Tacrolimus

All patients with a record of an allogeneic HSCT between 2006 and 2015 were identified in the Patient Register (n = 2147). This cohort and methods used for identification of cGVHD have been described previously [14 (link)]. Briefly, the following exclusion criteria were applied: absence of a haematological malignancy prior to the HSCT; reused proxy identification numbers; age <18 or >75; and death within 6 months post-HSCT (S1 Fig). cGVHD is commonly defined as occurring onwards of 6 months post-HSCT [16 (link), 17 (link)]. For patients who survived ≥6 months post-HSCT (index date), the 0–6-month follow-up period was therefore 6–12 months post-HSCT. End of follow-up was Dec 31, 2016 (Cancer Register and Patient Register) and Dec 31, 2017 (Prescribed Drug Register and Cause of Death Register). Patient register records were reviewed, and patients were classified as having non-, mild, or moderate-severe cGVHD based on timing and extent of treatments commonly used for cGVHD using criteria developed by the authors (Fig 1) [14 (link)].
Patients were classified as non-cGVHD if, after taper of post-HSCT GvHD prophylaxis immunosuppression, they received neither systemic corticosteroids nor systemic immunosuppressive treatment (including everolimus, cyclosporine, methotrexate, mycophenolate, sirolimus, and tacrolimus) during the entire observation period. In Sweden, GvHD prophylaxis post-HSCT is discontinued by 3 months for matched sibling donors, and by 5 months for matched unrelated donors.
Patients with low-level cGVHD require less intensive immunosuppressive treatment. Based on this rationale, mild cGVHD was defined as patients receiving either corticosteroids or immunosuppressants alone. The following four mild cGVHD groups were defined: 1) patients who received systemic corticosteroid treatment >3 months alone, 2) patients whose last date of systemic corticosteroid treatment ended <3 months before censoring, 3) patients whose last date of systemic corticosteroid treatment ended <6 months before death, and 4) patients who received immunosuppressive treatment only (Fig 1).
Treatment modalities are similar for patients with moderate and severe cGVHD, which meant that it was not possible to separate these two groups. Patients with moderate-severe cGVHD require more intensive treatment than those with mild cGVHD. Based on this rationale, the following three moderate-severe cGVHD groups were defined: 1) patients who received corticosteroid treatment (irrespective of duration) and immunosuppressive treatment, 2) patients who received corticosteroid treatment (irrespective of duration) and extracorporeal photopheresis (ECP), and 3) patients who only received ECP.
Patients were assigned retrospectively to respective groups based on treatment (or not) received.

This was a retrospective claim-based cohort study that utilized longitudinal claims data from the HealthCore Integrated Research Database^® (HIRD^®) from January 1, 2016 to August 31, 2019. The HIRD^® contains data from January 2006 on patient enrollment, inpatient and outpatient medical care, prescription, and health care utilization. It is a large longitudinal medical and pharmacy claims database of health plan members comprising all regions of the US.
The data were accessed and used in full compliance with the relevant provisions of the Health Insurance Portability and Accountability Act. The study was conducted under the research provisions of Privacy Rule 45 CFR 164.514(e). Researchers’ access to claims data was limited to data stripped of identifiers to ensure confidentiality. An Institutional Review Board did not review the study since only this limited data set was accessed. This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Pharmacoepidemiology Practices as well as legal and regulatory requirements.
Adult patients aged ≥ 18 years with CD (International Classification of Diseases, 10th Revision, Clinical Modification [ICD-10-CM] diagnosis codes: K50.x) or UC (ICD-10-CM diagnosis codes: K51.x) who initiated an advanced therapy during the index period of July 1, 2016 through August 31, 2018 were included in the study. Index date was defined as the first observed occurrence of a claim (medical or pharmacy) for any eligible advanced therapy during the index period. For patients who started more than one therapy, only the earliest one observed was used. Included patients were enrolled in commercial, Medicare Advantage, or Medicare Supplemental plus Part D insurance plans for ≥ 6 months before the index date (pre-index period) and ≥ 12 months after index date (follow-up period). Eligible patients were required to have ≥ 2 medical claims for CD or UC from a provider of any specialty at least seven days apart during the study period, of which ≥ 1 claim occurred during the pre-index period.
In this study, advanced therapies for CD included TNFi (adalimumab, certolizumab, infliximab) and non-TNFi (natalizumab, ustekinumab, vedolizumab). For UC, advanced therapies included TNFi (adalimumab, golimumab, infliximab), non-TNFi (vedolizumab; ustekinumab as a potential switcher but not index drug), and other therapies (tofacitinib). Conventional therapies included 5-aminosalicylic acid derivatives (mesalazine and sulfasalazine) and immunosuppressants (azathioprine, methotrexate, mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine).
Patients were excluded if they had claims for ≥ 1 advanced therapy during the 6-month pre-index period to identify new initiators of advanced therapy. Patients who had evidence for other autoimmune diseases including psoriasis, lupus, ankylosing spondylitis, psoriatic arthritis, or rheumatoid arthritis (defined as ≥ 2 claims on different dates for the same disease) were also excluded in order to avoid misclassification of the estimated response rate (e.g., related to non-adherence) due to multiple indications.