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Beaufils C, Proulx C, Blincoe A, Teira P, Bittencourt H, Cellot S, Duval M, Morin MP, De Bruycker JJ, Couture J, Samaan K, Decaluwe H, Kleiber N, El-Jalbout R, Touzot F, Haddad E, Barsalou J. Case report: Success of allogeneic hematopoietic stem cell transplantation for refractory systemic-onset juvenile idiopathic arthritis. Front Med (Lausanne) 2023; 10:1275927. [PMID: 37908851 PMCID: PMC10614021 DOI: 10.3389/fmed.2023.1275927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 09/18/2023] [Indexed: 11/02/2023] Open
Abstract
Objectives This study reports cases of systemic-onset juvenile idiopathic arthritis (sJIA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center and reviews published outcomes of allo-HSCT in sJIA. Methods We present a case report of two patients with sJIA who underwent allo-HSCT at a tertiary pediatric hospital. Each patient's disease course and allo-HSCT protocol/outcome are described. Outcomes of published cases of allo-HSCT in sJIA were compared to our experience. Results Two patients with sJIA had allo-HSCT. Both failed multiple lines of disease-modifying anti-rheumatic drugs and experienced severe disease/treatment-related complications. Despite post-HSCT complications, both recovered without sequelae. Five years post-HSCT, patient 1 is in complete remission (CR) and is off medications. Patient 2 was in CR until 11 months post-HSCT after which he developed three disease flares. At 4 years post-HSCT he is currently in CR on Adalimumab monotherapy. Engraftment was excellent with a donor chimerism of 100% for patient 1 and 93% for patient 2. In the literature, the outcome of allo-HSCT is reported in 13 sJIA patients. When merging those with our 2 patients, 1/15 patients died and 13/14 achieved CR, of which 12 are off medications (median [range] follow-up: 2.2 [0.2-7.0] years). Extended follow-up data on 11 of the 13 reported sJIA patients showed that an additional 3 patients flared at 3, 4, and 10 years post-HSCT. Conclusion We report two patients with severe/refractory sJIA who underwent successful allo-HSCT and achieved CR. Allo-HSCT is a potential curative option for severe/refractory sJIA. It should be considered only after failure of conventional sJIA treatments and when an HLA-matched donor is available in order to lower transplant-related mortality. The outcomes of reported sJIA patients who received allo-HSCT are encouraging but long-term follow-up data are needed to better characterized the risk-benefit ratio of this procedure.
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Affiliation(s)
- Camille Beaufils
- Division of Pediatric Rheumatology and Immunology, CHU Sainte-Justine, Montreal, QC, Canada
| | - Catherine Proulx
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Annaliesse Blincoe
- Division of Pediatric Rheumatology and Immunology, CHU Sainte-Justine, Montreal, QC, Canada
| | - Pierre Teira
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
- Division of Pediatric Hemato-Oncology, CHU Sainte-Justine, Montreal, QC, Canada
| | - Henrique Bittencourt
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
- Division of Pediatric Hemato-Oncology, CHU Sainte-Justine, Montreal, QC, Canada
| | - Sonia Cellot
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
- Division of Pediatric Hemato-Oncology, CHU Sainte-Justine, Montreal, QC, Canada
| | - Michel Duval
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
- Division of Pediatric Hemato-Oncology, CHU Sainte-Justine, Montreal, QC, Canada
| | - Marie-Paule Morin
- Division of Pediatric Rheumatology and Immunology, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Jean Jacques De Bruycker
- Division of Pediatric Rheumatology and Immunology, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Julie Couture
- Division of Pediatric Rheumatology and Immunology, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Kathryn Samaan
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
- Division of Pediatric Rheumatology, Immunology and Allergy, CHU Sainte-Justine, Montreal, QC, Canada
| | - Hélène Decaluwe
- Division of Pediatric Rheumatology and Immunology, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Niina Kleiber
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Ramy El-Jalbout
- Department of Radiology, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Fabien Touzot
- Division of Pediatric Rheumatology and Immunology, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Elie Haddad
- Division of Pediatric Rheumatology and Immunology, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Julie Barsalou
- Division of Pediatric Rheumatology and Immunology, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
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Muthu S, Jeyaraman M, Ranjan R, Jha SK. Remission is not maintained over 2 years with hematopoietic stem cell transplantation for rheumatoid arthritis: A systematic review with meta-analysis. World J Biol Chem 2021. [DOI: 10.4331/wjbc.v12.i6.0000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Muthu S, Jeyaraman M, Ranjan R, Jha SK. Remission is not maintained over 2 years with hematopoietic stem cell transplantation for rheumatoid arthritis: A systematic review with meta-analysis. World J Biol Chem 2021; 12:114-130. [PMID: 34904049 PMCID: PMC8637617 DOI: 10.4331/wjbc.v12.i6.114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/21/2021] [Accepted: 11/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hematopoietic stem cell (HSC) transplantation (HSCT) is being accepted as a standard of care in various inflammatory diseases. The treatment of rheumatoid arthritis (RA) has been closely evolving with the understanding of disease pathogenesis. With the rising resistance to the traditional disease-modifying anti-rheumatic drugs and targeted biological therapy, researchers are in pursuit of other methods for disease management. Since the ultimate goal of the ideal treatment of RA is to restore immune tolerance, HSCT attracts much attention considering its reparative, paracrine, and anti-inflammatory effects. However, a systematic review of studies on HSCT in RA is lacking.
AIM To investigate the role of HSCT in the management of RA.
METHODS A detailed search of PubMed, Scopus, EMBASE, Cochrane, and the Web of Science databases was made to identify the relevant articles till September 2020 following Cochrane and PRISMA guidelines. We extracted data including the number of patients, source of hematopoietic stem cells, their mobilization and conditioning regimens, results, and complications from the eligible studies. Results were dichotomized into success (ACR 50/70) and failure (ACR 20) based on the improvement from baseline characteristics. The methodological quality of the included studies was also assessed. Analysis was performed using OpenMeta[Analysis] software.
RESULTS We included 17 studies (1 randomized controlled trial, 11 prospective, and 5 retrospective studies) with 233 patients for analysis. HSCT provided a significantly beneficial overall improvement in the clinical grades of ACR criteria (Z = 11.309, P < 0.001). However, the remission was noted only till 24 mo and later on the significance of the result was lost (Z = 1.737, P = 0.082). A less than 1% treatment-related mortality was noted from the included studies. No major drug-related toxicities were noted in any of the included studies. All patients who underwent allogeneic HSCT received immunosuppression in the conditioning regimen to counteract the graft-vs-host reaction which made them vulnerable to infections. It is noted that the source of hematopoietic stem cells did not play a role in altering the functional outcome and both autologous (Z = 9.972, P < 0.001) and allogenic (Z = 6.978, P < 0.001) sources produced significant improvement in the outcome compared to the pre-operative state despite having a significant heterogeneity among the studies reporting them (I2 = 99.4, P < 0.001).
CONCLUSION Although the available literature is encouraging towards the use of HSCT in refractory cases with significant improvement from baseline till 2 years, the inclusion of HSCT into the standard of care of RA needs further exploration.
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Affiliation(s)
- Sathish Muthu
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Delhi 201306, Uttar Pradesh, India
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624001, Tamil Nadu, India
| | - Madhan Jeyaraman
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Delhi 201306, Uttar Pradesh, India
- Department of Orthopaedics, Faculty of Medicine, Sri Lalithambigai Medical College and Hospital, Chennai 600095, Tamil Nadu, India
| | - Rajni Ranjan
- Department of Orthopaedics, School of Medical Sciences and Research, Greater Noida 201306, Uttar Pradesh, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Delhi 201306, Uttar Pradesh, India
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Nilsen L, Santos BND, Leopoldo VC, Reis PEDD, Oliveira MCD, Clark AM, Silveira RCDCP. Nursing interventions in autologous stem cell transplantation for autoimmune diseases. J Adv Nurs 2020; 76:3473-3482. [PMID: 32989824 DOI: 10.1111/jan.14559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 07/16/2020] [Accepted: 08/10/2020] [Indexed: 11/27/2022]
Abstract
AIMS To identify clinical symptoms and nursing interventions for stem cell therapy in autoimmune diseases. DESIGN This is a retrospective, cross-sectional study. METHODS This study was undertaken with patients diagnosed with type 1 diabetes or multiple sclerosis, undergoing autologous haematopoietic stem cell transplantation from January 2004 - December 2018. Data were registered in a questionnaire, taken during the conditioning regimen comprising cyclophosphamide and rabbit anti-thymocyte globulin. Descriptive statistics and Fisher's exact test were used for data analysis. RESULTS There were 68 and 23 patients in the multiple sclerosis and type 1 diabetes groups respectively. Skin rash, nausea, vomiting and fever were more frequent and diverse in the type 1 diabetes group. Steroids were used as prophylaxis for anti-thymocyte globulin-associated allergic reactions in 97% of multiple sclerosis patients. Most of the identified symptoms and nursing interventions were more associated with one or other disease group (p < .05) and were more frequent in the type 1 diabetes group. CONCLUSION Patients with autoimmune diseases who underwent stem cell therapy present differences in their repertoire of adverse events and require disease-specific nursing actions. IMPACT Our results may enable nurses to establish transplant and disease-specific guidelines to improve prevention and management of adverse events and therefore optimize patient care and therapeutic success.
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Affiliation(s)
- Loren Nilsen
- Ribeirão Preto Medical School Clinical Hospital, University of São Paulo, Ribeirão Preto, Brazil
| | - Bruna N Dos Santos
- Ribeirão Preto Medical School Clinical Hospital, University of São Paulo, Ribeirão Preto, Brazil
| | - Vanessa C Leopoldo
- Ribeirão Preto Medical School Clinical Hospital, University of São Paulo, Ribeirão Preto, Brazil
| | | | - Maria C de Oliveira
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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Relaño-Ginés A, Lehmann S, Deville de Périère D, Hirtz C. Dental stem cells as a promising source for cell therapies in neurological diseases. Crit Rev Clin Lab Sci 2019; 56:170-181. [DOI: 10.1080/10408363.2019.1571478] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Aroa Relaño-Ginés
- DERBS, Faculty of Odontology, CHU de Montpellier, University of Montpellier, Montpellier, France
| | - Sylvain Lehmann
- LBPC-PPC - IRMB, CHU de Montpellier, University of Montpellier, Montpellier, France
| | - Dominique Deville de Périère
- DERBS, Faculty of Odontology, CHU de Montpellier, University of Montpellier, Montpellier, France
- LBPC-PPC - IRMB, CHU de Montpellier, University of Montpellier, Montpellier, France
| | - Christophe Hirtz
- DERBS, Faculty of Odontology, CHU de Montpellier, University of Montpellier, Montpellier, France
- LBPC-PPC - IRMB, CHU de Montpellier, University of Montpellier, Montpellier, France
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Abstract
Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis (SSc) and mainly encountered in patients with diffuse disease and/or anti-topoisomerase 1 antibodies. ILD develops in up to 75% of patients with SSc overall. However, SSc-ILD evolves to end-stage respiratory insufficiency in only a few patients. Initial pulmonary function tests (PFT) with measurement of carbon monoxide diffusing capacity, together with high-resolution computed tomography, allows for early diagnosis of SSc-ILD, before the occurrence of dyspnea. Unlike idiopathic ILD, SSc-ILD corresponds to non-specific interstitial pneumonia in most cases, whereas usual interstitial pneumonia is less frequently encountered. Therefore, the prognosis of SSc-ILD is better than that for idiopathic ILD. Nevertheless, ILD represents one of the two main causes of death in SSc patients. To detect SSc-ILD early, PFT must be repeated regularly, every 6 months to 1 year, depending on disease worsening. Conversely, broncho-alveolar lavage is not needed to evaluate disease activity in SSc-ILD but may be of help in diagnosing opportunistic infection. The treatment of SSc-ILD is not well established. Cyclophosphamide, which has been used for 20 years, has recently been evaluated in two prospective randomized studies that failed to demonstrate a major benefit for lung function. Open studies reported mycophenolate mofetil, azathioprine and rituximab as alternatives to cyclophosphamide. On failure of immunosuppressive agent treatment, lung transplantation can be proposed in the absence of other major organ involvement or severe gastro-esophageal reflux.
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Affiliation(s)
- Guillaume Bussone
- Université Paris Descartes, Institut Cochin, Inserm U1016, Paris, France
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Bussone G, Berezné A, Mouthon L. Complications infectieuses de la sclérodermie systémique. Presse Med 2009; 38:291-302. [DOI: 10.1016/j.lpm.2008.11.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2008] [Accepted: 11/17/2008] [Indexed: 12/29/2022] Open
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Mouthon L, Berezné A, Brauner M, Kambouchner M, Guillevin L, Valeyre D. [Interstitial lung disease in systemic sclerosis]. Rev Mal Respir 2008; 24:1035-46. [PMID: 18033190 DOI: 10.1016/s0761-8425(07)92767-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Interstitial lung diseases (ILD) in systemic sclerosis (SSc) are mainly encountered in patients with diffuse disease although they may occur less frequently in patients with limited cutaneous disease. BACKGROUND In SSc early detection of ILD should be achieved by high resolution computed tomography and pulmonary function tests, including measurement of DLCO. In total up to 75% of patients with SSc develop ILD but it is progressive in only a minority of patients. Unlike idiopathic ILD, SSc associated ILD corresponds to non-specific interstitial pneumonia rather than usual interstitial pneumonia in the majority of cases. This explains the better prognosis of SSc associated ILD compared with idiopathic ILD. Nevertheless ILD represents one of the two main causes of death in SSc. VIEWPOINT The treatment of SSc associated ILD is not well established. Anti-fibrosing treatments have failed to demonstrate benefit and cyclophosphamide, which has been used for about 15 years in the treatment of this condition, has recently been evaluated in two prospective randomised studies which showed a significant but modest effect on respiratory function. CONCLUSION A subgroup of patients with rapidly progressive ILD might benefit from pulsed intravenous cyclophosphamide combined with prednisone 15 mg daily, but this remains to be confirmed.
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Affiliation(s)
- L Mouthon
- Service de Médecine Interne, Hôpital Cochin, Centre de Référence pour la sclérodermie systémique, Assistance Publique-Hôpitaux de Paris et Université Paris-Descartes, Faculté de Médecine Paris-Descartes, Paris, France.
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Mouthon L, Berezné A, Brauner M, Kambouchner M, Guillevin L, Valeyre D. Pneumopathie infiltrante diffuse de la sclérodermie systémique. Presse Med 2006; 35:1943-51. [PMID: 17159721 DOI: 10.1016/s0755-4982(06)74929-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Interstitial lung diseases (ILD) associated with systemic sclerosis (SSc) are mainly encountered in patients with diffuse disease, although they may also be seen in patients with limited cutaneous SSc. ILD screening must be performed regularly, with high-resolution computed tomography and pulmonary function tests (TLCO). Up to 75% of patients with diffuse SSc develop a form of ILD. ILD remains stable in most patients and does not worsen. The nonspecific nature of SSc-associated ILD makes it different from idiopathic ILD and helps to explain its better prognosis. Nonetheless, ILD is one of the two leading causes of death in SSc patients. Treatment of SSc-associated ILD is not yet well codified. Antifibrotic treatments have not proved beneficial, and the efficacy of cyclophosphamide, which has been used to treat this condition for 15 years, has been shown to be very limited against SSc-associated ILD. A subgroup of patients with rapidly progressive ILD might benefit from intravenous cyclophosphamide pulses in association with 15 mg/d prednisone.
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MESH Headings
- Anti-Inflammatory Agents/administration & dosage
- Anti-Inflammatory Agents/therapeutic use
- Biopsy
- Cyclophosphamide/administration & dosage
- Cyclophosphamide/therapeutic use
- Disease Progression
- Drug Therapy, Combination
- Glucocorticoids/administration & dosage
- Glucocorticoids/therapeutic use
- Humans
- Immunosuppressive Agents/administration & dosage
- Immunosuppressive Agents/therapeutic use
- Injections, Intravenous
- Lung/pathology
- Lung Diseases, Interstitial/classification
- Lung Diseases, Interstitial/diagnosis
- Lung Diseases, Interstitial/diagnostic imaging
- Lung Diseases, Interstitial/drug therapy
- Lung Diseases, Interstitial/etiology
- Lung Diseases, Interstitial/mortality
- Lung Diseases, Interstitial/pathology
- Lung Diseases, Interstitial/therapy
- Peripheral Blood Stem Cell Transplantation
- Prednisone/administration & dosage
- Prednisone/therapeutic use
- Prognosis
- Prospective Studies
- Radiography, Thoracic
- Randomized Controlled Trials as Topic
- Respiratory Function Tests
- Scleroderma, Diffuse/complications
- Scleroderma, Limited/complications
- Scleroderma, Systemic/complications
- Scleroderma, Systemic/diagnosis
- Tomography, X-Ray Computed
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Affiliation(s)
- Luc Mouthon
- Service de Médecine Interne, Hôpital Cochin, Centre de Référence pour les Vascularites et la Sclérodermie Systémique, AP-HP, Paris.
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Farge D, Passweg J, van Laar JM, Marjanovic Z, Besenthal C, Finke J, Peter HH, Breedveld FC, Fibbe WE, Black C, Denton C, Koetter I, Locatelli F, Martini A, Schattenberg AVN, van den Hoogen F, van de Putte L, Lanza F, Arnold R, Bacon PA, Bingham S, Ciceri F, Didier B, Diez-Martin JL, Emery P, Feremans W, Hertenstein B, Hiepe F, Luosujärvi R, Leon Lara A, Marmont A, Martinez AM, Pascual Cascon H, Bocelli-Tyndall C, Gluckman E, Gratwohl A, Tyndall A. Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry. Ann Rheum Dis 2004; 63:974-81. [PMID: 15249325 PMCID: PMC1755096 DOI: 10.1136/ard.2003.011205] [Citation(s) in RCA: 171] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
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.
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Affiliation(s)
- D Farge
- St Louis Hospital, Paris, France.
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Rosenkranz ME, Lehman TJA. Clinical trials for pediatric scleroderma. Curr Rheumatol Rep 2002; 4:449-51. [PMID: 12427357 DOI: 10.1007/s11926-002-0049-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Progressive systemic sclerosis (PSS), or scleroderma, is a rare disease in the pediatric population. Many children with PSS have significant involvement of their internal organs, which leads to decreased survival. Because of the infrequency of the condition and delayed diagnosis, there are no large studies to evaluate therapy for PSS in children. Treatment is controversial in the adult literature, and its applicability to children is unclear. Only through collaborative efforts will researchers be able to clearly delineate the etiopathogenesis of PSS, and gather information from multicenter studies to ultimately provide appropriate and effective care for children with PSS.
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Affiliation(s)
- Margalit E Rosenkranz
- Division of Pediatric Rheumatology, Hospital for Special Surgery, Sanford Weill Medical College, Cornell University, 535 East 70th Street, New York, NY 10021, USA.
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12
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Abstract
Systemic Sclerosis (SSc) or Scleroderma is a generalized autoimmune disease with variable involvement of the skin and major organs. Etiology and pathogenesis are still largely unknown, but a variety of humoral and cellular autoimmune phenomena can be observed, and a pivotal role of T lymphocytes in SSc pathogenesis is postulated. The rarity of the disease, the wide spectrum of clinical manifestations and severity as well as a variable course render therapy in SSc a major challenge. In view of the immunopathogenesis of SSc, many (presumed) immunomodulatory agents have been used, but no single agent has been proven to be convincingly effective. Trials with extracorporeal therapies (such as photopheresis, plasmapheresis) or even stem cell transplantation are in progress. In contrast to the hitherto unsuccessful therapeutic approaches for the overall disease course, some life-threatening organ manifestations can often be treated successfully, e.g. interstitial pneumonitis with i.v. cyclophosphamide and scleroderma renal crisis with ACE inhibitors and haemodialysis, respectively. Furthermore, pharmacological and supportive treatment of Raynaud's phenomenon and gastrointestinal involvement can alleviate the burden of the disease. Current therapeutic options as well as hitherto investigated immunomodulators are reviewed in this article.
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Affiliation(s)
- G H Stummvoll
- Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna.
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Saba N, Flaig T. Bone marrow transplantation for nonmalignant diseases. JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH 2002; 11:377-87. [PMID: 11983109 DOI: 10.1089/152581602753658565] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Bone marrow transplantation (BMT) has emerged as a major therapeutic option for a number of nonmalignant disorders affecting the bone marrow and leading to clinical manifestations most likely affecting distant organs. Disorders such as autoimmune diseases, metabolic disorders, hemoglobinopathies, immunodeficiencies, and others have been the target of high-dose therapy and autologous or allogeneic bone marrow, stem cell, or cord blood transplantation. Successful results have been reported in a large number of these disorders. In most instances the goal of transplantation is to provide sufficient degree of marrow engraftment to allow long-term amelioration of disease phenotype. For many of these disorders, early diagnosis is crucial in achieving the desired results as transplantation becomes difficult when significant end-organ damage sets in. Major unsolved problems, including toxicity of conditioning regimens, graft-versus-host disease, and donor availability, need to be addressed. We attempt to provide a comprehensive review of BMT and discuss unique features of this modality for treatment of nonmalignant disorders.
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Affiliation(s)
- Nabil Saba
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Hennepin County Medical Center, Minneapolis, MN 55403, USA.
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Hensel M, Egerer G, Schneeweiss A, Goldschmidt H, Ho AD. Quality of life and rehabilitation in social and professional life after autologous stem cell transplantation. Ann Oncol 2002; 13:209-17. [PMID: 11885996 DOI: 10.1093/annonc/mdf031] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND In this study, we report on quality of life (QOL) in long-term survivors after high-dose chemotherapy and autologous stem cell transplantation (ASCT) with special emphasis on rehabilitation in social and professional life. PATIENTS AND METHODS The European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaire was sent by mail to 391 patients 1 to 12 years (median 31 months) after ASCT. The procedure was performed at our institution alone. Of the questionnaires 78% were returned and evaluated. RESULTS Of the 238 patients who had an occupation and were employed, 132 (55%) have returned full time (68%) or part time (32%) to their previous occupation. A total of 139 patients (46%) received a 3- to 4-week inpatient rehabilitation treatment in specialised institutions following ASCT. Employment status post-transplantation and QOL were similar in these patients as compared with those who did not participate in rehabilitation programmes. Of the 304 evaluable patients, 39% reported physical problems that reduced their satisfaction with sex and intimacy. The general QOL was significantly reduced in the first year, improved with interval to transplant, and reached the level of the general population after 4 years. CONCLUSIONS Our retrospective data showed that ASCT has a significant, unfavourable impact on QOL, including reintegration into social and professional life. Most symptoms and scores returned to normal after 3 to 6 years. Employment status and QOL were similar in patients who participated in a rehabilitation programme and those who did not.
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Affiliation(s)
- M Hensel
- Department of Medicine V, University of Heidelberg, Germany.
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Trendelenburg M, Gregor M, Passweg J, Tichelli A, Tyndall A, Gratwohl A. "Altered immunity syndrome", a distinct entity in long-term bone marrow transplantation survivors? Bone Marrow Transplant 2001; 28:1175-6. [PMID: 11803364 DOI: 10.1038/sj.bmt.1703300] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2001] [Accepted: 09/02/2001] [Indexed: 12/29/2022]
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Abstract
Systemic sclerosis (SS) is characterized by sclerosis of the dermis and internal organs and by vascular abnormalities. Although the pathophysiology of the disease has been partly elucidated, the efficacy of long-term treatments remains limited, with no significant increase in survival in prospective studies. Conventional drug treatments are disappointing in clinical practice, and in a recent prospective randomized study standard-dose D-penicillamine was not more effective than mini-dose D-penicillamine. New long-term treatments are emerging for diffuse SS, including cyclophosphamide for patients with progressive interstitial lung disease or stem cell transplantation for those with early organ involvement. The most effective treatments remain symptomatic, such as angiotensin-converting enzyme inhibitors for acute renal crisis, calcium channel antagonists for Raynaud's phenomenon, and proton pump inhibitors for the complications of gastroesophageal reflux. This review article focuses on long-term treatments that are most likely to be effective and suggests symptomatic treatment strategies tailored to specific organ involvements.
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Affiliation(s)
- L Mouthon
- Internal Medicine Department, Hôpital Avicenne, Université Paris-Nord, Bobigny France.
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Abstract
Remarkable advances have been made in bone marrow transplantation (BMT), which now has become a powerful strategy for the treatment of leukemia, aplastic anemia, congenital immunodeficiency disorders, and autoimmune diseases. Using various animal models, allogeneic BMT has been found to be useful in the treatment of autoimmune diseases. In MRL/lpr mice, which are radiosensitive (<8.5 Gy) and are an animal model for autoimmune disorders, conventional BMT resulted in only transient effects; the manifestations of the autoimmune diseases recurred 3 months after BMT. However, the combination of BMT plus bone grafts (to recruit donor stromal cells) was capable of preventing the recurrence of autoimmune diseases in MRL/lpr mice. This strategy was found to be ineffective in the treatment of MRL/lpr mice that had developed autoimmune diseases, because these mice were more sensitive to the effects of radiation after the onset of lupus nephritis due to uremic enterocolitis. We have recently discovered a safer strategy for treatment of autoimmune diseases, which includes fractionated irradiation (5.5 Gy x 2) (day -1) followed by portal venous injection (day 0) plus intravenous injection (day 5) of donor unfractionated bone marrow cells. We successfully treated autoimmune diseases in MRL/lpr mice using this strategy; 100% of MRL/lpr mice treated in this fashion survive >1 year after treatment. We identified the mechanisms underlying the components of this approach and have found that stromal cells play a crucial role in successful BMT. In this review, the conditions essential for successful allogeneic BMT are discussed.
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Affiliation(s)
- S Ikehara
- First Department of Pathology, Transplantation Center, Kansai Medical University, Osaka, Japan.
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Abstract
In systemic lupus erythematosus hyperactive helper T-cells drive polyclonal B-cell activation and secretion of pathogenic auto-antibodies. The auto-antibodies form immune complexes with their respective auto-antigens, which in turn deposit in sites such as the kidney and initiate a destructive inflammatory reaction. Lupus nephritis can be managed successfully in the majority of cases; however, the most widely used immunosuppressive therapies, notably corticosteroids and cyclophosphamide are non-specific and are associated with substantial toxicities. Novel treatments for lupus nephritis have to be at least as effective and less toxic than existing therapies. The ultimate aim is to develop treatments that target specific steps in the disease process. Novel therapeutic strategies in the short-term more likely will focus on refining regimens of drugs that are already in use (mycophenolate mofetil, adenosine analogues) and combinations of existing chemotherapeutic agents, as well as attempts to achieve immunological reconstitution using immunoablative chemotherapy with or without haematopoietic stem cell rescue. Several new agents targeting specific steps in the pathogenesis of lupus are in various phases of clinical development. Interrupting the interactions between T-lymphocytes and other cells by blocking co-stimulatory molecules, such as CD40 ligand or CTLA4-Ig, may interfere with the early steps of pathogenesis. Blocking IL-10 may decrease auto-antibody production and help normalise T-cell function. Treating patients with DNase or interfering with the complement cascade by blocking C5, or neutralising pathogenic antibodies by administering specific binding peptides or inducing specific anti-idiotype antibodies may prevent immune complex formation and/or deposition.
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Affiliation(s)
- G G Illei
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Building 10, Rm 9S205, Bethesda, MD 20892, USA.
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Wulffraat NM, Sanders EA, Kamphuis SS, Rijkers GT, Kuis W, Lilien M, Slaper-Cortenbach IC. Prolonged remission without treatment after autologous stem cell transplantation for refractory childhood systemic lupus erythematosus. ARTHRITIS AND RHEUMATISM 2001; 44:728-31. [PMID: 11263789 DOI: 10.1002/1529-0131(200103)44:3<728::aid-anr123>3.0.co;2-d] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Rosen O, Massenkeil G, Hiepe F, Pest S, Hauptmann S, Radtke H, Burmester G, Thiel A, Radbruch A, Heymer B, Arnold R. Cardiac death after autologous stem cell transplantation (ASCT) for treatment of systemic sclerosis (SSc): no evidence for cyclophosphamide-induced cardiomyopathy. Bone Marrow Transplant 2001; 27:657-8. [PMID: 11319598 DOI: 10.1038/sj.bmt.1702829] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2000] [Accepted: 12/14/2000] [Indexed: 12/29/2022]
Abstract
In patients with systemic sclerosis (SSc) treatment-related mortality after autologous stem cell transplantation (ASCT) appears to be increased as compared to patients with hematological malignancies. In our phase I/II study on ASCT in autoimmune diseases a patient with SSc died on day 2 after ASCT. Here we report the results of the autopsy which revealed advanced pulmonary and cardiac fibrosis as the most probable cause of death. In spite of detailed technical examination before enrollment, the cardiopulmonary function tests did not reflect the advanced stage of the disease. We conclude that in selected patients with SSc, biopsies should be performed to reduce mortality after ASCT.
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Affiliation(s)
- O Rosen
- Department of Oncology/Haematology, University Hospital Charité (Campus Mitte), Berlin, Germany
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van Laar JM. Immune ablation and stem-cell therapy in autoimmune disease. Immunological reconstitution after high-dose immunosuppression and haematopoietic stem-cell transplantation. ARTHRITIS RESEARCH 2000; 2:270-5. [PMID: 11094440 PMCID: PMC130008 DOI: 10.1186/ar101] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/24/1999] [Accepted: 02/02/2000] [Indexed: 12/29/2022]
Abstract
Studies on immunological reconstitution after immune ablation and stem-cell therapy may yield important clues to our understanding of the pathogenesis of human autoimmune disease, due to the profound effects of function and organization of the immune system. Such studies are also indispensable when linking clinical sequelae such as opportunistic infections to the state of immune deficiency that ensues after the treatment. Much has been learnt on these issues from comparable studies in haemato-oncological diseases, although it remains to be proven that the data obtained from these studies can be extrapolated to rheumatological autoimmune diseases. Preliminary results from pilot studies in various rheumatological conditions not only pointed to clinical efficacy of the new treatment modality but also unveiled marked effects on T-cell receptor repertoires of circulating T lymphocytes, on titres of autoantibodies and T- and B-cell subsets.
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Affiliation(s)
- J M van Laar
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
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Breedveld FC. Immune ablation and stem-cell therapy in autoimmune disease. Introduction. ARTHRITIS RESEARCH 2000; 2:268-9. [PMID: 11094443 PMCID: PMC130007 DOI: 10.1186/ar100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/05/2000] [Accepted: 05/05/2000] [Indexed: 12/29/2022]
Affiliation(s)
- F C Breedveld
- Department of Rhueumatology, Leiden University Medical Center, Leiden, The Netherlands
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