Appendix (Table S1-S16) Table S1: ICD-9-CM codes for patient enrollment from HIS (main or secondary diagnoses) ICD-9-CM CODES DISEASE 555 Crohn s disease 556 (EXCLUDING: 556.0, 566.1, 556.4,556.8) Ulcerative colitis Table S2: Codes for patient enrollment from copayment exemption register CODES DISEASE 900.555 Crohn s disease 900.556 Ulcerative colitis Table S3: ICD-9-CM codes for exclusion criteria from diagnosis reported in discharge abstract (main or secondary) ICD-9-CM CODES DISEASE 714 Rheumatoid arthritis 696.0 Psoriatic arthritis 720.0 Ankylosing spondylitis Table S4: ATC codes for exclusion criteria from drug utilization in the year before index date: ATC Active agent Therapeutic area L01XC02 Rituximab Rheumatoid arthritis, Leukemia, Lymphocytic Chronic B- Cell,Non-Hodgkin lymphoma L04AA13 Leflunomide Psoriatic arthritis, Rheumatoid arthritis L04AA24 Abatacept Juvenile rheumatoid arthritis, Rheumatoid arthritis, L04AB01 Etanercept Juvenile rheumatoid arthritis, Psoriatic arthritis, Rheumatoid arthritis, Psoriasis, Ankylosing spondylitis, L04AB05 Certolizumab pegol Rheumatoid arthritis, L04AC03 Anakinra Rheumatoid arthritis, L04AC07 Tocilizumab Juvenile rheumatoid arthritis, Rheumatoid arthritis
Table S5: ICD-9-CM codes for comorbid conditions, registered in the 12 months preceding the index date ICD-9-cm codes Co-morbidity 410-414 Ischemic disease 428 Congestive Heart failure 430-438 Cerebrovascular Diseases 290-294 Dementia 440-448 Peripheral vascular disease 250.0-259.0 Diabetes 300-316, 311, 301.12, 300.4, 309.0, 309.1 Anxiety 334.1,336.2,348.1,3483,784.3,333.4,333.5, 342-344, Neurological disease 331,332,334,335, 341, 345, 356-359 290.0-290.4, 295-298, 311, 301.12, 293.8, 299.1, 331.0, Psychiatric 294.1, 300.4, 309.0, 309.1 582-588, V42.0, V45.1, procedures Renal disease (38.95,39.95,54.98,55.6) 571-572 Liver Disease 401-405 Hypertension
Table S6: ICD-9-CM codes used to characterize disease course, registered in the 12 months preceding the index date Condition ICD9cm code Description Anemia / malabsorption 280.0 Secondary to blood loss (chronic) 280.9 Iron deficiency anemia, unspecified 579.9 Unspecified intestinal malabsorption Intestinal stenosis / obstruction 569.2 Stenosis of rectum and anus 560.89 Acute pseudo-obstruction of intestine Mural thickening causing obstruction 560.9 Unspecified intestinal obstruction 569.2 Stenosis of rectum and anus 537.3 Other obstruction of duodenum 751.2 Atresia and stenosis of large intestine, rectum, and anal canal Intestinal fistula / abscess/ ulcer 537.4 Fistula of stomach or duodenum 569.81 Fistula of intestine, excluding rectum and anus 576.4 Fistula of bile duct 575.5 Fistula of gallbladder 593.82 Intestinoureteral fistula 599.1 Urethral fistula 565.1 Anal fistula 619 Fistula involving female genital tract 596.1 Intestinovesical fistula 566 Abscess of anal and rectal regions 569.5 Abscess of intestine 569.82 Ulceration of intestine 569.41 Ulcer of anus and rectum 569.83 Perforation of intestine Haemorrhage 578 Gastrointestinal hemorrhage 578.9 Hemorrhage of gastrointestinal tract, unspecified 569.3 Hemorrhage of rectum and anus 578.1 Blood in stool
Table S7: ATC codes for drug prescription patterns, registered in the year preceding the index date Drug Class Generic Name ATC code Antimetabolites Mercaptopurine L01BB02 Methotrexate L01BA01 Immunosuppressants Azathioprine L04AX01 Intestinal Antiinfectives Rifaximin A07AA11 Steroids Corticosteroids acting locally A07EA Corticosteroids for systemic use H02 Aminosalicylic acid and similar agents Mesalamine A07EC02 Sulfasalazine Balsalazide A07EC01 A07EC04 Antibacterials Metronidazole J01XD01 Ciprofloxacin J01MA02
Table S8: ICD-9-CM procedure codes for IBD-related bowel surgery used as effectiveness outcomes ICD-9-CM codes Procedure 458 Tot Intra-Abd Colectomy 485 Abd-Perineal Rect Resect 4561 Mult Seg Sm Bowel Excis 4562 Part Sm Bowel Resect Nec 4563 Total Removal Sm Bowel 4571 Mult Seg Lg Bowel Excis 4572 Cecectomy 4573 Right Hemicolectomy 4574 Transverse Colon Resect 4575 Left Hemicolectomy 4576 Sigmoidectomy 4579 Part Lg Bowel ExcisNec 4590 Intestinal Anastom Nos 4591 Sm-To-Sm Bowel Anastom 4592 Sm Bowel-Rect Stump Anas 4593 Small-To-Large Bowel Nec 4594 Lg-To-Lg Bowel Anastom 4595 Anal Anastomosis 4610 Colostomy Nos 4611 Temporary Colostomy 4613 Permanent Colostomy 4614 Delay Opening Colostomy 4620 Ileostomy Nos 4621 Temporary Ileostomy 4622 Continent Ileostomy 4623 Permanent Ileostomy Nec 4624 Delay Opening Ileostomy 4841 Soave SubmucRect Resect 4849 Pull-Thru RectResecNec 4861 TranssacRectosigmoidect 4862 Ant Rect Resect W Colost 4863 Anterior Rect Resect Nec 4864 Posterior Rect Resection 4865 Duhamel Rectal Resection 4869 Rectal Resection Nec
Table S9: List of serious and opportunistic infections used as safety outcome, registered in discharge abstract (principal or secondary diagnosis) after index date and throughout followup. ICD-9-CM codes Description 010-018 Tuberculosis 31 Diseases due to other mycobacteria 36 Meningococcal infection 38 Septicemia 42 Human immunodeficiency virus [HIV] disease 046.2 Subacute sclerosing panencephalitis 046.3 Progressive multifocal leukoencephalopathy 53 Herpes zoster 54 Herpes simplex 75 Infectious mononucleosis 078.5 Cytomegaloviral disease convert 078.5 to ICD-10-CM 079.5 Retrovirus in conditions classified elsewhere and of unspecified site 079.6 Respiratory syncytial virus (RSV) convert 079.6 to ICD-10-CM 079.8 Other specified viral and chlamydial infections 110-118 Mycoses 130 Toxoplasmosis 131 Trichomoniasis
Table S10: Patients discharged from hospital after index date and throughout follow-up with diagnosis (principal or secondary) of any of the following conditions. Disease CD CU Condition Infusion reaction (ICD-9-CM codes: 995.0, 995.2, 995.3) Dermomiosytis (ICD-9-CM codes: 710.3) Brain neoplasm (ICD-9-CM codes: 191.9) Acquired hemolytic anemias (ICD-9-CM codes: 283.0, 283.1, 283.10, 283.11, 283.19, 283.2, 283.9) IFX (N=367) ADA (N=505) IFX (N=469) ADA (N=91) Sum % Sum % Sum % Sum % 3 0.8 4 0.8 9 1.9.................... 1 0.2 1 0.2..
Figure 1: Unadjusted time to event analysis, Kaplan-Meier survivor curves for drug discontinuation or switch*, among CD or UC patients. As treated study design. Drug discontinuation or switch Crohn's disease Proportion of patients free of events 0.25 0.50 0.75 1.00 Log-rank test Pr>chi2 < 0.001 ADA IFX 0.5 1 1.5 2 Time (years) Number at risk (events) 505 (35) 470 (70) 400 (44) 319 (41) 250 367 (33) 334 (30) 304 (21) 259 (14) 216 exp = ADA exp = IFX Drug discontinuation or switch Ulcerative colitis Proportion of patients free of events 0.25 0.50 0.75 1.00 Log-rank test Pr>chi2 < 0.001 ADA IFX 0.5 1 1.5 2 Time (years) Number at risk (events) 90 (12) 78 (18) 60 (10) 43 (11) 29 467 (28) 439 (24) 415 (23) 362 (12) 310 exp = ADA exp = IFX * Whichever comes first. IFX: Infliximab, ADA: Adalimumab.
Table S11: Patient characteristics included in the predictive model (Intention to treat study design): Results of stepwise Cox regression models. Hazard ratios for abdominal surgery and serious and opportunistic infections among Crohn s disease patients Characteristic HR (Abdominal surgery) LCL UCL P-Value Gender Male 1 - - - Female 1.39 0.94 2.06 1.64 Age class (years) 0-19 1 - - - 20-34 0.63 0.33 1.21 0.169 35-49 0.72 0.38 1.36 0.313 50-64 0.42 0.20 0.88 0.021 >64 0.30 0.10 0.95 0.041 Intestinal obstruction/stenosis No 1 - - - Yes 1.83 0.92 3.64 0.083 Previous surgery No 1 - - - Yes 0.55 0.280 1.09 0.088 Number of comorbidities None 1 - - - 1 or more 2.37 1.35 4.13 0.002 Characteristic HR (Infections) LCL UCL P-Value Intestinal fistola/ulcera/abscess No 1 - - - Yes 2.77 1.05 7.32 0.040 Number of comorbidities None 1 - - - 1 or more 4.36 1.52 12.47 0.006
Table S12: Patient characteristics included in the predictive model (Intention to treat study design): Results of stepwise Cox regression models. Hazard ratios for corticosteroids utilization (60 days after index date) among Crohn s disease patients Characteristic Remote or no users Previous steroid utilization (within 365 days before index date) Recent users HR* LCL UCL P-Value HR* LCL UCL P-Value Time from last evidence of IBD from HIS to index date More than 5 years before index date 1 - - - Within 5 years before index date 0.64 0.44 0.93 0.022 Number of comorbidities None 1 - - 1 or more 0.17 0.04 0.076 0.021 Anemia/hemorrage No 1 - - Yes 2.62 1.25 5.47 0.010 Intestinal obstruction/stenosis No 1 - - Yes 0.41 0.168 1.04 0.061 Age class (years) 0-19 1 - - - 1 - - - 20-34 1.24 0.57 2.69 0.580 0.96 0.59 1.56 0.886 35-49 0.99 0.45 2.18 0.991 1.51 0.94 2.41 0.081 50-64 0.73 0.32 1.66 0.460 1.92 1.18 3.12 0.008 > 64 0.96 0.32 2.88 0.947 1.85 1.03 3.31 0.037 Previous aminosalicylic acid prescription Remote or no user 1 - - Recent user 1.77 1.21 2.59 0.003 * HR of corticosteroids utilization (60 days after index date) Previous drugs utilization (within 365 days before index date) - Recent: last prescription <= 6 months before index date - Remote or no users: last prescription > 6 months before index date or no prescriptions
Table S13: Patient characteristics included in the predictive model (Intention to treat study design): Results of stepwise Cox regression models. Hazard ratios for corticosteroids utilization (60 days after index date) among Ulcerative colitis patients Remote or no users Previous steroid utilization (within 365 days before index date) Recent users Characteristic HR* LCL UCL P-Value HR* LCL UCL P-Value Place of residence Rome municipality 1 - - - 1 - - - Rome province 1.03 0.78 1.35 0.812 Other Lazio provinces 1.50 1.16 1.94 0.002 Age class (years) 0-34 1 - - - 1 - - - 35-49 1.38 1.05 1.81 0.021 >49 1.76 1.35 2.32 0.001 Number of comorbidities None 1 - - - 1 - - - 1 or more 1.99 1.19 3.34 0.009 Previous immunosuppressant prescription Remote or no user 1 - - - 1 - - - Recent user 1.24 0.99 1.56 0.067 Anemia/hemorrage No 1 - - - Yes 2.06 0.96 4.44 0.064 * HR of corticosteroids utilization (60 days after index date) Previous drugs utilization (within 365 days before index date) - Recent: last prescription <= 6 months before index date - Remote or no users: last prescription > 6 months before index date or no prescriptions
Table S14: Patient characteristics included in the propensity score. Characteristics of Crohn s Disease patients according to exposure before and after adjustment for propensity score quintile. Infliximab Adalimumab n=367 n=505 p-value After adjustement for propensity score quintile N % N % p-value Gender Male 203 55.3 232 45.9 0.006 0.82 Female 164 44.7 273 54.1 Age class (years) 0-19 33 10.0 37 6.5 0.02 0.43 20-34 153 28.3 104 30.3 35-49 172 31.9 117 34.1 50-64 111 24.3 89 22.0 >64 36 5.5 20 7.1 Residence Rome municipality 191 52.0 241 47.7 0.03 0.88 Rome province 89 24.3 127 25.1 Other Lazio provinces 87 23.7 137 27.1 CD disease form (ICD9-CM code) Regional enteritis of small intestine (555.0) 87 23.7 145 28.7 0.017 0.70 Regional enteritis of large intestine (555.1) 38 10.4 33 6.5 Regional enteritis of small intestine with large intestine (555.2) 118 32.2 131 25.9 Regional enteritis of unspecified site (555.9) 69 18.8 110 21.8 CU diagnosis in CD patients 18 4.9 7 1.4 Patients not discharge within 5 years before index date 37 10.1 79 15.6 Time from last evidence of IBD from HIS to index date Within 5 years before index date 230 62.7 277 54.9 0.021 0.78 More than 5 years before index date 137 37.3 228 45.1 Risk factors for surgery Intestinal fistola/ulcera/abscess 96 26.2 66 13.1 0.000 0.48 Drug exposure Corticosteroid (local/systemic) No 124 33.8 150 29.7 0.20 0.59 Recent (<= 6 months) 207 56.4 294 58.2 Remote (>6 months) 36 9.8 61 12.1
Table S15: Patient characteristics included in the propensity score. Characteristics of Ulcerative colitis patients according to exposure before and after adjustment for propensity quintile score Infliximab Adalimumab n=467 n=90 p-value After adjustement for propensity score quintile N % N % p-value Gender Male 272 58.0 40 44.0 0.014 0.79 Female 197 42.0 51 56.0 Age class 0-34 157 33.6 30 33.3 0.05 0.97 35-49 158 33.8 27 30.0 > 49 152 32.6 33 36.7 Residence Rome municipality 200 42.6 43 47.3 0.002 0.85 Rome province 128 27.3 24 26.4 Other Lazio provinces 141 30.1 24 26.4 UC disease form (ICD9-CM code) Ulcerative enterocolitis/ulcerative ileocolitis/pseudopolyposis of colon (556.0/ 556.1/ 556.4) 51 10.9 7 7.7 0.01 0.82 Ulcerative proctitis/ulcerative proctosigmoiditis (556.2/ 556.3) 66 14.1 4 4.4 Left-sided ulcerative colitis (556.5) 138 29.4 11 12.1 Pancolitis (556.6) 72 15.4 14 15.4 Other ulcerative colitis/ulcerative colitis, unspecified (556.8) 36 7.7 5 5.5 CD diagnosis in CU patients 33 7.0 15 16.5 Patients not discharged within 5 year before index date 73 15.6 35 38.5 Risk factors for surgery Anemia/hemorrage 70 14.9 2 2.2 0.005 0.198 Drug exposure Aminosalicylic acid No 38 8.1 19 20.9 0.02 0.90 Remote (>6 months) 399 85.1 63 69.2 Recent (<= 6 months) 32 6.8 9 9.9 Immunosuppressant No 304 64.8 65 71.4 0.02 0.82 Remote (>6 months) 139 29.6 17 18.7 Recent (<= 6 months) 26 5.5 9 9.9
Table S16: Rates and HR of abdominal surgery and infections among patients of UC treated with Infliximab versus those treated with Adalimumab. Intention to treat approach. Disease Outcome UC Events IFX ADA Crude HR Adjusted HR Rate (per 100 PY) Events Rate (per 100 PY) Estimate ICL ICU P Value Estimate ICL ICU P Value Surgery 42 4.6 3 2.6 2.40 0.74 7.75 0.144 1.57 0.67 3.66 0.30 Infections 9 1.0 1 0.9 1.51 0.19 8.54 0.70 0.68 0.19 2.44 0.56 IFX: Infliximab, ADA: Adalimumab, CD: Crohn sdisease, UC: Ulcerative colitis.py 100 person years. ICL / ICU: 95% lower / upper confidence limits.