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J M van Laar

Publications and source records attributed to J M van Laar.

At least 19 recordsLinked to original sources
PubMed2006

Comparison of efficacy of arthroscopic lavage plus administration of corticosteroids, arthroscopic lavage plus administration of placebo, and joint aspiration plus administration of corticosteroids in arthritis of the knee: A randomized controlled trial.

OBJECTIVE: To compare the efficacy of arthroscopic lavage plus administration of corticosteroids (ALC), arthroscopic lavage plus administration of placebo (ALP), and joint aspiration plus administration of corticosteroids (JAC) in knee arthritis, and to evaluate whether clinical or histologic characteristics determine outcome. METHODS: Patients with knee arthritis (not due to gout, osteoarthritis, or septic arthritis) were randomized over 3 treatment arms: ALC, ALP, and JAC. The primary end point was event-free survival, with events defined as 1) recurrence or persistence of symptomatic knee swelling necessitating local re-treatment, or 2) nonimprovement of the knee joint score. Synovial tissue specimens were collected and analyzed histologically to identify predictive factors of responsiveness. RESULTS: A total of 78 patients were enrolled; 3 patients did not receive their allocated therapy and 3 were lost to followup. The median time until recurrence was 9.6 months after ALC, 3.0 months after JAC, and 1.0 month after ALP, corresponding to a relative risk (RR) of arthritis recurrence of 2.2 for JAC (95% confidence interval [95% CI] 1.2-4.2, P = 0.02) and 4.7 for ALP (95% CI 2.3-9.4, P < 0.0001) compared with ALC. A high versus low synovial extent of fibrosis conferred an RR for recurrence of 5.7 (95% CI 1.6-20.5, P < 0.01) after ALC. CONCLUSION: Arthroscopic lavage plus administration of corticosteroids was more effective than arthroscopic lavage plus administration of placebo or joint aspiration plus injection of corticosteroids. The absence of fibrosis was a histologic predictor of a beneficial response.

Adrenal Cortex Hormones↗
PubMed2006

Adult stem cells in the treatment of autoimmune diseases.

During the past 10 yrs, over 700 patients suffering from severe autoimmune disease (AD) have received an autologous haematopoietic stem cell transplant as treatment of their disorder with durable remission being obtained in around one-third. The most commonly transplanted ADs have been systemic sclerosis (scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus. A fewer number of patients have received an allogeneic transplant. The initially reported overall treatment-related mortality of 7% has since fallen, with no further cases being reported in systemic sclerosis or multiple sclerosis in the past 3 yrs. This is thought to be due to more careful patient selection. The phase I/II data has led to currently running prospective randomised trials in systemic sclerosis, multiple sclerosis and systemic lupus erythematosus in Europe and North America. Immune reconstitution data suggests a 'resetting' of autoimmunity in those patients achieving stable remission, rather than simply prolonged immunosuppression. Recent results from in vitro experiments, animal models and early human experience in severe acute graft vs host disease suggest that multipotent mesenchymal stromal cells obtained from the bone marrow and expanded ex vivo, may exert a clinically useful immunomodulatory effect. Such cells are immune privileged and apparently of low toxicity. Further characterization of these cells and consideration of their possible clinical application in AD is underway.

Animals↗
PubMed2006

CTLA-4IG suppresses reactive oxygen species by preventing synovial adherent cell-induced inactivation of Rap1, a Ras family GTPASE mediator of oxidative stress in rheumatoid arthritis T cells.

OBJECTIVE: Oxidative stress contributes to the inflammatory properties of rheumatoid arthritis (RA) synovial T lymphocytes. This study was undertaken to investigate the mechanisms leading to production of reactive oxygen species (ROS) and oxidative stress in RA synovial T lymphocytes. METHODS: ROS production in T lymphocytes from the peripheral blood (PB) of healthy donors and from the PB and synovial fluid (SF) of RA patients was measured by ROS-dependent fluorescence of 6-carboxy-2',7'-dichlorofluorescein. Rap1 GTPase activation was assessed by activation-specific probe precipitation. Proliferation of RA PB and SF T lymphocytes was assayed by 3H-thymidine incorporation. In some experiments, RA PB T cells were preincubated with autologous SF or with PB or SF adherent cells. Experiments were performed in the absence or presence of transwell membranes or CTLA-4Ig fusion proteins. Short- and long-term stimulations of healthy donor PB T lymphocytes were performed with inflammatory cytokines, in the absence or presence of activating anti-CD28 antibodies. RESULTS: T lymphocyte ROS production and Rap1 inactivation were mediated by cell-cell contact with RA synovial adherent cells, and this correlated with T cell mitogenic hyporesponsiveness. CTLA4-Ig blockade of synovial adherent cell signaling to CD28 T cells reversed the inhibition of Rap1 activity and prevented induction of ROS. Introduction of active RapV12 into T cells also prevented induction of ROS production. Coincubation of T cells with stimulating anti-CD28 antibodies and inflammatory cytokines synergistically increased T cell ROS production. CONCLUSION: Cell-cell contact between T cells and RA synovial adherent cells mediates Rap1 inactivation and subsequent ROS production in T lymphocytes following exposure to inflammatory cytokines. This process can be blocked by CTLA4-Ig fusion protein.

Abatacept↗
PubMed2005

Outcome of intensive immunosuppression and autologous stem cell transplantation in patients with severe rheumatoid arthritis is associated with the composition of synovial T cell infiltration.

OBJECTIVE: To determine clinical and immunological correlates of high dose chemotherapy (HDC) + autologous stem cell transplantation (ASCT) in patients with severe rheumatoid arthritis (RA), refractory to conventional treatment. METHODS: Serial samples of peripheral blood and synovial tissue were obtained from seven patients with RA treated with HDC and autologous peripheral blood grafts enriched for CD34+ cells. Disease activity was assessed with the Disease Activity Score (DAS), serum concentrations of C reactive protein (CRP), and human immunoglobulin (HIg) scans, and the extent of immunoablation was determined by immunophenotyping of peripheral blood mononuclear cells, and immunohistochemistry and double immunofluorescence of synovium. RESULTS: Clinical responders (n = 5) had a larger number of cells at baseline expressing CD3, CD4, CD27, CD45RA, CD45RB, and CD45RO in synovium (p < 0.05), higher activity on HIg scans (p = 0.08), and a trend towards higher concentrations of CRP in serum than non-responders (n = 2). Subsequent remissions and relapses in responders paralleled reduction and re-expression, respectively, of T cell markers. A relatively increased expression of CD45RB and CD45RO on synovial CD3+ T cells was seen after HDC + ASCT. No correlations were found between DAS and changes in B cells or macrophage infiltration or synoviocytes. CONCLUSIONS: HDC + ASCT results in profound but incomplete immunoablation of both the memory and naïve T cell compartment, which is associated with longlasting clinical responses in most patients. The findings provide strong circumstantial evidence for a role of T cells in established RA, and demonstrate a role for the synovium in post-transplantation T cell reconstitution.

Adult↗
PubMed2005

Intracellular free radical production in synovial T lymphocytes from patients with rheumatoid arthritis.

OBJECTIVE: To investigate the cellular and molecular sources of oxidative stress in patients with rheumatoid arthritis (RA) through analysis of the production of reactive oxygen species (ROS) in synovium. METHODS: Cytochemical procedures based on the 3,3'-diaminobenzidine (DAB)-Mn2+ deposition technique were used on unfixed cryostat sections of synovium from RA patients and rheumatic disease controls. For immunophenotyping, sections were incubated, fixed, and stained with fluorescein isothiocyanate-labeled antibodies. Fluorescence-activated cell sorter analysis of the ROS-reactive dye 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate-di(acetoxymethyl ester) was used to measure intracellular ROS in T lymphocytes from peripheral blood and synovial fluid. To determine which enzymes produced ROS, different inhibitors were tested. RESULTS: Large quantities of DAB precipitated in the majority of RA synovial T lymphocytes, indicative of intracellular ROS production. These ROS-producing T lymphocytes were observed throughout the synovium. Polymerization of DAB was observed to a lesser extent in other forms of chronic arthritis, but was absent in osteoarthritis. DAB staining of cytospin preparations of purified RA synovial fluid T cells confirmed the presence of ROS-producing cells. One of the ROS involved appeared to be H2O2, since catalase suppressed intracellular ROS production. Superoxide dismutase, which uses superoxide as a substrate to form H2O2, diphenyleneiodonium (an inhibitor of NADPH oxidase), N(G)-monomethyl-L-arginine (an inhibitor of nitric oxide synthesis), nordihydroguaiaretic acid (an inhibitor of lipoxygenase), and rotenone (an inhibitor of mitochondrial ROS production) failed to suppress ROS production. CONCLUSION: Our findings show that chronic oxidative stress observed in synovial T lymphocytes is not secondary to exposure to environmental free radicals, but originates from intracellularly produced ROS. Additionally, our data suggest that one of the intracellularly generated ROS is H2O2, although the oxidase(s) involved in its generation remains to be determined.

Arthritis, Rheumatoid↗
PubMed2005

Long-term followup of health status in patients with severe rheumatoid arthritis after high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation.

OBJECTIVE: High-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (HSCT) is a new treatment for patients with severe, refractory rheumatoid arthritis (RA). The present study was undertaken to assess the health status of patients with severe RA over a long-term followup period after treatment with HDC + HSCT. METHODS: Health status and utility scores were assessed in 8 patients before and after treatment with HDC + HSCT. Patients were followed up for 5 years posttransplantation. Health status was assessed by the Health Assessment Questionnaire (HAQ), the RAND-36 version of the Short Form 36 (SF-36) health survey, and the Arthritis Impact Measurement Scales (AIMS). Utility scores were calculated using the EuroQol (EQ-5D) questionnaire and the SF-36-derived utility index (called the SF-6D), from which quality-adjusted life years (QALYs) were derived. RESULTS: Most measures of health status improved compared with baseline in the first 2 years posttransplantation, notably HAQ and AIMS scores and scores on the functional status, general health, and health change summary scales of the RAND-36 version of the SF-36. Utility scores derived from the EQ-5D questionnaire and the SF-6D also increased significantly after transplantation. This was reflected in the 0.28 QALYs gained compared with baseline. For a putative 50-year-old RA patient with a life expectancy of 20 years, a threshold analysis revealed that HDC + HSCT yielded more QALYs than conventional therapy when treatment-related mortality (TRM) was <2.8%. CONCLUSION: HDC + HSCT temporarily increased the functionality and health status of patients with severe, refractory RA. With a reported TRM of 1.3%, HDC + HSCT can be considered a realistic treatment option for patients with severe RA.

Adult↗
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

Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF alpha and IL18 but not CXCL12.

BACKGROUND: Tumour necrosis alpha (TNF alpha) blocking agents lead to pronounced clinical effects and reduced synovial infiltrate in rheumatoid arthritis. Laboratory and clinical studies suggest that TNF alpha independent pathways play a role in the disease. OBJECTIVES: To evaluate the immunopathological effects of combination therapy on rheumatoid synovial tissue in order to identify TNF alpha independent mechanisms. METHODS: 12 rheumatoid patients, including four DMARD (disease modifying antirheumatic drug) naive patients with early disease, were studied for the effect of combination therapy with infliximab and methotrexate on the synovial infiltrate. Biopsies and clinical assessments (DAS28) were carried out before the first and after the third infusion of infliximab. Synovial inflammation was scored semiquantitatively. Co-expression of CD38(+) cells was studied by an immunofluorescent double labelling technique. RESULTS: Marked clinical responses were associated with a global reduction in the synovial infiltrate and expression of cytokines, notably interleukin 18 and TNF alpha, but low grade disease activity persisted. There was no effect on the expression of CXC chemokine ligand (CXCL12), and germinal centre-like structures were still detectable in synovial tissue in two patients after treatment. CD38(+) activated T cells were more resistant to treatment than CD38(+) plasma cells. No differences in clinical response or effects on synovial infiltrate were observed between DMARD refractory and DMARD naive patients. CONCLUSIONS: Persistent expression of CXCL12 and incomplete resolution of lymphocytic infiltrates after infliximab plus methotrexate indicates that TNF alpha independent mechanisms are operative in rheumatoid arthritis. This may contribute to low grade disease activity, even in DMARD naive patients with early disease.

Adult↗
PubMed2005

High dose chemotherapy and syngeneic stem cell transplantation in a patient with refractory rheumatoid arthritis: poor response associated with persistence of host autoantibodies and synovial abnormalities.

BACKGROUND: Immunoablative therapy combined with haematopoietic stem cell transplantation (SCT) is a possible treatment for patients with severe rheumatoid arthritis (RA). CASE REPORT: A patient with rheumatoid factor positive, progressively erosive RA, refractive to treatment, was treated with high dose cyclophosphamide, followed by reinfusion of an unmanipulated peripheral blood graft derived from her identical twin sister. The clinical response was unsatisfactory, necessitating reinstitution of treatment with disease modifying antirheumatic drugs, which was associated with persistence of host serum autoantibodies and a cellular infiltrate in synovium, notably of plasma cells. DISCUSSION: The effectiveness of syngeneic SCT may be critically dependent on the degree of immunoablation achieved or on the composition of the graft.

Adult↗
PubMed2004

Consensus statement concerning cardiotoxicity occurring during haematopoietic stem cell transplantation in the treatment of autoimmune diseases, with special reference to systemic sclerosis and multiple sclerosis.

Autologous haematopoietic stem cell transplantation is now a feasible and effective treatment for selected patients with severe autoimmune diseases. Worldwide, over 650 patients have been transplanted in the context of phase I and II clinical trials. The results are encouraging enough to begin randomised phase III trials. However, as predicted, significant transplant-related morbidity and mortality have been observed. This is primarily due to complications related to either the stage of the disease at transplant or due to infections. The number of deaths related to cardiac toxicity is low. However, caution is required when cyclophosphamide or anthracyclines such as mitoxantrone are used in patients with a possible underlying heart damage, for example, systemic sclerosis patients. In November 2002, a meeting was held in Florence, bringing together a number of experts in various fields, including rheumatology, cardiology, neurology, pharmacology and transplantation medicine. The object of the meeting was to analyse existing data, both published or available, in the European Group for Blood and Marrow Transplantation autoimmune disease database, and to propose a safe approach to such patients. A full cardiological assessment before and during the transplant emerged as the major recommendation.

Anthracyclines↗
PubMed2004

Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry.

OBJECTIVE: To analyse the durability of the responses after haematopoietic stem cell transplantation (HSCT) for severe systemic sclerosis (SSc) and determine whether the high transplant related mortality (TRM) improved with experience. This EBMT/EULAR report describes the longer outcome of patients originally described in addition to newly recruited cases. METHODS: Only patients with SSc, treated by HSCT in European phase I-II studies from 1996 up to 2002, with more than 6 months of follow up were included. Transplant regimens were according to the international consensus statements. Repeated evaluations analysed complete, partial, or non-response and the probability of disease progression and survival after HSCT (Kaplan-Meier). RESULTS: Given as median (range). Among 57 patients aged 40 (9.1-68.7) years the skin scores improved at 6 (n = 37 patients), 12 (n = 30), 24 (n = 19), and 36 (n = 10) months after HSCT (p<0.005). After 22.9 (4.5-81.1) months, partial (n = 32) or complete response (n = 14) was seen in 92% and non-response in 8% (n = 4) of 50 observed cases. 35% of the patients with initial partial (n = 13/32) or complete response (n = 3/14) relapsed within 10 (2.2-48.7) months after HSCT. The TRM was 8.7% (n = 5/57). Deaths related to progression accounted for 14% (n = 8/57) of the 23% (n = 13/57) total mortality rate. At 5 years, progression probability was 48% (95% CI 28 to 68) and the projected survival was 72% (95% CI 59 to 75). CONCLUSION: This EBMT/EULAR report showed that response in two thirds of the patients after HSCT was durable with an acceptable TRM. Based on these results prospective, randomised trials are proceeding.

Adolescent↗
PubMed2003

Superior effect of arthroscopic lavage compared with needle aspiration in the treatment of inflammatory arthritis of the knee.

OBJECTIVES: To compare the duration of symptom relief after arthroscopic lavage versus needle aspiration in gonarthritis. METHODS: A retrospective chart analysis was performed in 50 patients with non-septic inflammatory arthritis of the knee who underwent arthroscopic lavage because of relapsing or persisting arthritis after needle aspiration. The primary outcome measure was the time until symptomatic recurrence of knee synovitis. RESULTS: Needle aspiration was associated with a 3.0 times greater risk of recurrence of arthritis compared with arthroscopic lavage within 12 months (P<0.001, 95% confidence interval 2.1-4.4). Patients with longer disease duration and who had used more disease-modifying anti-rheumatic drugs (DMARDs) had a significantly lower risk of recurrence of arthritis compared with patients with shorter disease duration and a lower number of previous DMARDs (P=0.04 and 0.02 respectively). Corticosteroids augmented the effect of both interventions. CONCLUSIONS: Our results indicate that arthroscopic lavage is an effective therapeutic modality in the treatment of inflammatory arthritis of the knee refractory to joint aspiration, especially in patients with longstanding disease.

Administration, Topical↗
PubMed2001

High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy.

OBJECTIVE: To assess the feasibility, safety, and efficacy of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) in patients with severe, refractory rheumatoid arthritis (RA). METHODS: Fourteen patients (3 male, 11 female, mean age 43 years, mean disease duration 10 years) with active, destructive, refractory RA entered the study. Autologous hematopoietic stem cells were collected by leukapheresis after mobilization with a single infusion of cyclophosphamide (CYC; 4 gm/m2) and subcutaneous injections of filgrastim (granulocyte colony-stimulating factor). Immunomagnetic selection of CD34+ cells from the leukapheresis products was performed to deplete potentially autoreactive lymphocytes. The conditioning regimen consisted of intravenous administration of high doses of CYC (cumulative dose 200 mg/kg), with subsequent reinfusion of the graft. Patients were monitored for disease activity, disability, adverse effects, and hematopoietic and immunologic reconstitution. RESULTS: All 14 patients completed the mobilization and leukapheresis procedures successfully, and 12 proceeded to receive conditioning and transplantation. Engraftment occurred in all of these patients, with rapid hematologic recovery. No major unexpected toxicity was observed. Marked improvement of disease activity was recorded in 8 of 12 patients at >50% of the visits, with a followup ranging from 7 months to 21 months. The clinical responders included 2 patients who had previously failed treatment with tumor necrosis factor (TNF) blocking agents. CONCLUSION: High-dose chemotherapy followed by autologous HSCT is feasible and safe, and can result in long-term improvement of disease activity in patients whose condition previously did not respond to conventional antirheumatic drugs or TNF blocking agents. The persistence of active disease in some patients may reflect the heterogeneity of the underlying disease process.

Adolescent↗
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↗
PubMed2001

High dose chemotherapy followed by autologous peripheral blood stem cell transplantation or conventional pharmacological treatment for refractory rheumatoid arthritis? A Markov decision analysis.

OBJECTIVE: To evaluate the effect of high dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) in comparison to conventional pharmacological therapy in the treatment of patients with refractory, progressively erosive rheumatoid arthritis (RA). METHODS: Decision analysis using a Markov model with a 5.5 year time horizon. Probabilities of transition towards 5 different health states, ranging from 70% improvement to death, were derived from published case reports, patient series, and expert panels. Quality of life (QOL) estimates were obtained from 2 RA clinical trials. Patients were hypothetical cohorts of 50-year-old female patients with progressively erosive, active RA, who failed treatment with methotrexate, combination therapy, and tumor necrosis factor blocking agents. Interventions were HDC + ASCT versus conventional pharmacological treatment with a (combination) therapy of disease modifying antirheumatic drugs. As main outcome measures, we included the number of quality adjusted life years (QALY) after HDC + ASCT compared to conventional therapy. Sensitivity analysis was performed to investigate the influence of treatment related mortality (TRM) and the influence of QOL during HDC + ASCT, and to assess the minimal desired effectiveness of HDC + ASCT for a given TRM of 1% and 10%. RESULTS: HDC + ASCT and conventional pharmacological treatment were equally effective in the base-case analysis (3.48 vs 3.46 QALY). A TRM of less than 3.3% favored HDC + ASCT as the preferred treatment. The analysis showed that when TRM was set at 1%, a relatively short period of efficacy was sufficient to remain the preferred strategy, whereas a TRM of 10% would require a sustained response for several years. CONCLUSION: This model predicted equally favorable effects of HDC + ASCT and conventional therapy in the treatment of refractory RA in the base-case. The minor differences in terms of QALY seem to indicate that clinical decision making should be guided by patient preferences. However, better clinical efficacy might be achieved by adaptation of the treatment regimen of HDC + ASCT and patient selection. The model supports the need for randomized clinical trials and may contribute to an optimal study design.

Antirheumatic Agents↗
PubMed2001

Intensive immunosuppression and autologous stem cell transplantation for patients with severe rheumatoid arthritis: the Leiden experience.

Ten patients with active, destructive rheumatoid arthritis refractory to antirheumatic therapy enrolled in a study to evaluate the effects of intensive immunosuppression followed by autologous stem cell transplantation. Intensive immunosuppression was achieved with high dose cyclophosphamide as part of the mobilization (4 g/m2) and conditioning (200 mg/kg) regimen. The autologous stem cell products were enriched for CD34+ cells to minimize the chance of reinfusing autoreactive lymphocytes. Eight patients completed all consecutive treatment steps, one patient withdrew after mobilization because of improvement, one patient was taken off study because of pulmonary embolism. The treatment appeared feasible and safe, and marked sustained clinical improvement was observed in 6 patients, 2 of whom were previously unresponsive to tumor necrosis factor blocking therapy. In 5 patients disease modifying antirheumatic drugs were successfully withdrawn after transplantation. The treatment induced significant lymphopenia, with low levels of naive CD4+ T cells in particular, without clinical sequelae. Titers of rheumatoid factor dropped but did not normalize.

Adult↗
PubMed2000

[Immunology in the medical practice.XXXII. Transplantation of autologous hematopoietic stem cells for treatment of refractory auto-immune diseases; preliminary favorable results with 35 patients].

The objective of this study was to document the experiences in the first Dutch pilot studies of the effect of transplantation of autologous haematopoietic stem cells in patients with therapy-resistant autoimmune disease. The first results in 21 adults and 14 children are promising: remission of the disease was achieved in 13 patients, while in the others a significant reduction of disease activity was seen with a corresponding improvement of the quality of life. Infectious complications were frequently observed. Two children with systemic juvenile idiopathic arthritis developed a fatal infection-associated macrophage activation syndrome. Multicentre randomised studies are necessary to study the effects of autologous stem cell transplantation and modifications such as T-cell depletion.

Adolescent↗