Sulfasalazine

After obtaining Institutional Review Board approval, we used data from a cohort of patients diagnosed with RA by a rheumatologist on the basis of the American College of Rheumatology 1987 criteria [21 (link)]. These patients were participants in the longitudinal Department of Veterans Affairs (VA) RA registry (VARA), which has been described elsewhere [22 (link)]. All VARA participants provided their written informed consent. VARA contains demographic, clinical and RA-specific information, including the Disease Activity Score using 28 joint counts (DAS28), as assessed by physicians using the DAS28 [23 (link)] and the Clinical Disease Activity Index (CDAI) [24 (link)], as well as a biorepository with banked DNA, serum and plasma. VARA data have been collected by rheumatologists at 11 VHA facilities throughout the United States since 2003. We linked VARA participants to the Veterans Health Administration's Medical SAS Datasets present in the VHA administrative databases from 2002 to 2010 to obtain medical and pharmacy claims.
Among VARA enrollees, we used claims data to identify eligible individuals in whom a biologic agent had been initiated. Biologics of interest included abatacept, adalimumab, etanercept, infliximab and rituximab. We defined "initiation" as no prior use of that biologic agent during the past 6 months. Eligible participants must have had a baseline VARA visit on the same day or within 1 month of biologic initiation. The date of initiation of the biologic (the index date) defined the start of a 1-year "treatment episode." To confirm that patients were receiving medications through the VA system, eligible individuals must have filled at least one prescription (of any duration) for any oral medication during the 6 to 12 months prior to the index date. Participants must also have had a follow-up VARA visit that occurred at 1 year ± 2 months after the index date. If there was no VARA visit at 1 year, then these treatment episodes were excluded, as there was no clinical gold standard with which to compare the algorithm's performance. VARA data were used only to capture the DAS28, the CDAI and other clinical characteristics measured at the baseline and outcome VARA visits. All other data used for the analysis were abstracted from the administrative claims data.
To test the performance of the effectiveness algorithm and to see whether it was similar for nonbiologic RA treatments, we performed a separate analysis of RA patients enrolled in VARA who were starting leflunomide (LEF), sulfasalazine (SSZ) or hydroxychloroquine (HCQ) and who also had any prior or current use of methotrexate (MTX). New MTX users were not represented in this analysis, because MTX is typically considered an "anchor" drug for RA patients and generally is continued even if the patient's therapeutic response is suboptimal, in contrast to other RA therapies, where the drugs are typically discontinued if they are not effective. Because of similarities in both the descriptive characteristics of the study populations of biologic and nonbiologic disease-modifying anti-rheumatic drug(DMARD) users and the performance characteristics of the effectiveness algorithm between biologic and DMARD treatment episodes, the data are shown throughout for the biologic users as a unique group and for a combined group of new biologic and nonbiologic DMARD users.

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.

The algorithm to identify inadequate response to index advanced therapy was derived from a claims-based algorithm originally developed by Curtis et al. [16 (link)] and validated for rheumatoid arthritis. The first claim for advanced therapy is set as index date. Some modifications were made to the algorithm for UC and CD. The absence of all criteria listed in Table 1 denoted adequate response (stable disease); presence of one or more of them denoted inadequate response. For example, low index therapy adherence reflects inadequate response. All criteria were calculated based on the 1-year follow-up period for each patient. Details of the algorithm used are presented in Additional file 1: Table S1. In brief, the parameters of the algorithm included low adherence (defined as proportion of days covered [PDC] < 80%), switched/added new advanced therapy/new biologic, added a new conventional therapy, increased dose/frequency of advanced therapy/biologics, addition or dose increase of oral glucocorticoids, used a new pain medication, or had surgery for UC or CD.Table 1

Inadequate response criteria evaluated over 1-year follow-up for both Crohn’s disease and ulcerative colitis

Criteria based on the reference algorithm [16 (link)]

Low adherence to index advanced therapy (defined as proportion of days covered [PDC] < 80%)

Switch/add non-index advanced therapy

Add new conventional therapy (methotrexate, sulfasalazine, and others)

Dose or frequency increase of index advanced therapy (> 20% higher than the index dose)

Addition or dose increase of oral glucocorticoid

Additional criteria for this study

Use of pain medication classa not observed at pre-index period

Use of surgery (Current Procedural Terminology codes for surgery are presented in Additional file 1: Table S2)

^aOpioids, nonsteroidal anti-inflammatory drugs, non-narcotic analgesics, neuromodulators (anti-depressants, anticonvulsants, muscle relaxants)

A 31-year-old incarcerated AA male complained of hematochezia and fever requiring admission to the hospital and was diagnosed with Clostridium difficile colitis. CT scan and colonoscopy showed left-sided colitis. Following treatment with oral vancomycin, outpatient colonoscopy was consistent with residual proctosigmoiditis. Through SDM, he was started on mesalamine enemas but had difficulty retaining them and decision was made to start on UST for ease of dosing and avoidance of per-rectum therapies per patient preference. The UST was infused at the clinic during a scheduled visit. He missed multiple doses due to inconsistent transport to clinic for nurse-led administration of medication. He was then released from custody and off all therapy until developing C. difficile infection requiring hospitalization. He was treated with vancomycin and then resumed on PO and PR mesalamine as an outpatient. However, upon reincarceration with questionable access to medication, he developed worsening symptoms and was started on sulfasalazine. Repeat colonoscopy showed Mayo 3 pancolitis with pathology confirming moderate inflammation. He resumed UST therapy with a standard loading dose given at a clinic appointment and 90 mg SC every 8 weeks consistently while incarcerated. The patient has since been released from the detention center and has a steady job. He has been in frequent contact with the PCMH and the behavioral health social worker who assists him in coming to appointments and receiving his medication in a timely fashion from the specialty pharmacy. Clinically, he is doing well and is planned for endoscopic evaluation shortly once his insurance is valid. Additional biochemical evaluation is pending given the cost associated with self-pay laboratory studies.