Multicentre study and systematic review: Allopurinol exposure during pregnancy.

BACKGROUND: Data about the safety of allopurinol in pregnant women are sparsely reported. AIMS: To investigate the risk of adverse pregnancy outcome and congenital abnormalities after in utero exposure to allopurinol in inflammatory bowel disease (IBD) pregnancies and in general. METHODS: We collected safety data of patients with IBD who were treated with allopurinol during pregnancy between January 2013 and March 2022. Additionally, we performed a systematic review about the teratogenic potential of allopurinol. RESULTS: We collected data from 42 allopurinol-exposed pregnancies, including one twin pregnancy; in all women, allopurinol was combined with a thiopurine. Six pregnancies (14.3%) resulted in miscarriage and one in stillbirth at 32 weeks. A congenital anomaly was observed in one newborn (coarctation of the aorta discovered postpartum). Three pregnancies, including the twin pregnancy, ended in moderate preterm delivery and one in very preterm delivery. Five neonates (15.2%) were small for gestational age. From our literature search, we identified an additional 102 allopurinol-exposed pregnancies resulting in 129 live births, including 36 infants from our cohort. Ten infants (7.8%) were born with a congenital anomaly. Two (1.6%) had a comparable pattern of multiple anomalies. The systematic review sub-analysis including only infants born to mothers with IBD (n = 76) revealed that 2.6% of infants had congenital anomalies after in utero exposure to a low dose of allopurinol. CONCLUSIONS: Overall, the teratogenicity of allopurinol remains inconclusive. Children conceived by mothers treated for IBD with allopurinol/thiopurine co-therapy do not seem to have an increased risk of congenital anomalies.

Comparing quality, safety, and costs of colonoscopies performed by nurse vs physician trainees.

BACKGROUND & AIMS: We evaluated the quality and safety of colonoscopies performed by nurse and physician endoscopy trainees as well as the cost differences. METHODS: We performed a study of 7 nurse and 8 physician (gastroenterology fellows) endoscopy trainees at 2 medical centers in the Netherlands from September 2008 through April 2012. At the beginning of the study, the subjects had no experience in endoscopy; they were trained in gastrointestinal endoscopy according to the regulations of the Dutch Society of Gastroenterology, performing a minimum of 100 colonoscopies. Each trainee then performed 135 consecutive colonoscopies (866 total by nurse trainees and 1080 by physician trainees) under supervision of a gastroenterologist; the colonoscopies were evaluated for quality and safety. We performed statistical analyses of data, assessing multilevel and cost minimization. The mean age of the patients was 57 years, and about half were women in each group. RESULTS: The endoscopic quality and safety were comparable between nurse and physician trainees. Overall rates of cecal intubation were 95% for nurses and 93% for physicians (P = .38), including procedures that required assistance from a supervisor; mean withdrawal times were 10.4 and 9.8 minutes, respectively (P = .44). Each group detected 27% of adenomas and had a 0.5% rate of complication. In both groups, the rates of unassisted cecal intubation gradually increased with the number of colonoscopies performed, from 70% for nurses and 74% for physicians at the beginning to 89% and 86%, respectively, at the end of the assessment period. Using a strategy in which 1 gastroenterologist supervises 3 nurses, the personnel costs decreased from $64.65 to $54.58. CONCLUSIONS: In a supervised setting, nurse endoscopists perform colonoscopies according to quality and safety standards that are comparable with those of physician endoscopist and can substantially reduce costs.

Differential responsiveness to immunoablative therapy in refractory rheumatoid arthritis is associated with level and avidity of anti-cyclic citrullinated protein autoantibodies: a case study.

In order to identify pathogenic correlates of refractory rheumatoid arthritis (RA), antibodies against anti-cyclic citrullinated protein (ACPAs) were investigated in RA patients in whom the dysregulated immune system had been ablated by high-dose chemotherapy (HDC) and autologous haematopoietic stem cell transplantation (HSCT). Six patients with refractory RA were extensively characterized in terms of levels of total immunoglobulins, RA-specific autoantibodies (ACPAs and rheumatoid factor) and antibodies against rubella, tetanus toxoid (TT) and phosphorylcholine before and after HDC plus HSCT. Additionally, the avidity of ACPAs was measured before and after treatment and compared with the avidity of TT antibodies following repeated immunizations. Synovial biopsies were obtained by arthroscopy before HDC plus HSCT, and analyzed by immunohistochemistry. In the three patients with clinically long-lasting responses to HDC plus HSCT (median 423 days), significant reductions in ACPA-IgG levels after therapy were observed (median level dropped from 215 to 34 arbitrary units/ml; P = 0.05). In contrast, stable ACPA-IgG levels were observed in three patients who relapsed shortly after HDC plus HSCT (median of 67 days). Clinical responders had ACPA-IgG of lower avidity (r = 0.75; P = 0.08) and higher degree of inflammation histologically (r = 0.73; P = 0.09). Relapse (after 38 to 530 days) in all patients was preceded by rising levels of low avidity ACPA-IgG (after 30 to 388 days), in contrast to the stable titres of high avidity TT antibodies. In conclusion, humoral autoimmune responses were differentially modulated by immunoablative therapy in patients with synovial inflammation and low avidity ACPA-IgG autoantibodies as compared with patients with high levels of high avidity ACPA-IgG. The distinct clinical disease course after immunoablative therapy based on levels and avidity of ACPA-IgG indicates that refractory RA is not a single disease entity.

Reduction of joint damage in severe rheumatoid arthritis by high-dose chemotherapy and autologous stem cell transplantation.

OBJECTIVE: To examine the influence of high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) on joint damage in patients with rheumatoid arthritis. METHODS: Eight patients with active, refractory, progressively erosive RA were treated. The conditioning regimen consisted of intravenous administration of high doses of cyclophosphamide (totaling 200 mg/kg), with subsequent reinfusion of the positively selected graft. Radiographs of hands and feet were obtained before, and at 1 and 2 years after transplantation. All radiographs of hands and feet obtained up to 6 years before transplantation were also collected to compare radiographic progression before and after HDC + ASCT. Scoring of all radiographs was performed according to the Larsen scale by a trained investigator who was blinded with regard to the clinical data. RESULTS: Radiographic assessment by the Larsen scale showed a decreased progression of joint damage. Before transplantation, the mean Larsen score increased at a rate of 8.9 points per year. During the 2 years after transplantation, the mean rate of progression in the Larsen score decreased to 2.7 points per year (P = 0.023 by paired t-test). CONCLUSION: The results of the present analysis demonstrate major beneficial effects of HDC + ASCT on the rate of joint destruction during the first 2 years of followup after treatment.

Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia.

We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3-4 months. Both cohorts produced naive T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort.

Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, inflammatory disease of the synovium of uncertain pathogenesis. A number of phenotypic and functional T-cell defects have been described in RA, including abnormal clonal expansions and suppressed proliferative responses, which suggest a defect in T-cell differentiation. Here, we show that RA patients possess fewer naive CD4(+) T cells than healthy controls. Furthermore, a smaller proportion of these cells contains a T-cell receptor excision circle (TREC). Patients with RA also have unusual populations of T cells. These include immature cells characterized as CD45RB(bright)CD45RA(+)CD62L(-) by flow cytometry and a large population that coexpresses CD45RA and CD45RO. These cells are hyperresponsive to mitogen and TCR stimulation when compared to naive cells. Additionally, an unusual putative central memory subset expressing CD62L, but not CD45RA, appears in RA patients at the expense of more typical cells. Levels of C-reactive protein correlate inversely with the TREC content of naive T cells and positively with the sizes of naive and immature atypical T-cell subsets. These data suggest that inflammation drives proliferation of naive T cells in RA and encourages their differentiation into atypical, hyperresponsive progeny. TREC content of individual naive and atypical T-cell subsets suggests an ontogeny consistent with this hypothesis. These studies provide further evidence of a T-cell differentiation defect in RA, which could explain some of the well-characterized immunologic features of the disease.

High dose chemotherapy and hematopoietic stem cell transplantation: a study of treatment preference in patients with rheumatoid arthritis and rheumatologists.

OBJECTIVE: Patients with intractable rheumatoid arthritis (RA) may benefit from treatment with high dose chemotherapy followed by rescue with autologous hematopoietic peripheral blood stem cell transplant (HSCT). We investigated whether the risks of this approach are acceptable to patients with RA and rheumatologists and whether risk taking by patients was associated with disease characteristics, socioeconomic variables, and/or personality traits. METHODS: A survey in the outpatient clinic was conducted among 2 cohorts of 45 (cohort A) and 51 (cohort B) RA patients with active disease. Patients received information about the potential benefit of HSCT (2/3 chance of a good clinical response, 1/3 no response) and treatment related morbidity and mortality. Cure was assumed not to be a realistic perspective. Cohort A was asked to choose between their own disease state for an indefinite time or HSCT. Nonparametric tests were performed to evaluate putative predictive factors that led patients to accept transplant related mortality (TRM): swollen joint count, tender joint count, visual analog scale (VAS) measures of disease activity and pain, erythrocyte sedimentation rate, Health Assessment Questionnaire (HAQ), socioeconomic variables, RA Quality of Life Questionnaire (RAQoL), and the Life Orientation Test. Cohort B was asked to consider a worst case scenario with respect to their disease activity. The minimal duration of benefit was assessed, given a TRM of 0.01% and 2%. To evaluate treatment preference of physicians, 96 Dutch rheumatologists responded to a hypothetical clinical case analogous to the interviews with RA patients. The minimum duration of benefit was assessed, given a TRM of 2% and the maximal TRM acceptable to rheumatologists if duration of benefit was 2 years in 2/3 patients. RESULTS: In cohort A, 5 of 45 patients were willing to accept risk of death. VAS disease activity (p = 0.006), VAS pain (p = 0.021), and HAQ (p = 0.05) were significantly higher in patients willing to accept risk of death. Religiosity (p = 0.093), a higher Ritchie Articular Index (p = 0.096), and low quality of life (by RAQoL) (p = 0.133) showed trends toward risk taking. In cohort B, 22 of 50 patients (44%) were willing to accept a risk of TRM related to HSCT. For the 22 patients the median required duration of benefit given a TRM of 2% was 5 years (range 1-15). Physicians also required a median duration of benefit of 5 years. CONCLUSION: We evaluated risk taking in patients with RA and physicians based on a realistic perspective in which the tradeoff between short term risks and possible longterm benefit of HSCT was investigated. Based on current efficacy data for HSCT (2 years improvement in 2/3 patients), half the patients would accept the current TRM of 2%, based on registry results. Patients willing to accept TRM had higher VAS disease activity, VAS pain, and HAQ. Doctors were more willing to accept mortality in the treatment of RA.