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Biomedical subjects

N M Wulffraat

Publications and source records attributed to N M Wulffraat.

At least 19 recordsLinked to original sources
PubMed2005

Treatment of refractory autoimmune diseases with autologous stem cell transplantation: focus on juvenile idiopathic arthritis.

Autologous stem cell transplantation (ASCT) can be performed in a variety of refractory autoimmune diseases. A retrospective multicenter analysis is presented to evaluate safety and efficacy of ASCT for refractory juvenile idiopathic arthritis. In all, 18 of the 34 patients (53%) with a follow-up of 12 to 60 months achieved a drug-free complete remission. There were three cases (9%) of transplant-related mortality and two cases of disease-related mortality (6%). Infectious complications were seen frequently. We propose adjustments in future protocols to reduce this mortality in this high-risk patient group.

Arthritis, Juvenile↗
PubMed2005

How to improve the search for an unrelated haematopoietic stem cell donor. Faster is better than more!

Many patients do not reach haematopoietic stem cell transplantation. Shortage of unrelated donors (UDs) is still seen as the main cause. However, with a worldwide UD pool containing more than 8 million donors, it is possible that other impediments are becoming more important. We analysed 549 UD searches for Dutch patients, performed between 1987 and 2000, in order to find the reasons for failure or success to reach transplantation. Between 1996 and 2000, 59% of the patients of Northwest European origin received a graft from an UD with a median time span of 4.4 months from the start of the search. In all, 11% of the patients lacked a compatible donor, while 30% became medically unfit for transplantation. This is in contrast to the patients of non-Northwest European origin for whom UD shortage is still the most important impediment; only 32% were transplanted while 50% lacked a compatible donor. We conclude that the shortage of donors is no longer the biggest constraint in unrelated stem cell transplantation for patients of Northwest European origin. It may be more effective to optimize the chance on transplantation by making the search process more efficient.

Data Collection↗
PubMed2005

Autologous hematopoietic stem cell transplantation for autoimmune diseases.

Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune disease treated with autologous HSCT between 1995 and 2003, from 110 centers participating in the European Group for Blood and Marrow Transplantation (EBMT) autoimmune disease working party database. Survival, transplant-related mortality, treatment response and disease progression were assessed. In all, 420 patients (89%; 86+/-4% at 3 years, median follow-up 20 months) were alive, 53 (11%) had died from transplant-related mortality (N=31; 7+/-3% at 3 years) or disease progression (N=22; 9+/-4% at 3 years). Of 370 patients, 299 evaluable for response (81%) showed a treatment response, which was sustained in 213 (71% of responders). Response was associated with disease (P<0.001), was better in patients who received cyclophosphamide during mobilization (relative risk (RR)3.28 (1.57-6.83)) and was worse with increasing age (>40 years, RR0.29 (0.11-0.82)). Disease progression was associated with disease (P<0.001) and conditioning intensity (high intensity, RR1; intermediate intensity, RR1.81 (0.96-3.42)); low intensity, RR2.34 (1.074-5.11)). These data from the collective EBMT experience support the hypothesis that autologous HSCT can alter disease progression in severe autoimmune disease.

Autoimmune Diseases↗
PubMed2005

Haemopoietic stem cell transplantation in autoimmune diseases: a European perspective.

The potential of haemopoietic stem cell transplantation (HSCT) for the treatment of autoimmune and inflammatory diseases was originally supported by almost three decades of animal experiments and by the serendipitous remissions of autoimmune disease observed in patients undergoing transplantation for haematological disorders. Improved safety of both autologous and allogeneic HSCT over the last decade has been followed by increasing acceptance of HSCT as an experimental treatment for severe autoimmune diseases that are resistant to conventional treatment. International databases have collated over 700 procedures performed specifically for a variety of autoimmune diseases. Phase III clinical trials are in progress for some diseases. This review provides a comprehensive update on the efficacy and toxicity of HSCT in severe autoimmune disease. Future directions in the context of other evolving therapies are discussed.

Animals↗
PubMed2004

Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity.

OBJECTIVE: To evaluate the safety and efficacy of autologous stem cell transplantation (ASCT) for refractory juvenile idiopathic arthritis (JIA). DESIGN: Retrospective analysis of follow up data on 34 children with JIA who were treated with ASCT in nine different European transplant centres. Rheumatological evaluation employed a modified set of core criteria. Immunological reconstitution and infectious complications were monitored at three month intervals after transplantation. RESULTS: Clinical follow up ranged from 12 to 60 months. Eighteen of the 34 patients (53%) with a follow up of 12 to 60 months achieved complete drug-free remission. Seven of these patients had previously failed treatment with anti-TNF. Six of the 34 patients (18%) showed a partial response (ranging from 30% to 70% improvement) and seven (21%) were resistant to ASCT. Infectious complications were common. There were three cases of transplant related mortality (9%) and two of disease related mortality (6%). CONCLUSIONS: ASCT in severely ill patients with JIA induces a drug-free remission of the disease and a profound increase in general wellbeing in a substantial proportion of patients, but the procedure carries a significant mortality risk. The following adjustments are proposed for future protocols: (1) elimination of total body irradiation from the conditioning regimen; (2) prophylactic administration of antiviral drugs and intravenous immunoglobulins until there is a normal CD4+ T cell count.

Arthritis, Juvenile↗
PubMed2003

Long-term follow-up of autologous stem cell transplantation for refractory juvenile idiopathic arthritis.

Since 1997, autologous stem cell transplantation (ASCT) had been applied to more than 40 children with polyarticular or systemic juvenile idiopathic arthritis (JIA). For this review, results of the follow-up are available from 25 children with systemic JIA and six with polyarticular JIA that were reported in detail from eight different pediatric European transplant centers. Before ASCT all children had progressive disease despite the use of corticosteroids, methotrexate (MTX) up to 1 mg/kg/week, cyclosporin (2.5 mg/kg/day) and/or anti-TNFalpha therapy. The clinical follow-up of these children ranges from 8 to 60 months (median 33 months).

Arthritis, Juvenile↗
PubMed2003

Nonlethal transfusion associated graft-versus-host disease in a severe combined immunodeficient patient.

An X-linked severe combined immunodeficient (SCID) patient received a nonirradiated erythrocyte transfusion and developed transfusion-associated graft-versus-host disease (TAGVHD), which was controllable with high-dose corticosteroids. Haplo-identical SCT was performed, after a myeloablative conditioning regimen. At day +26, he developed GVHD. Chimerism studies revealed DNA of the erythrocyte transfusion donor (ETD) and recipient only. Because of early nonengraftment and the presence of alloreactive T cells of ETD origin, the patient was treated with an immunosuppressive conditioning regimen followed by a second SCT from the same donor. While tapering immunosuppression, he again developed mild GVHD, and DNA of ETD and bone marrow donor origin were both present. On cyclosporin, the ETD-DNA signal finally disappeared. High-resolution HLA typing revealed haplo-identity between BMD, ETD and the patient, which might have contributed to the relative mild course of the TAGVHD.

Adrenal Cortex Hormones↗
PubMed2003

Reduced perforin expression in systemic juvenile idiopathic arthritis is restored by autologous stem-cell transplantation.

OBJECTIVES: Familial haemophagocytic lymphohistiocytosis (FHL) is a disorder characterized by deficient cytotoxic T-cell function and activated macrophages, owing to a defect in the perforin gene and absent perforin expression. Because symptoms of patients with systemic juvenile idiopathic arthritis (sJIA) are sometimes clinically very similar to those with FHL, we studied whether perforin expression in sJIA patients would be reduced also. METHODS: We determined the perforin expression levels on two subsets of CD8(+) cells (CD8(+)CD28(-)CD45RA(-) and CD8(+)CD28(-)CD45RA(+)) and natural killer (NK) cells from patients with sJIA under conventional treatment as well as before and after autologous stem-cell transplantation (ASCT). RESULTS: CD45RA(-) cytotoxic effector cells of sJIA patients (n=13) express significantly lower levels of perforin than polyarticular juvenile idiopathic arthritis (pJIA, n=9) patients [sJIA mean fluorescence intensity (MFI) 34.6; pJIA MFI 98.0] or control donors (MFI 124.6, n=5). A similar pattern was seen in the CD45RA(+) subset. Also NK cells from sJIA patients expressed significantly less intracellular perforin (sJIA MFI 398.4; controls MFI 972.4). In four patients with sJIA who were treated with ASCT, a clear increase in perforin expression was found at 12 months after ASCT in both cytotoxic effector cell subsets (CD45RA(-) subset before ASCT MFI 13.2; 12 months after ASCT MFI 172.3). CONCLUSION: We conclude that perforin expression can be severely reduced in sJIA. This finding may implicate defective cytotoxicity and haemophagocytosis and could thus explain why sJIA may be complicated by macrophage activation syndrome. ASCT leads to a reconstitution of the (T cell) immune system with a normal expression of perforin.

Adolescent↗
PubMed2003

Myeloid related protein 8 and 14 secretion reflects phagocyte activation and correlates with disease activity in juvenile idiopathic arthritis treated with autologous stem cell transplantation.

OBJECTIVES: To determine whether myeloid related proteins (MRP8/MRP14), a complex of two S100 proteins related to neutrophil and monocyte activation, might be used as a marker for disease activity, and as an early indicator of relapse in juvenile idiopathic arthritis. PATIENTS AND METHODS: A group of 12 patients who underwent an autologous haematopoietic stem cell transplantation (ASCT) for refractory juvenile idiopathic arthritis (JIA) were studied. MRP8/MRP14 serum concentrations were determined by a sandwich enzyme linked immunosorbent assay (ELISA) as described. Improvement from baseline was described by a definition of improvement employing a core set of criteria as detailed previously by Giannini. RESULTS: After ASCT, MRP8/MRP14 serum concentrations in JIA showed a positive correlation with the Child Health Assessment Questionnaire (CHAQ; r=0.80) and erythrocyte sedimentation rate (r=0.45), but not with the total leucocyte count (r=0.26). Mean MRP8/MRP14 serum concentrations dropped markedly in the first three months after ASCT (p=0.0039) and clinical parameters of disease activity such as CHAQ markedly improved (p=0.0039). During a transient relapse there was an increase in MRP8/MRP14. CONCLUSIONS: MRP8/MRP14 serum concentration can be used as a marker for disease activity in patients who receive an ASCT for refractory JIA. This indicates a role of macrophage activation in the pathogenesis of JIA. The occurrence of MAS in three patients in this study was not preceded by significant changes in MRP8/MRP14 concentration.

Adolescent↗
PubMed2002

[Children with fever peaks and bone and joint pain: systemic juvenile idiopathic arthritis or acute lymphoblastic leukemia after all?].

In two 3-year-old infants, a girl and a boy, systemic juvenile idiopathic arthritis was suspected because of daily fever peaks, signs of polyarthritis and general malaise. Drug treatment was unsuccessful, and after extensive laboratory investigation acute lymphoblastic leukaemia (ALL) was diagnosed and treated adequately. ALL is the most common malignancy in childhood. About one-third of the patients present with joint or bone pain and fever. In this group of children, it can be difficult to identify ALL because it may mimic the clinical picture of systemic juvenile idiopathic arthritis and because of the possibility of a normal blood count at presentation. ALL should always be considered in the differential diagnosis in children with musculoskeletal pain and fever, even in the face of a normal blood count. In any case, a bone-marrow examination should be done before steroid treatment is given.

Arthralgia↗
PubMed2002

[Pneumonia due to Legionella pneumophila in an immunocompromised child].

A one-year-and-seven-months-old boy was hospitalised because of fever, cough and general malaise. A diagnosed tonsillitis and pneumonia were treated with intravenous antibiotics. His clinical condition worsened despite antibiotic therapy. After immunologic investigations revealed both a cellular and a humoral immune disorder, a broncho-alveolar lavage was performed. The culture revealed Legionella pneumophila. Antibiotic treatment was then changed to erythromycin in combination with rifampicin, with a good response. Although rarely described in childhood, one should consider L. pneumophila as a possible pathogen in immunocompromised children presenting with pneumonia.

Anti-Bacterial Agents↗
PubMed2001

Collection of hematopoietic stem cells from patients with autoimmune diseases.

We reviewed data from 24 transplant centers in Asia, Australia, Europe, and North America to determine the outcomes of stem cell collection including methods used, cell yields, effects on disease activity, and complications in patients with autoimmune diseases. Twenty-one unprimed bone marrow harvests and 174 peripheral blood stem cell mobilizations were performed on 187 patients. Disease indications were multiple sclerosis (76 patients), rheumatoid arthritis (37 patients), scleroderma (26 patients), systemic lupus erythematosus (19 patients), juvenile chronic arthritis (13 patients), idiopathic autoimmune thrombocytopenia (8 patients), Behcet's disease (3 patients), undifferentiated vasculitis (3 patients), polychondritis (1 patient) and polymyositis (1 patient). Bone marrow harvests were used in the Peoples Republic of China and preferred worldwide for children. PBSC mobilization was the preferred technique for adult stem cell collection in America, Australia, and Europe. Methods of PBSC mobilization included G-CSF (5, 10, or 16 microg/kg/day) or cyclophosphamide (2 or 4 g/m2) with either G-CSF (5 or 10 microg/kg/day) or GM-CSF (5 microg/kg/day). Bone marrow harvests were without complications and did not affect disease activity. A combination of cyclophosphamide and G-CSF was more likely to ameliorate disease activity than G-CSF alone (P < 0.001). g-csf alone was more likely to cause disease exacerbation than the combination of cyclophosphamide and g-csf (P = 0.003). Three patients died as a result of cyclophosphamide-based stem cell collection (2.6% of patients mobilized with cyclophosphamide). When corrected for patient weight and apheresis volume, progenitor cell yields tended to vary by underlying disease, prior medication history and mobilization regimen. Trends in the approaches to, and results of, progenitor cell mobilization are suggested by this survey. While cytokine-based mobilization appears less toxic, it is more likely to result in disease reactivation. Optimization with regard to cell yields and safety are likely to be disease-specific and prospective disease-specific studies of mobilization procedures appear warranted.

Adolescent↗