the final visit, 69% of patients were employed compared with 64% at baseline

Binion,2011ACCESS, CARE, CHOICE, EXTEND

Meta-analysis N=1,202

Adalilumab every 2 weeks 

0-20 weeks (CARE), 0-24 weeks (ACCESS and CHOICE) 0- 52 weeks (EXTEND)

WPAI:CD Pooled estimates (95% CIs) for absenteeism: -9% (-10% to -7%)

Steenholdt,2015

N=69 with IFX treatment failure

Intensified IFX regimen (n = 36) Personalized treatment defined by IFX and anti-IFX antibodies (n = 33)

0-6 months WPAI:CD Absenteeism in employed individuals (n=38) was negligible during the entire study period.

Louis2013CARE

N=945N=785 (83%) completed 20 weeks

Adalimumab every 2 weeks

0, 2, 4, 8, 12, 20 weeks WPAI:CD Mean change from baseline in absenteeism was -9.6 at 4 weeks (N=353) and -9.8 at 20 weeks (N=328)

Saro 2017EFICA- DEC

N=126 bio-naïve patients

Adalimumab according to clinical practice

1, 3, 6, 9, and 12 months WPAI:CD CD-caused absenteeism > 50% decreased from 1/3 to 1/10 from baseline to 12 months

Current study 2019

N=853 bio-naïve patients and N=326 patients starting 2nd line treatment

Any TNF inhibitor -6 months to 18 months Lost workdays according to the Social Insurance Agency

7%-8% reduction in absenteeism from start of treatment to week 24 in bio-naïve patients and 1%-6% reduction in absenteeism for second line treatment

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Supplementary Table 2. ICD-codes that, if occurring before Jan 1st 2007, excluded the

patient from participation in the study

ICD-7 ICD-8 ICD-9 ICD-101964-1968 1969-1986 1987-1996 1997-

Ulcerative colitis (UC) 572,20 ; 572,21; 578,03

563,10 ; 563,99 ; 569,02

556 K51

Crohn’s disease (CD) 572,00 ; 572,09 563,00 555 K50

IBD unclassified (IBD-U) UC+CD UC+CD UC+CD UC + CD, or K52.3

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Supplementary Table 3. ICD codes for medication used in patients with Crohn’s

disease

Drug group Substance ATC-code Conversion factor to Prednisolon equivalents*

Immunomodulators Azathioprine L04AX01Mercaptopurine L01BB02Methotrexate L04AX03/L01BA01

Biologics Infliximab L04AB02 (L04AA12 before 2008)

Adalimumab L04AB04 (L04AA17 before 2008)

Golimumab L04AB06Vedolizumab L04AA33Certolizumab L04AB05Ustekinumab L04AC05

Oral corticosteroids Betamethasone H02AB01 8.33Dexamethasone H02AB02 6.67Methylprednisolone H02AB04 1.25Prednisolone H02AB06 1Prednisone H02AB07 1

Aminosalicylates (5-ASA) Sulfasalazine A07EC01Mesalazine A07EC02Olsalazine A07EC03Balsalazide A07EC04

* Conversion calculated according to Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol 2013;9:30.

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Supplementary table 4. Surgical procedure codes

Surgical procedure 7th rev(KKÅ97)

Intestinal surgery

Ileocecal resectionJFB20, JFB21, JFB30, JFB31, JFB33, JFB34

Small bowel resection JFB00, FFB01

ColectomyJFH00, JFH01, JFH10, JFH11, JFH20, JFH96,

JFH30

Segmental colon resection

JFB40, JFB41, JFB43, JFB44, JFB46, JFB47, JFB50, JFB51, JFB60, JFB61, JFB63, JFB64, JGB00, JGB01, JGB10,

JGB11

ProctectomyJFH20, JGB30, JGB31, JGB40, JGB96, JGB97

Other bowel surgery

Strictureplasty JFA60, JFA63

Enterorraphy JFA70, JFA71, JFA80,

JFA81Closure of fistula JFA76, JFA86

Other intestinal resection JFB96, JFB97

Intestinal anastomosis and by-pass

JFC00, JFC01, JFC10, JFC11, JFC20, JFC21, JFC30, JFC31, JFC50,

JFC51

Formation of stoma

JFF10, JFF11, JFF13, JFF16, JFF23, JFF24, JFF26, JFF27, JFF30, JFF31, JFF96, JFF97

Operations on intestinal stoma or reservoir

JFG40, JFG50, JFG53, JFG56, JFG60, JFG73, JFG76, JFG80, JFG83,

JFG86, JFG96Other intestinal surgery JFW96, JFW97

Ileoanal anastomosisJGB50, JGB60, JFH30,

JFH33, JFH40Ileorectal anastomosis JFC40, JFC41

Perianal surgery

Perianal incision and drainage JHA00

Dilatation of the anal sphincter JHD00

Lay open or excision of perianal fistula JHD20

Partial lay open or excision of perianal fistula (including seton placement) JHD30

Completion lay open or excision of perianal fistula JHD33

Excision of perianal fistula with advancement flap JHD50

Occlusion of perianal fistula with collagen plug JHD60

Occlusion of perianal fistula with fibrin glue JHD63

Other anal or perianal surgery (e.g. examination under anesthesia) JHW96

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Supplementary table 5. ICD codes for extraintestinal manifestations

ICD-10

Primary Sclerosing Cholangitis K83.0

Cutaneous manifestations

Erythema nodosum L52

Pyoderma gangraenosum L88

Sweet syndrome L98.2

Ocular manifestation

Iridocyclitis H20

Joint manifestations

Arthropaty in Crohn’s disease M07.4

Arthropaty in Ulcerative colitis M07.5

Other defined arthropathy in gastrointestinal disorders M07.6

Juvenile arthritis in Crohn’s disease M09.1

Juvenile arthritis in Ulcerative colitis M09.2

Bechterew’s disease M45

Spondylarthritis, inflammatory NOD M460, M461, M468, M469

Arthritis NOD M139, M255

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Supplementary table 6. ICD codes for Montreal classification. Patients’ phenotypes were defined by the highest available degree of anatomic distribution of inflammation. Patients who were never diagnosed with a code representing a specific location were classified as LX.

Montreal classification Diagnostic codesLocation

L1 Small bowel disease or terminal ileitis K50.0L2 Colon K50.1L3/LX Ileocecal Crohn’s disease or location not

definedK50.8, K50.9

BehaviorB1 Non-stricturing, non-penetrating None of the ICD-codes for B2 or B3.B2 Stricturing Crohn’s disease AND any of the

following codes (K56.5; K56.6; K56.7; K62.4)

B3 Penetrating Crohn’s disease AND any of the following diagnostic codes (K63.0,

K63.2, K31.6, N82.2, N82.3, N82.4) OR any of the following surgical procedure

codes (JFA76, JFA86).P Perianal disease Crohn’s disease AND any of the

following diagnostic codes: (K60.3, K60.4, K60.5, K61.0, K61.1, K61.2, K61.3,

K61.4, K62.4) OR any of the following surgical procedure codes: (JHD20,

JHD30, JHD33, JHD50, JHD60, JHD63, JHA00, JHD00, JHW96)

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Supplementary Table 7. Characteristics of working-age patients with Crohn’s disease diagnosed July 1st 2006- Sep 30th 2013 and matched population comparators subjects

Patients with Crohn’s disease

Population comparator subjects

P-value1

N 3,956 19,716Sex, n (%) 0.97Men, n (%) 1,926 (49) 9,590 (49)Women, n (%) 2,030 (51) 10,126 (51)Age at diagnosis/matchMedian (25th-75th; min-max) years 34 (25-46;19-59) 34 (25-46;19-59) 0.87Categories, n (%) 1.0019-29 years 1,572 (40) 7,853 (40)30-39 years 810 (20) 4,047 (21)40-49 years 839 (21) 4,178 (21)50-59 years 735 (19) 3,638 (18)Education, n (%) 0.699 years 596 (15) 2,974 (15)10-12 years 2,107 (53) 10,531 (53)≥12 years 1,187 (30) 5,932 (30)unknown 66 (1.7) 279 (1.4)Follow-up time Median (25th-75th; min-max) years

5.3 (3.6-7.1;0-9.2) 5.4 (3.6-7.1;0-9.2) 0.11

Death during follow-up n (%) 66 (1.7) 106 (0.54) <0.0001Medication for Crohn’s disease, n(%)Aminosalicylates 1547 (39)Immunomodulators 2,043 (52)Systemic corticosteroids 2,560 (65)TNF inhibitors 853 (22)Surgery for Crohn’s disease, n (%)Any intestinal surgery 719 (18)Ileocecal or small bowel resection 621 (16)Partial or total colectomy 140 (3.5)Other intestinal surgery 704 (18)Perianal surgery 276 (7.0)

1 Wilcoxon signed rank test or Chi square test

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Supplementary Table 8. Mean number of lost workdays from 6 months before to 18 months after start of treatment with aminosalicylate, immunomodulator, TNF inhibitor, and intestinal surgery in all patients starting treatment (first column), and in patients not requiring additional or other treatment (second column)

Aminosalicylate Immunomodulator 1st line TNF inhibitor 2nd line TNF inhibitor Intestinal surgery

Starting treatmentMean days (95% CI)

Continuing treatmentMean days (95% CI)

Starting treatmentMean days (95% CI)

Continuing treatmentMean days (95% CI)

Starting treatmentMean days (95% CI)

Continuing treatmentMean days (95% CI)

Starting treatmentMean days (95% CI)

Continuing treatmentMean days (95% CI)

Starting treatmentMean days (95% CI)

Continuing treatmentMean days (95% CI)

-6 3.66 (3.15-4.17)

3.66 (3.19-4.12)

3.83 (3.45-4.22)

3.83 (3.42-4.25)

4.42 (3.82-5.03)

4.42 (3.72-5.11)

5.56 (4.49-6.63)

5.56 (4.51-6.61)

5.54 (4.83-6.25) 5.54 (4.75-6.33)

-3 4.36 (3.87-4.86)

4.36 (3.93-4.80)

4.63 (4.19-5.07)

4.63 (4.20-5.07)

5.63 (4.95-6.32)

5.63 (4.90-6.37)

6.06 (4.92-7.20)

6.06 (4.93-7.19)

6.78 (6.02-7.55) 6.78 (6.02-7.55)

0 6.21 (7.72-6.70)

6.21 (5.67-6.75)

6.46 (5.93-6.99)

6.18 (5.66-6.71)

7.24 (6.51-7.97)

7.20 (6.34-8.07)

6.15 (4.99-7.30)

5.85 (4.68-7.01)

16.9 (16.1-17.7) 16.5 (15.6-17.3)

3 4.60 (4.12-5.08)

4.11 (3.62-4.60)

4.89 (4.41-5.37)

4.45 (3.99-4.90)

5.48 (4.70-6.26)

5.06 (4.37-5.75)

5.76 (4.55-6.98)

4.57 (3.27-5.87)

7.19 (6.28-8.09) 6.84 (5.83-7.86)

6 4.44 (3.95-4.93)

4.00 (3.44-4.56)

4.37 (3.93-4.80)

4.00 (3.53-4.47)

5.17 (4.47-5.87)

4.83 (4.07-5.59)

5.69 (4.32-7.06)

3.98 (2.38-5.59)

6.36 (5.51-7.21) 5.92 (4.99-6.85)

9 4.27 (3.72-4.81)

3.79 (3.23-4.35)

4.16 (3.72-4.61)

3.83 (3.42-4.23)

4.93 (4.13-5.73)

4.26 (3.54-4.99)

5.65 (4.32-6.98)

3.24 (1.85-4.64)

6.21 (5.36-7.05) 5.63 (4.73-6.52)

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4.25 (3.78-4.72)

3.80 (3.23-4.37)

4.12 (3.67-4.56)

3.53 (3.05-4.02)

4.87 (4.05-5.69)

4.19 (3.51-4.88)

6.14 (4.56-7.72)

3.50 (1.84-5.16)

5.81 (4.87-6.75) 5.23 (4.18-6.28)

15

4.04 (3.51-4.58)

3.63 (3.04-4.23)

3.97 (3.55-4.40)

3.46 (3.00-3.92)

4.48 (3.85-5.11)

3.74 (2.97-4.51)

5.46 (3.92-7.01)

3.52 (1.82-5.23)

5.28 (4.41-6.16) 4.75 (3.88-5.62)

18

3.94 (3.43-4.44)

3.67 (3.09-4.24)

3.84 (3.42-4.25)

3.36 (2.89-3.84)

4.52 (3.84-5.19)

3.80 (3.04-4.56)

5.31 (4.09-6.53)

3.02 (1.60-4.44)

4.71 (3.86-5.56) 4.28 (3.44-5.12)

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Supplementary Figure 1. Flow-chart of participants and registers used

10

Supplementary Figure 2. Mean number of lost workdays per month from 6 months

before to 18 months after start of TNF inhibitor in patients and matched population

comparators in subgroups stratified for sex (men/women), age (19-39, 40-49, 50-59

years), and education (9, 10-12, >12 years)

11

Supplementary Figure 3. Mean number of lost workdays per month from 6 months

before to 18 months after start of aminosalicylate in patients and matched population

comparators in subgroups stratified for sex (men/women), age (19-39, 40-49, 50-59

years), and education (9, 10-12, >12 years)

12

Supplementary Figure 4. Mean number of lost workdays per month from 6 months

before to 18 months after start of immunomodulator in patients and matched

population comparators in subgroups stratified for sex (men/women), age (19-39, 40-

49, 50-59 years), and education (9, 10-12, >12 years)

13

Supplementary Figure 5. Mean number of lost workdays per month from 6 months

before to 18 months after intestinal surgery in patients and matched population

comparators in subgroups stratified for sex (men/women), age (19-39, 40-49, 50-59

years), and education (9, 10-12, >12 years)

14