Diffuse and limited cutaneous systemic scleroderma

Juvenile systemic scleroderma (jSSc) is a rare disease. Based on the first large data collection on this patient group, the disease course was demonstrated to differ from that in adults. The concept of persistence of maternal cells in patients with SSc remains pathogenetically fascinating, as does the resemblance with graft-versus-host-disease. In view of new therapeutic options, controlled trials have not established a gold standard for treatment, but autologous bone marrow transplantation may be considered a rescue therapy for selected patients. Palliative therapies have also improved markedly in recent years. The first controlled trials for patients with jSSc are being proposed.     

Haematopoietic stem cell transplantation in the treatment of autoimmune diseases

PURPOSE: During the past ten years, more than 1000 patients suffering from severe autoimmune disease have received an autologous haematopoietic stem cell transplant. These new therapeutic have been used in systemic sclerosis (scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus. CURRENT KNOWLEDGE AND KEY POINTS: Autologous haematopoietic stem cell transplantation has become a curative option for condition with very poor prognosis as severe systemic sclerosis, lupus erythematosus or other systemic diseases. This review summarizes the current experience in the phase I and II clinical trials in Europe and North America. We describe the main results and the limits of stem cell transplantation in systemic diseases. FUTURE PROSPECTS AND PROJECTS: Autologous haematopoietic stem cell transplant in the treatment of autoimmune disease has evolved from a experimental concept to a clinically feasible and powerful therapy for selected patients with severe disease.     

Systemic sclerosis and localized scleroderma in childhood

Juvenile scleroderma syndromes, including the systemic and the localized varieties, represent the third most frequent chronic rheumatic conditions in pediatric rheumatology practice. In children, systemic sclerosis shows a significantly less frequent involvement of all organs, a higher prevalence of arthritis and myositis, and a better outcome than in adults. Recently, new classification criteria were proposed, which help improve patient care by enabling earlier, more definite diagnoses and by standardizing the conduct of clinical trials. Localized scleroderma is the more frequent subtype of scleroderma in childhood. It comprises a group of distinct conditions that involve mainly the skin and subcutaneous tissues. They range from small plaques of fibrosis involving only the skin to diseases causing significant functional deformity with various extracutaneous features.     

Role of autologous stem cell transplantation in chronic lymphocytic leukemia

Autologous hematopoietic stem sell transplantation is increasingly considered for treatment of patients with high-risk chronic lymphocytic leukemia. Patients not eligible for allogeneic hematopoietic stem cell transplantation with poor prognosis disease, documented chemosensitivity, and a minimal tumor burden at the time of hematopoietic stem cell transplantation can be treated with autologous hematopoietic stem cell transplantation currently using peripheral blood stem cells. Different purging methods to obtain sources of stem cells free of tumor contamination are currently being evaluated. Major concerns are judicious selection of which patients may benefit from this approach, the subsequent risk of relapse of disease, and the long-term risk of development of secondary malignancies, including myelodysplastic syndrome and acute myelogenous leukemia. Recognizing and reducing the risk factors that contribute to relapse and complications of the procedure should improve outcome after autologous hematopoietic stem cell transplantation. With the increasing use, increasing effectiveness, and low treatment-related mortality associated with nonmyeloablative conditioning regimens, the question of whether a patient should be offered autologous or allogeneic hematopoietic stem sell transplantation can be a difficult one. Defining salvage settings for relapse and implementing a tandem autologous/allogeneic hematopoietic stem cell transplantation approach may provide a method to improve outcome for selected patients.     

Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation

Autologous stem cell transplantation with or without in vitro lymphocyte depletion has been suggested as a new treatment option for severe autoimmune diseases. We describe five patients with autoimmune diseases (CREST syndrome, myasthenia gravis and Hashimoto's thyroiditis, systemic lupus erythematosus, atopic dermatitis, and rheumatoid arthritis) who underwent autologous bone marrow (n = 1) or peripheral blood progenitor cell (n = 4) transplantation with unmanipulated grafts as treatment for the autoimmune disease in one case or as treatment for a malignant disorder with a concomitant autoimmune disorder in four cases. In all patients serological and clinical signs of the autoimmune disease recurred early or persisted. These observations should be regarded as a cautionary note concerning the efficacy of high-dose therapy followed by transplantation of unmanipulated autologous stem cells for treatment of severe autoimmune diseases.     

Autologous and allogeneic transplantation with peripheral blood CD34+ cells: a pediatric experience

BACKGROUND AND OBJECTIVE: Peripheral blood stem cells (PBSC) have replaced bone marrow (BM) as the primary form for autologous hematopoietic stem cell transplantation. Furthermore, the use of allogeneic PBSC transplantation is now rapidly expanding and several centers have adopted this procedure. A new strategy in the use of PBSC is positive selection of CD34+ hematopoietic progenitor (CD34+) cells, and indeed large-scale devices for the clinical exploitation of CD34+ cell selection are now commercially available. In the autologous setting, the primary advantage of using CD34+ selected PBSC is reduced tumor cell contamination during PBSC preparation. On the other hand, in the allogeneic setting, CD34+ selection methods are used to reduce the incidence and severity of GvHD. Initial trials of CD34+ selected PBSC transplants have mainly been performed in adult cancer patients, and experience with CD34+ selected PBSC transplantation in pediatric populations is still limited. The purpose of this review is to clarify the status of CD34+ selected PBSC transplantation in the pediatric population. EVIDENCE AND INFORMATION SOURCES: All authors of the present review work in the field of pediatric stem cell transplantation and in a stem cell processing laboratory, and have contributed to original papers published in peer-reviewed journals. The materials examined in the present review include articles and abstracts published in journals covered by the Science Citation Index and Medline. However, since there is still limited experience with CD34+ cell selection in pediatric populations, information on experience in adults will be discussed regarding the CD34+ cell-selection procedures and transplantation. Pediatric experience with transplants with CD34+ selected cells will be presented and discussed primarily based on our own experience. Specific problems related to PBSC mobilization and collection in children will also be discussed. STATE OF THE ART: A review of the literature shows that with current CD34+ selection methods, purity of the CD34+ cell fraction can range from 30% to 90%, and two to three logs of T-cell depletion can be achieved. Tumor cell contamination has not yet been fully evaluated. The clonogenic activity of progenitor cells after CD34+ selection from PB remains high. Transplantation of autologous selected CD34+ cells from PBSC gives prompt and stable engraftment. The long-term therapeutic efficacy should be evaluated with regard to tumor recurrence. Allogeneic CD34+ selected cells successfully engraft immunomyeloablated recipients though a mega-cell dose effect between HLA-matched pairs. The results of allogeneic CD34+ selected cell transplantation from HLA-mismatched donors are, so far, not satisfactory because of the high rate of rejection, severe infectious complications and relapse of the disease. CD34+ selection may also be used as a target of gene therapy, as a source of dendritic cells for cancer immunotherapy and for the treatment of patients with autoimmune disease.     

Juvenile scleroderma

Juvenile scleroderma is a rare childhood condition characterized by fibrosis of the skin and internal organs. Clinical manifestations of childhood scleroderma are different from adult disease and early recognition, correct classification and treatment can improve long-term outcome. This review explores the most recent actualizations on clinical manifestations, classification criteria, treatment options and prognosis of juvenile scleroderma. There are two main forms of the disease: localized scleroderma and systemic sclerosis. Localized scleroderma is the most common form in children and mostly restricted to the skin. Juvenile diffuse systemic sclerosis is related to visceral involvement and cardiac disease which is the main cause of death in these patients. The outcome of juvenile systemic sclerosis is better compared with the adult form. Treatment remains a medical challenge and the EULAR task force proposed an approach to juvenile scleroderma treatment based on expert's opinion and guidelines used for the treatment of adults. Larger studies on childhood scleroderma are warranted.     

Therapeutische Strategien im Frühstadium der systemischen Sklerose

Increasing knowledge about the rare disease systemic sclerosis and improved diagnostic methods in the course of recent decades has led to the possibility of diagnosing systemic sclerosis at earlier disease stages. However, earlier diagnosis has an impact on routine clinical care of affected patients, and rheumatologists need to know about early symptoms, their diagnosis, and clinical management. In this review, the therapeutic management of early disease stages is described. In particular, we focus on diagnostic tools which should be included in a “basic assessment” of systemic sclerosis and discuss the diagnosis and treatment options of early symptoms such as Raynaud phenomenon, puffy fingers and hand edema, digital ulcers, calcinosis cutis, and cardiopulmonary, renal, and gastrointestinal involvement. Finally, the options of early immunosuppressive treatment and autologous stem cell transplantation for patients with rapid progressive and severe disease are reviewed.     

Scleroderma--clinical and pathological advances

The spectrum of scleroderma spans Raynaud's phenomenon, localized forms of skin fibrosis and the clinically most important forms of systemic sclerosis that involve inflammatory, vascular and fibrotic pathology. A closer relationship between these disparate conditions is now appreciated, and skin sclerosis is no longer regarded as mandatory for the diagnosis of systemic sclerosis. There have been recent and substantial changes in disease classification, the appreciation of its natural history and the investigation and treatment of organ-based complications. Although scleroderma still has a high case-specific mortality, there have been major improvements in the management of renal and pulmonary disease, and areas such as gastrointestinal tract involvement can also often be improved. Each of these areas is reviewed, and progress in understanding pathogenesis also described. The management of organ-based complications has benefited from advances in other branches of medicine. Angiotensin-converting enzyme inhibitors for scleroderma renal crisis, proton pump inhibitors for reflux oesophagitis and advanced therapies for classes III and IV pulmonary arterial hypertension exemplify progress in the treatment of systemic sclerosis. There is also the prospect of targeted, cytokine-directed treatments that may for the first time offer the prospect of genuine disease-modifying intervention in early-stage disease. In parallel with these developments, there has been substantial progress in disease assessment with the construction and initial validation of tools to assess skin biomechanics, functional impairment and the severity and activity of systemic sclerosis. It is likely that clinical trials performed over the next few years will transform the management of systemic sclerosis and help to dispel its reputation as one of the least treatable of the autoimmune rheumatic diseases.     

Long-term endoscopic remission of crohn disease after autologous stem cell transplantation for acute myeloid leukaemia

A favourable course of Crohn disease has been observed after allogeneic bone marrow transplantation. and there is now mounting evidence that autologous stem cell may be an effective treatment for severe autoimmune diseases. Here, we present the first long-term endoscopic follow-up of a patient with Crohn disease undergoing autologous stem cell transplantation for haematological disease. A 54-year-old woman developed Crohn disease and was submitted to ileocaecal resection. Four months after surgery, the patient contracted acute myeloid leukaemia. She was initially treated with chemotherapy, and subsequently underwent autologous stem cell transplantation. Following transplantation, the patient has remained in clinical remission regarding both diseases, without anti-inflammatory medication. She has undergone ileo-colonoscopy with normal findings at 1, 2, 3 and 5 years after transplantation. This case suggests that autologous stem cell transplantation can change not only the clinical course, but also the natural history of intestinal inflammation in Crohn disease. This has pathophysiological as well as therapeutic implications.     

Long-term Endoscopic Remission of Crohn Disease after Autologous Stem Cell Transplantation for Acute Myeloid Leukaemia

A favourable course of Crohn disease has been observed after allogeneic bone marrow transplantation, and there is now mounting evidence that autologous stem cell may be an effective treatment for severe autoimmune diseases. Here, we present the first long-term endoscopic follow-up of a patient with Crohn disease undergoing autologous stem cell transplantation for haematological disease. A 54-year-old woman developed Crohn disease and was submitted to ileocaecal resection. Four months after surgery, the patient contracted acute myeloid leukaemia. She was initially treated with chemotherapy, and subsequently underwent autologous stem cell transplantation. Following transplantation, the patient has remained in clinical remission regarding both diseases, without anti-inflammatory medication. She has undergone ileo-colonoscopy with normal findings at 1, 2, 3 and 5 years after transplantation. This case suggests that autologous stem cell transplantation can change not only the clinical course, but also the natural history of intestinal inflammation in Crohn disease. This has pathophysiological as well as therapeutic implications.     

The combination topotecan, temozolomide and dexamethasone associated with radiotherapy as treatment of central nervous system myeloma relapse

A 46-year-old woman with IgA-λ myeloma in partial remission, after a tandem autologous hematopoietic stem cells transplantation, complained of progressive lower back pain associated with paraplegia and neurological bladder 6 months after the second transplant. A lumbar puncture revealed atypical malignant plasma cells in the cerebral spinal fluid associated with multiple foci of altered signal intensity of brain and spinal cord demonstrated by magnetic resonance. Considering the lack of efficacious chemotherapies for neurological myeloma, an experimental systemic treatment with topotecan, temozolamide, and dexamethasone associated with concurrent radiotherapy of brain and spinal cord was initiated. During this treatment, the patient rapidly improved with disappearance of back pain, paresthesia, and urinary incontinence lasting 5 months, before dying of progressive disease. The proposed systemic chemotherapy associated with concurrent radiotherapy may have an antitumor activity against MM with CNS involvement.     

Recurrence of Autoimmune Disease after Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma

There have been a number of reports on the improvement of concomitant autoimmune disease (AID) after autologous hematopoietic stem cell transplantation (SCT) performed for hematologic malignancy. However, in some cases of hematologic malignancy with AID, exacerbation of AID after autologous SCT has been reported. We have treated 27 adults with multiple myeloma with single or tandem autologous SCT. After peripheral blood stem cells were collected and stored without CD34+ cell selection or T-cell depletion, all patients received melphalan (200 mg/m²) as a conditioning regimen. In 2 patients with a history of AID (one with rheumatoid arthritis [RA] and the other with bullous pemphigoid [BP]) and in 1 patient with Sjögren syndrome, AID recurred 7 to 12 months after autologous SCT.The RA and BP were in durable remission before SCT, and no Sjögren syndrome-related disease activity was clinically documented at the time of SCT. No progression of the myeloma was observed when the AIDs recurred.The patients required systemic steroid therapy for their AID, and successful control of the disease was achieved. Our experience suggests that autologous SCT with unmanipulated stem cells for myeloma is unlikely to cure preexisting AID; rather, the AID may worsen. Transplantation physicians should be aware of this possible complication.     

Long-term follow-up after nonmyeloablative allogeneic hematopoietic stem cell transplantation for systemic sclerosis

Systemic sclerosis (SSc) characteristically consists of fibrotic changes in various organs, and immunological abnormality is the main cause of the disease. Although high-dose immunosuppressive therapies with autologous or allogeneic hematopoietic stem cell support can reverse the disease course, they have a high treatment-related mortality. We report the successful use of nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for SSc. A 40-year-old woman with diffuse scleroderma and interstitial pneumonia underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling after conditioning with low-dose total-body irradiation and fludarabine. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and mycophenolate mofetil. No infection or acute GVHD developed. One year after transplantation, the patient developed membranous glomerulopathy caused by chronic GVHD that was successfully treated with prednisolone. The patient's skin score decreased dramatically, and her pulmonary function is stable 4 years after transplantation. Nonmyeloablative allogeneic HSCT may be more effective than conventional therapies for SSc.     

Hematopoietic cell transplantation for acute lymphoblastic leukemia in adult patients

Acute lymphoblastic leukemia (ALL) consists of precursor B ALL or T ALL phenotypes. In the pediatric population, ALL patients enjoy an 80% long-term survival with the current pediatric chemotherapy protocols as compared with 50% long-term survival in the adult population. In adults, complete remission rates are similar to those of pediatric patients; however, long-term survival is much lower with the majority of deaths attributable to relapsed disease. Postremission consolidation strategies in adults include chemotherapy, autologous, or allogeneic transplant. Pediatric-inspired chemotherapy protocols are being explored as a consolidation modality in adults. Assigning patients to either modality depends on patient and disease characteristics. Here, we review the literature on the use of hematopoietic cell transplantation as a consolidation modality in the treatment of adult ALL.     

Therapy for immunoglobulin light chain amyloidosis: the new and the old

An accurate diagnosis of amyloidosis and its subtype classification are essential for disease prognostication and treatment. In primary amyloidosis, overall median survival is approximately 2 years and may be less in patients with cardiomyopathy. Current therapy for primary amyloidosis is suboptimal. Controlled studies suggest that treatment with melphalan and prednisone may provide marginal survival benefit. A more aggressive approach such as autologous hematopoietic stem cell transplantation may offer potential for long-term benefit. Although patients undergoing autologous hematopoietic stem cell transplantation are highly selected, response rates can approach 60%, and patients with amyloidosis who respond to treatment have potential for long-term survival. New treatment modalities that were shown to have antitumor activity in multiple myeloma (high-dose dexamethasone and thalidomide) may also be of therapeutic value in primary amyloidosis. Systemic chemotherapy would not be expected to have any beneficial effect on other forms of amyloid and carries significant risk.     

A case of disseminated histoplasmosis following autologous stem cell transplantation for Hodgkin's lymphoma: an initial misdiagnosis with a false-positive serum galactomannan assay

Abstract: Systemic histoplasmosis is uncommonly reported in patients who have undergone bone marrow or solid organ transplantation. Diagnosis of systemic histoplasmosis in recipients of transplants may be hampered by lack of consideration of this infection in the differential diagnosis and may be confounded by conflicting information from other testing performed to evaluate for opportunistic infections in this population. We report successful treatment of a case of disseminated histoplasmosis in a patient with Hodgkin's lymphoma who had undergone autologous stem cell transplantation. The diagnosis was delayed by the finding of a positive serum galactomannan assay.     

Second autologous stem cell transplant for multiply relapsed Hodgkin's disease

Therapeutic options for patients with Hodgkin's disease who relapse after high-dose chemotherapy with autologous stem cell support are limited. Salvage chemotherapy is not curative, and allogeneic stem cell transplantation in this setting is associated with mortality rates of 40-65%. We report our institution's experience with second autologous transplants in this patient population. Five patients (median age 36) with relapsed Hodgkin's disease underwent a second autologous stem cell transplant at a median of 66 months after first transplant. Four patients received CBV, and one patient received BuCy as conditioning. Neutrophil and platelet engraftment occurred by days +10 and +16, respectively. All patients achieved a complete response, and no relapses have occurred after a median follow-up of 42 months. All four patients who received CBV developed interstitial pneumonitis, and two patients died of pulmonary complications 37 and 48 months following second transplant. Three patients remain alive and disease-free 41, 42 and 155 months after second transplant. These data indicate that second autologous transplantation should be considered for selected patients who relapse after a prolonged response to first autologous transplant. However, BCNU pneumonitis is the major toxicity in patients who have undergone previous mantle radiation and received busulfan with first transplant.     

Treatment of systemic sclerosis

Proper classification of patients into diffuse cutaneous and limited cutaneous subsets and the anticipation of complications are the keys to the management of individuals with systemic sclerosis (scleroderma). Patients with early diffuse disease and rapidly progressive skin thickening are at highest risk to develop serious internal organ involvement (intestine, lung, heart, kidney) and should be considered for disease modifying therapy. The targets of the disease and sites of possible intervention are vascular endothelium (vasoprotection agents), mononuclear cell subsets (immunosuppressive agents), and fibroblasts (colchicine, D-penicillamine). A number of new therapeutic agents with sound scientific rationale are undergoing therapy trials. Much can be done to improve the lifestyle of the scleroderma sufferer. The most dramatic recent development is the ability to reverse kidney involvement with prompt use of angiotensin converting enzyme inhibitors and modern methods of renal dialysis and transplantation. Scleroderma is not a hopeless disease.     

Review for best practice in clinical rheumatology juvenile systemic sclerosis – Updates and practice points

Juvenile systemic sclerosis (jSSc) is a rare, severe autoimmune disease associated with life-threatening multiorgan inflammatory-driven fibrosis. Recognition early in the disease process, when treatment is more effective, is critical. We outline insights from the authors, who specialize and host jSSc cohorts, combined with recent literature review combining available juvenile-onset and applicable adult-onset studies regarding SSc evaluation, which can be extrapolated to children. Practice tips are provided for each main organ system.