Risk of complications during hematopoietic stem cell collection in pediatric sibling donors: a prospective European Group for Blood and Marrow Transplantation Pediatric Diseases Working Party study.

We investigated prospectively factors influencing the safety of hematopoietic stem cell (HSC) collection in 453 pediatric donors. The children in the study donated either BM or peripheral blood stem cells (PBSCs) according to center policy. A large variability in approach to donor issues was observed between the participating centers. Significant differences were observed between BM and PBSC donors regarding pain, blood allotransfusion, duration of hospital stay, and iron supplementation; however, differences between the groups undergoing BM vs PBSC donation preclude direct risk comparisons between the 2 procedures. The most common adverse event was pain, reported mainly by older children after BM harvest, but also observed after central venous catheter (CVC) placement for PBSC collection. With regard to severe adverse events, one patient (0.7%) developed a pneumothorax with hydrothorax after CVC placement for PBSC collection. The risk of allotransfusion after BM harvest was associated with a donor age of < 4 years and a BM harvest volume of > 20 mL/kg. Children < 4 years were at higher risk than older children for allotransfusion after BM harvest and there was a higher risk of complications from CVC placement before apheresis. We conclude that PBSC and BM collection are safe procedures in children.

Long-term outcomes of hematopoietic stem cell transplantation for severe treatment-resistant autoimmune cytopenia in children.

We analyzed the long-term outcomes of pediatric patients registered in the European Group for Blood and Marrow Transplantation database who underwent hematopoietic stem cell transplantation (HSCT) for severe treatment refractory autoimmune cytopenia. With a median follow-up of 100 months, event-free survival was 54% overall, with no significant difference between allogeneic HSCT (n = 15) and autologous HSCT (n = 7) recipients (58% versus 42%; P = .50). Despite a trend toward failure of response or relapse after autologous HSCT compared with allogeneic HSCT, the difference was not significant (43% versus 13%; P = .30). Treatment-related mortality was high in both HSCT groups (29% and 16%; P = .09). Based on the limited numbers of subjects in this retrospective analysis, both allogeneic and autologous HSCT may induce complete and persistent responses in approximately one-half of pediatric patients with severe refractory autoimmune cytopenia, although treatment-related toxicity is high.

Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.

BACKGROUND: Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting. METHODS: In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948. FINDINGS: Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls. INTERPRETATION: Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT. FUNDING: Gentium SpA, European Group for Blood and Marrow Transplantation.

No difference in outcome between children and adolescents transplanted for acute lymphoblastic leukemia in second remission.

Acute lymphoblastic leukemia (ALL) in second complete remission is one of the most common indications for allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. We compared the outcome after HCST of adolescents, aged 14 to 18 years, with that of children (ie, patients < 14 years of age). Enrolled in the study were 395 patients given the allograft between January 1990 and December 2007; both children (334) and adolescents (61) were transplanted in the same pediatric institutions. All patients received a myeloablative regimen that included total body irradiation in the majority of them. The donor was an HLA-identical sibling for 199 patients and an unrelated volunteer in the remaining 196 patients. Children and adolescents had a comparable cumulative incidence of transplantation-related mortality, disease recurrence, and of both acute and chronic graft-versus-host disease. The 10-year probability of overall survival and event-free survival for the whole cohort of patients were 57% (95% confidence interval, 52%-62%) and 54% (95% confidence interval, 49%-59%), respectively, with no difference between children and adolescents. This study documents that adolescents with ALL in second complete remission given HSCT in pediatric centers have an outcome that does not differ from that of patients younger than 14 years of age.

Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group.

T cell-depleted haploidentical hematopoietic stem cell transplantation (haploHSCT) is an option to treat children with very high-risk acute lymphoblastic leukemia (ALL) lacking an HLA-identical donor. We analyzed 127 children with ALL who underwent haploHSCT in first (n = 22), second (n = 48), or third (n = 32), complete remission or in relapse (n = 25). The 5-year leukemia-free survival (LFS) was 30%, 34%, 22%, and 0%, respectively. A risk-factor analysis was performed for patients who underwent transplantation in remission (n = 102). Five-year nonrelapse mortality (NRM), relapse incidence (RI), and LFS were 37%, 36%, and 27%, respectively. A trend of improved LFS rate and decreased RI was observed for children given a graft with higher number of CD34(+) cells (adjusted P = .09 and P = .07, respectively). In a multivariate analysis, haploHSCT performed in larger centers (performing > or = 231 allotransplantations in the studied period) was associated with improved LFS rate and decreased RI (adjusted P = .01 and P = .04, respectively), adjusting for different patient-, disease-, and transplant-related factors such as number of previous autotransplantations, cytomegalovirus serology status, type of T-cell depletion, and use of total body irradiation and antithymocyte globulin. In conclusion, higher CD34(+) cell dose and better patient selection may improve outcomes of children with ALL who undergo a haploHSCT. Transplant centers initiating programs on haploHSCT for children may collaborate with more experienced centers.

Acute graft-versus-host disease in pediatric allogeneic hematopoietic stem cell transplantation. Single-center experience during 10 yr.

a-GvHD may complicate allogeneic HSCT. In this retrospective single-center study, we evaluated incidence and risk factors of a-GvHD in 197 consecutive allogeneic pediatric HSCTs applying Glucksberg and NIH a-GvHD classifications. Among 179 eligible transplants, the cumulative incidence of grade 0-I a-GvHD was 48% and grade II-IV was 52%. None of the considered variables significantly influenced the incidence of grade II-IV a-GvHD. Malignancy and myeloablation were associated with an increased risk of classic a-GvHD (p < 0.01). Seventy-two percentage of children are alive, with a significant difference in OS and TRM between grade 0 and I vs. grade II and IV a-GvHD; this observation was reproduced in the non-malignant setting, while only a disparity in TRM was evidenced in children with malignancy. In our experience, the incidence of a-GvHD was similar, regardless of donor type. Myeloablation and malignant disease represented the only risk factors for classic a-GvHD. Our results highlight the need for a better prevention of this complication in the non-malignant setting.

Upper age limits for accessing pediatric oncology centers in Italy: a barrier preventing adolescents with cancer from entering national cooperative AIEOP trials.

A limited proportion of adolescents with cancer currently receives treatment at pediatric oncology centers and this factor is considered one of the possible explanations for the lack of improvement in survival trends observed over the years in this age group. The adoption of inflexible upper age limits for admitting patients to pediatric units may help to explain this situation. This paper reports the results of a national survey on adolescents' access to, and age limits adopted by, Italian pediatric oncology centers, briefly discussing possible actions to bridge the gap in adolescents' access to care. The analysis showed a great variability in the upper age limits adopted at Italian pediatric oncology centers; in many cases age limits are set at 16, 15, or even 14 years. As major finding, a correlation was documented between age limits and number of adolescents treated in the pediatric centers. In principle, this finding should suggest that increasing the upper age limit may result in an increase of the access of adolescents in pediatric oncology centers.

Allogeneic hematopoietic stem cell transplantation in children and adolescents with recurrent and refractory Hodgkin lymphoma: an analysis of the European Group for Blood and Marrow Transplantation.

Ninety-one children and adolescents 18 years or younger after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed or refractory Hodgkin lymphoma (HL) were analyzed. Fifty-one patients received reduced intensity conditioning (RIC); 40 patients received myeloablative conditioning (MAC). Nonrelapse mortality (NRM) at 1 year was 21% (+/- 4%), with comparable results after RIC or MAC. Probabilities of relapse at 2 and 5 years were 36% (+/- 5%) and 44% (+/- 6%), respectively. RIC was associated with an increased relapse risk compared with MAC; most apparent beginning 9 months after HSCT (P = .01). Progression-free survival (PFS) was 40% (+/- 6%) and 30% (+/- 6%) and overall survival (OS) was 54% (+/- 6%) and 45% (+/- 6%) at 2 and 5 years, respectively. Disease status at HSCT was predictive of PFS in multivariate analysis (P < .001). Beyond 9 months, PFS after RIC was lower compared with MAC (P = .02). Graft-versus-host disease did not affect relapse rate and PFS. In conclusion, children and adolescents with recurring HL show reasonable results with allogeneic HSCT. Especially patients allografted in recent years with good performance status and chemosensitive disease show highly encouraging results (PFS: 60% +/- 27%, OS: 83% +/- 15% at 3 years). Because relapse remains the major cause of treatment failure, additional efforts to improve disease control are necessary.

Early (day -7) versus conventional (day -1) inception of cyclosporine-A for graft-versus-host disease prophylaxis after unrelated donor hematopoietic stem cell transplantation in children. Long-term results of an AIEOP prospective, randomized study.

We carried out a randomized, multicenter study comparing the inception of cyclosporine- A (CsA) on day -7 to conventional CsA (on day -1) to evaluate the influence of this modification on graft-versus-host disease (GVHD), treatment-related mortality (TRM), relapse rate (RR), and event-free survival (EFS) in children with hematologic malignancies given unrelated donor (UD) hematopoietic stem cell transplantation (HSCT). Between 1997 and 2002, 152 children transplanted for acute leukemia (102), myelodysplastic syndromes (23), chronic myelogenous leukemia (20), and non-Hodgkin lymphoma (7) were enrolled in the study and randomized to receive either early CsA (group 1, N = 72) or conventional CsA (group 2, N = 80), after stratification according to HLA compatibility and disease phase. The cumulative incidence of both grade II-IV and grade II-IV acute GVHD (aGVHD), as well as of chronic GVHD (cGVHD), did not differ between the 2 groups. No significant differences were observed also with regard to TRM and RR. The 8-year Kaplan-Meier estimates of EFS were 56% in group 1, and 46% in group 2 (P = NS). In the Cox model, advanced disease phase, male recipient, older donor, and occurrence of grade III-IV aGVHD predicted inferior overall EFS. These data indicate that early inception of CsA does not improve posttransplantation outcome of children with hematologic malignancies given UD-HSCT.

Osteochondroma after hematopoietic stem cell transplantation in childhood. An Italian study on behalf of the AIEOP-HSCT group.

A retrospective study was conducted among Italian children treated with hematopoietic stem cell transplant (HSCT) to evaluate the incidence and risk factors in the development of osteochondroma (OC). OC occurred in 27 patients who received autologous or allogeneic HSCT. The estimated 5-, 10-, and 15-year cumulative risk of developing OC was 0.5%, 3.2%, and 6.1%, respectively. Analysis of cumulative risk stratified by the various risk factors revealed that male sex (P=.026), autologous HSCT (P=.001), age at HSCT (< or =3 years) (P < .0001), and total body irradiation (TBI) (P <.0001) significantly affected the risk of OC. Multivariate analysis, restricted only to tumor types with at least 1 case of OC, showed that earlier age at HSCT (P =.0004) and TBI (P < .0001) were the only factors that were significantly associated with OC.

Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study.

BACKGROUND: Severe graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic transplantation with haemopoietic stem cells. Mesenchymal stem cells modulate immune responses in vitro and in vivo. We aimed to assess whether mesenchymal stem cells could ameliorate GVHD after haemopoietic-stem-cell transplantation. METHODS: Patients with steroid-resistant, severe, acute GVHD were treated with mesenchymal stem cells, derived with the European Group for Blood and Marrow Transplantation ex-vivo expansion procedure, in a multicentre, phase II experimental study. We recorded response, transplantation-related deaths, and other adverse events for up to 60 months' follow-up from infusion of the cells. FINDINGS: Between October, 2001, and January, 2007, 55 patients were treated. The median dose of bone-marrow derived mesenchymal stem cells was 1.4x10(6) (min-max range 0.4-9x10(6)) cells per kg bodyweight. 27 patients received one dose, 22 received two doses, and six three to five doses of cells obtained from HLA-identical sibling donors (n=5), haploidentical donors (n=18), and third-party HLA-mismatched donors (n=69). 30 patients had a complete response and nine showed improvement. No patients had side-effects during or immediately after infusions of mesenchymal stem cells. Response rate was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had lower transplantation-related mortality 1 year after infusion than did patients with partial or no response (11 [37%] of 30 vs 18 [72%] of 25; p=0.002) and higher overall survival 2 years after haemopoietic-stem-cell transplantation (16 [53%] of 30 vs four [16%] of 25; p=0.018). INTERPRETATION: Infusion of mesenchymal stem cells expanded in vitro, irrespective of the donor, might be an effective therapy for patients with steroid-resistant, acute GVHD.

Cardiac and pulmonary late effects do not negatively influence performance status and non-relapse mortality of children surviving five yr after autologous hematopoietic cell transplantation: report from the EBMT Paediatric Diseases and Late Effects Working Parties.

The current prospective study dealt with clinical outcome associated with pulmonary and cardiac late effects of AuHCT in children with malignancies. We prospectively evaluated 58 children, utilizing pulmonary function tests and cardiac shortening fraction, performed in pre-AuHCT phase and then annually. The overall five-yr survival was 68%. The five-yr cumulative incidence of lung and cardiac function impairment in survivors was 21% in both cases. None of the patients presented with restrictive or obstructive pulmonary pathology at the last follow-up and performance status for all survivors, ranged from 90% to 100%. The cumulative incidence of non-relapse mortality was 12.6% (range 6.3-25.3%), whereas relapse mortality was 19.7% (range 11.6-33.5). In conclusion, our study shows no significant deterioration in post-AuHCT pulmonary and cardiac function and in particular, no negative impact of lung and heart late effects on performance status and non-relapse mortality.

Eligibility for allogeneic transplantation in very high risk childhood acute lymphoblastic leukemia: the impact of the waiting time.

The advantage of allogeneic transplant from compatible related donors versus chemotherapy in children with very-high-risk acute lymphoblastic leukemia in first complete remission was previously demonstrated in an international prospective trial. This study quantified the impact of time elapsed in first remission in the same cohort. Of 357 pediatric patients with very-high-risk acute lymphoblastic leukemia, 259 received chemotherapy, 55 transplantation from compatible related and 43 from unrelated donors. The 5-year disease-free survival was 44.2% overall and 42.5% for chemotherapy only patients. The chemotherapy conditional 5-year disease-free survival increased to 44.4%, 47.6%, 51.7%, and 60.4% in patients who maintained their first remission for at least 3, 6, 9, and 12 months respectively. The overall outcome was superior to that obtained with chemotherapy-only at any time-point. The relative advantage of transplant from compatible related donors in very-high-risk childhood acute lymphoblastic leukemia was consistent for any time elapsed in first remission.

Osteonecrosis after allogeneic stem cell transplantation in childhood. A case-control study in Italy.

A case-control study was conducted among Italian children treated with a stem cell transplant (SCT). Cases (n = 43) were allogeneic recipients with osteonecrosis, and the controls (n = 129) were matched to the corresponding cases on the basis of survival, SCT center and date of transplant. Univariate analysis showed that older age at SCT (OR 1.39; 95% CI 1.24-1.57), total body irradiation (TBI) (OR 5.73; 95% CI 2.38-13.83), chronic graft-versus-host disease (GvHD) (OR 4.31; 95% CI 2.05-9.07), and duration of steroid treatment after SCT (OR 1.118; 95% CI 1.034-1.209) were statistically correlated with osteonecrosis. However, multivariate analysis revealed that the only factors that were significantly associated with osteonecrosis were older age at SCT (p = 0.0001), TBI (p = 0.001) and chronicGvHD (p = 0.001).

Human natural killer cells undergoing in vivo differentiation after allogeneic bone marrow transplantation: analysis of the surface expression and function of activating NK receptors.

Patients undergoing allogeneic bone marrow transplantation (BMT) offer a unique system to analyze the NK cell development in vivo. We analyzed NK cells from 24 such patients to assess the acquisition of activating receptors. Five patients displayed an immature NK cell surface phenotype at engraftment, as they were CD16(-), KIRs(-) and NKG2D(-) while expressed low levels of NKp46, NKp30, 2B4 and NKG2A. These NK cells had particularly low cytolytic activity against the HLA-class I-negative melanoma F01 cell line and the 721.221 Epstein-Barr virus (EBV)B-infected cells. Moreover, cytoxicity was inhibited upon mAb-mediated crosslinking of 2B4. Analysis of NK cells at day 30 after BMT revealed the occurrence of both phenotypic and functional maturation. These data are in agreement with a previous in vitro study showing that immature NK cell precursors express CD16, NKGD2 and killer Ig-like receptors (KIR) only at a late stage of differentiation and also express inhibitory 2B4. Remarkably, one of these patients did not display any phenotypic and functional maturation of NK cells and experienced a fatal post transplant EBV-related lymphoproliferative disease. Our present study allows a better understanding of the NK cell differentiation in vivo.

Very late nonfatal consequences of fractionated TBI in children undergoing bone marrow transplant.

PURPOSE: To describe long-term late consequences in children who received total body irradiation (TBI) for hematopoietic stem cell transplantation 10 years earlier. METHODS AND MATERIALS: A cohort of 42 children treated with TBI between 1985 and 1993, still alive at least 10 years after fractionated TBI (FTBI), was evaluated. Twenty-five patients received FTBI at 330 cGy/day for 3 days (total dose 990 cGy), whereas 17 children were administered fractions of 200 cGy twice daily for 3 days (total dose 1200 cGy). Twenty-seven patients received autologous and 16 allogeneic hematopoietic stem cell transplantation. Median age at TBI was 6.3 years, and 18.4 years at most recent follow-up. RESULTS: Cataract was diagnosed in 78% of patients after a median of 5.7 years. Hypothyroidism was detected in 12%, whereas thyroid nodules were observed in 60% of our population after a median interval of 10.2 years. Patients treated with 990 cGy developed thyroid nodules more frequently than those treated with 1200 cGy (p = 0.0002). Thyroid carcinoma was diagnosed in 14% of the total population. Females who received FTBI after menarche more frequently developed temporary ovarian dysfunction than those treated before menarche, but cases of persistent ovarian dysfunction did not differ between the two groups. Indirect signs of germinal testicular dysfunction were detected in 87% of males. Restrictive pulmonary disease was observed in 74% of patients. Osteochondroma was found in 29% of patients after a median interval of 9.2 years. This latter complication appeared more frequently in patients irradiated before the age of 3 years (p < 0.001). CONCLUSIONS: This study shows that late effects that are likely permanent, although not fatal, are frequent in survivors 10 years after TBI. However, some of the side effects observed shortly after TBI either disappeared or remained unchanged without signs of evolution. Monitoring is recommended to pursue secondary prevention strategies and counseling on family planning.

V(H)3 and V(H)6 immunoglobulin M repertoire reconstitution after hematopoietic stem-cell transplantation in children.

BACKGROUND: Immune reconstitution after hematopoietic stem-cell transplantation (HSCT) occurs gradually. Thus, a variable period of immunodeficiency may be present, leading to immunomediated complications, such as graft-versus-host disease (GVHD) and opportunistic infections. METHODS: To better understand the kinetics of B-cell repertoire reconstitution in children, 49 pediatric patients were analyzed before and after transplantation by immunoglobulin (Ig) HCDR3 fingerprinting, which is a molecular technique that analyzes one of the hypervariable segments of the Ig heavy chain, which provides the amino acid residues that are essential to interact with antigens. RESULTS: In healthy donors, the CDR3 fingerprinting profile shows 16 to 20 bands, and each band corresponds to a particular length of CDR3. This situation is considered polyclonal. Patients analyzed just after transplantation show strong oligoclonality, because only a few CDR3 bands are detected within the first 3 to 6 months. CONCLUSIONS: The authors' data show a significant lag in diversification of the B-cell repertoire, which reaches the polyclonal situation of normal healthy donors approximately 6 months after HSCT. This period may vary depending on the type of transplant (autologous vs. allogeneic) and on the immunosuppressive therapy related to GVHD.

Cytomegalovirus infection after bone marrow transplantation in children.

Cytomegalovirus (CMV) is a well-known cause of disease occurring after bone marrow transplantation (BMT). The manifestations of CMV range from asymptomatic infection, defined as active CMV replication in the blood in the absence of clinical manifestations or organ failure abnormalities, to CMV disease, characterized by CMV infection with clinical symptoms or organ function abnormalities. Diagnostic procedures to assess the viral load have improved greatly with the increased use of antigenemia, CMV DNA, and immediate early-messenger RNA. Many conditions concur in determining the risk of developing CMV reactivation or disease after bone marrow transplant with serologic status of donor and recipient, type of bone marrow transplant, presence of graft-versus-host disease being the most studied. However, time and quality of immune reconstitution seems to be the pivotal factors. Pneumonia and gastrointestinal involvement are the most frequently documented clinical pictures with late-onset CMV reactivation or disease representing a new challenge. CMV prophylaxis or pre-emptive therapy adopted during the last few years in allogeneic BMT recipients has changed the natural history of the disease, reducing the risk of CMV disease, CMV-associated death, transplant-related mortality, and has prolonged the period at risk. Specific studies on children are lacking, however, the clinical pictures and features seems to be similar both in children and adults.

Infliximab treatment for steroid-refractory acute graft-versus-host disease.

BACKGROUND AND OBJECTIVES: Tumor necrosis factor a is one of the principal cytokines involved in the pathogenesis of acute graft-versus-host-disease (GVHD). Infliximab is an antibody to this cytokine. DESIGN AND METHODS: We performed a retrospective analysis to evaluate the activity of infliximab in 32 patients with severe steroid-refractory acute GVHD. The patients received a median of 3 weekly courses of infliximab. The main organs involved in the patients were skin (n=2) liver (n=1), bowel (n=19), liver and bowel at the same stage (n=10). RESULTS: Nineteen out 32 patients (59%) responded to infliximab with 6 (19%) complete and 13 (40%) partial responses. Age younger than 35 years, intestinal involvement and a longer time between hematopoietic stem cell transplantation and infliximab administration were factors predicting a favorable response. Infective episodes developed in 23/32 (72%) patients. All the 13 unresponsive patients died of GVHD shortly after infliximab. Thirteen of 19 responsive patients were alive at a median follow-up of 449 days (range 155-842) after infliximab, with no signs of chronic GVHD (n=5), limited (n=5) or extensive involvement (n=3). Six patients who responded subsequently died, one of chronic lung GVHD, the others of vascular complications or infections (2 fungal diseases). INTERPRETATION AND CONCLUSIONS: We conclude that infliximab is active in the treatment of severe steroid-refractory acute GVHD, particularly when the intestine is involved. Infections commonly followed its administration. The clinical activity of infliximab and the possibility that it increases the risk of infections are worth investigating in prospective trials.