Edward J. Feldman

Thioguanine: a potential alternate thiopurine for IBD patients allergic to 6-mercaptopurine or azathioprine.

OBJECTIVE:Approximately 10% of inflammatory bowel disease (IBD) patients receiving 6-mercaptopurine (6-MP) or azathioprine (AZA) develop drug hypersensitivity reactions necessitating early discontinuation of these traditional thiopurines. These allergic reactions typically reoccur upon rechallenge. Our recently published pilot study suggested that thioguanine (6-TG), a closely related thiopurine, was efficacious and well tolerated in IBD patients resistant to 6-MP/AZA. The aim of this study was to determine if hypersensitivity reactions to 6-MP/AZA reoccur with 6-TG therapy.METHODS:IBD patients allergic to 6-MP and/or AZA were treated with 6-TG as an alternate thiopurine. Hypersensitivity reactions to 6-MP/AZA must have been documented within 6 wk of 6-MP/AZA initiation.RESULTS:6-TG was initiated in 21 IBD patients at a median (range) dose of 20 (10–40) mg/day. 6-TG hypersensitivity reaction occurred in only four of 21 (19%) patients after a median time interval of 9 days. Pancreatitis did not reoccur with 6-TG. Eighty-two percent of 6-TG tolerant patients were assessed as improved at last follow-up.CONCLUSIONS:These results suggest that 6-TG may be considered as a possible alternate thiopurine in patients allergic to traditional 6-MP/AZA. Despite these favorable results, candidates for 6-TG should be selected with caution, and its use should be reserved for IBD patients well informed about potential toxicities.

Combined Immunosuppression Impairs Immunogenicity to Tetanus and Pertussis Vaccination Among Patients with Inflammatory Bowel Disease

Background:Pertussis epidemics have recently emerged across the United States, prompting broad public health recommendations for adult Tdap vaccination (tetanus, diphtheria, acellular pertussis). The impact of immunosuppressive regimens for inflammatory bowel disease (IBD) on vaccine responses to the Tdap vaccine is not known. Methods:We performed a prospective controlled trial between April 2011 and March 2012. Adults with IBD were consecutively stratified based on therapeutic regimen into one of 5 groups: A: no IBD therapy or 5-aminosalicylates alone; B: maintenance biologic monotherapy; C: maintenance immunomodulator monotherapy; D: combined biologic and immunomodulator therapy; and E: healthy age-matched controls. Subjects received Tdap, and serum antibody levels against tetanus toxoid, pertussis toxoid, and filamentous hemagglutinin (FHA) were drawn just before and approximately 4 weeks after vaccination. The primary outcome was the booster response rate to each antigen. Secondary outcomes included the differences in pregeometric and postgeometric mean titers. Results:A total of 98 subjects enrolled, and 84 completed the study. Tetanus response rates were 55%, 56%, 40%, 27%, and 63% across groups A to E, respectively. Group D rates were lower than those of group B (P = 0.02). Postvaccination pertussis toxoid responses were 59%, 72%, 47%, 45%, and 75%, while FHA responses were 86%, 72%, 80%, 64%, and 75% across groups A to E, respectively. Prevaccination and postvaccination geometric mean titer differences for FHA were lower in group D than those in group A (P = 0.05). Conclusions:Antibody responses to tetanus and pertussis vaccination may be affected by therapeutic drug regimen. Patients with IBD should optimally receive Tdap before starting immunomodulators, particularly when used in combination with anti–tumor necrosis factor alpha agents.

Patient-reported Outcomes of Quality of Life, Functioning, and Gi/psychiatric Symptom Severity in Patients with Inflammatory Bowel Disease (ibd)

Background: Patients with inflammatory bowel disease (IBD) are at risk for psychiatric disorders that impact symptom experience and health-related quality of life (HRQOL). Therefore, comprehensive biopsychosocial assessments should be considered in ambulatory care settings. Patient-Reported Outcomes Measurement Information System (PROMIS) measures created by the National Institutes of Health have shown construct validity in a large IBD internet-based cohort, but their validity in ambulatory settings has not been examined. We sought to validate PROMIS patient-reported measures of HRQOL, functioning, and psychiatric symptom severity at a tertiary IBD clinic. Methods: Adult patients (n = 110) completed the PROMIS Global Health scale, PROMIS-29, SF-12, and WHODAS 2.0. Pearsons correlation coefficients (r) determined the relationships between scores to validate the PROMIS Global Health Physical and Mental metrics, compared with the SF-12 and WHODAS 2.0. We compared these measures by disease subtype of Crohns disease or ulcerative colitis. Results: PROMIS measures were highly correlated (r range = 0.64–0.82) with standard measures of HRQOL and functioning. On the PROMIS Global Health measures, 20.9% had impaired physical health, and 13.7% had impaired mental health. Impairments were reported in pain interference (20% of patients), anxiety (18.2%), satisfaction with social role (15.5%), physical functioning (10.9%), fatigue (10%), depression (7.3%), and sleep disturbance (5.5%). Patients with Crohns disease had worse scores than those with ulcerative colitis on measures of the global physical health (P = 0.027), physical functioning (P = 0.047), and pain interference (P = 0.0009). Conclusions: PROMIS instruments provide valid assessment of HRQOL and functioning in ambulatory adults with IBD. Of note, patients with Crohns disease demonstrated significantly worse impairments than those with ulcerative colitis.

Idiosyncratic adverse reactions to 6-mercaptopurine (6-MP) and azathioprine(AZA) can be averted by switching to thiioguanine(6-TG) in patients with IBD

were either started on mesalazine 1.2 gm/day or had the dose increased by an equivalent amount. They were taught to self-administer enemas which contained either EGF (5 mcg EGF in 100 ml) or an inert carrier (control) once a day for 14 days. They were reviewed at 14 and 28 days. Results: Eleven patients received EGF and 12 placebo. Both groups had similar baseline characteristics. Eight patients in the EGF group and nine in the p~acebo group were on mesalazine before recruitment to the study. Two patients from the placebo group developed worsening colitis and were withdrawn. After 2 weeks of enema treatment, there were significant improvements in the EGF treated group in symptom score (score 0 or 1 for the absence or presence of liquid stools, nocturnal diarrhoea and visible blood in stools) from median 3 to 1 (p=O.O02), diarrhoea from median 5 to 2 motions/24 hours (p<O.05), sigmoidoscopic score (Baron et al Br Med J 1:89-92, 1964) from median 3 to 1 (p = 0.004) and histological score (Richards eta/ Br Med J 1:160-165, 1960) from median 3 to 1 (p=O.O02). These parameters were significantly better in the EGF group than in the placebo group at 2 and 4 weeks (p<O.O05 for all). No significant change in these parameters was seen in the placebo group. Nine (82%) patients in the EGF group as compared to one (8%) in the placebo group achieved remission after 2 weeks (p = 0.005). Eight of these 9 maintained their remission up to the end of the study. At 4 weeks, nine patients in the EGF group and three in the placebo group were in remission (p<O.O01). Conclusions: EGF enema is an effective treatment for left-sided ulcerative colitis. A dose increase of 1.2 gm mecalazine had little effect in inducing remission in these patients.

Sa1182 Single-Center Experience of Vedolizumab in Patients With Inflammatory Bowel Disease: Does Age Matter?

Background: Vedolizumab, an anti-α4β7 integrin which inhibits lymphocyte migration to the gastrointestinal tract, was recently approved in the United States for the treatment of ulcerative colitis (UC) and Crohns disease (CD). The study aims were to describe the safety and efficacy of vedolizumab in adult patients at a tertiary care IBD center and to determine predictors of vedolizumab efficacy. Methods: IBD patients 18 years or older treated with vedolizumab from June through November 2014 were assessed for safety and response to treatment. Laboratory and clinical data (demographics, surgical history, disease behavior, location of disease, prior medications, C-reactive protein (CRP)) along with IBD-associated serologies (p-ANCA) were assessed at baseline. The primary measure of response was a 50% reduction in CRP. Other measures of disease activity included the physician global assessment (PGA) (0=remission, 1=mild, 2=moderate, 3=severe), CRP at week 6 and week 14 infusions. Descriptive statistics and univariate analyses were used to compare differences in outcomes based on clinical and serologic factors. Results: 66 patients received vedolizumab; median age at diagnosis was 19 (range 7-72) years and median disease duration of 8.6 (range 155) years. Median CRP at baseline was 0.4 (IQR 0.12-1.64) mg/dL. Seven patients (11%) switched from natalizumab. Twenty-two patients (37%) were on a concomitant immunomodulator (IMM) at their first infusion. Only 5 patients (8%) were anti-TNF naive and 20 patients (32%) received one prior anti-TNF agent, 38 patients (61%) received two or more prior anti-TNF agents (median 2). Seven patients switched from natalizumab. Of the 37 patients with available serologic data, 13 (35%) had elevated p-ANCA. At weeks 6 and 14, 49% and 42% of patients respectively, had a decrease in CRP by at least 50%. In patients starting therapy with active disease (abnormal CRP or elevated PGA), responders were significantly older both at week 6 (mean age 42.5 vs. 25.5 years, p=0.01) and at week 14 (mean age 43.6 vs. 20.9 years, p=0.02). No differences in response were seen when patients were compared by disease type (CD vs UC), IMM use, prior natalizumab, time from last anti-TNF agent, prior anti-TNF exposure and p-ANCA elevation. Vedolizumab was generally well tolerated; 15% had transient transaminitis (<2x normal). Two patients discontinued therapy due to headaches/insomnia or musculoskeletal pain. One patient on concomitant corticosteroids developed herpes zoster. Conclusion: Early experience with vedolizumab at a tertiary care center demonstrates clinical efficacy, and appears to be well tolerated. Older age may correlate with a higher likelihood of response. Further experience with vedolizumab is needed to help understand which clinical and serologic factors predict response. Results

A Multidisciplinary Approach to Biopsychosocial Care for Adults With Inflammatory Bowel Disease: A Pilot Study

Background This study reports on the logistics and feasibility of a novel multidisciplinary approach to biopsychosocial care at a tertiary adult inflammatory bowel disease (IBD) center. Methods Consecutive patients referred for a new IBD consultation completed the following self-assessments: the Short Form-12, the Patient Reported Outcome Measurement Information System (PROMIS) Global Health Scale, the World Health Organization Disability Assessment Schedule 2.0, and the PROMIS-29. These measures were scored at the time of appointment check-in by a trained licensed clinical social worker (SW), and those scoring 1.5 standard deviations below the population mean were targeted for SW assessment and intervention at the point of care; patients or providers could also request a SW evaluation even if cutoffs were not met. In this stepped-care model, the SW could refer to same-day on-site psychiatry services or outside interventions and services. In addition, we implemented a 12-month curriculum with a monthly didactic and case-based education seminar for health care providers who interact with patients with IBD. Results Between February 2014 and May 2015, 110 patients (53% male; mean age, 42 years) completed a self-assessment. All patients completed their self-assessment within 10 minutes. Of these, 36.4% (40/110) were targeted for SW assessment and intervention. The SW interventions were grouped into 4 categories: psychological education and coping tools for symptom management and emotional wellness (n = 30); psychotherapy referrals (n = 30); financial/governmental programs (n = 11); and psychiatry referrals for consultation and/or medication prescription (n = 21). The educational seminars were highly rated by participating providers. Conclusions A multidisciplinary biopsychosocial approach to adult IBD care is feasible. Education for providers and close coordination across specialties are critical to the success of a multidisciplinary biopsychosocial program.