Review: Hematopoietic Stem Cell Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary Involvement
Year: 2016
Type: review
Abstract: Could a greater miracle take place than for us to look through each other's eyes for an instant?Henry David Thoreau As seen from both patients' and physicians' points of view, there is wide agreement that systemic sclerosis (SSc) is one of the autoimmune disorders with the highest morbidity and mortality rates. In this review, we will follow the evolution of a new approach to its treatment. Support for using hematopoietic stem cell transplantation (HSCT) for SSc arose from seminal studies of genetic and antigen-induced experimental models of autoimmune disease that demonstrated that high-dose immunosuppression followed by either allogeneic (same species) or autologous (self) bone marrow transplantation (BMT) could prevent and even reverse damage from autoimmune diseases. Three decades after these initial preclinical observations, our understanding of the therapeutic potential of immune restoration following autologous HSCT has deepened, and the clinical evidence for its application in scleroderma has broadened. In this review we will examine the outcome of conventional therapy for scleroderma lung disease; detail the techniques, toxicities, and results of HSCT for SSc; and explore the biology of immune restoration following autologous transplantation. We will compare the design and outcomes of randomized trials comparing HSCT with cyclophosphamide (CYC) treatment and formulate criteria for the timely referral of patients with scleroderma lung disease for HSCT. The heterogeneous manifestations of SSc are the result of 3 primary pathogenic processes: vasculopathy, inflammation, and fibrosis. As with the other connective tissue diseases, there is no single genetic abnormality conferring susceptibility to the disease; however, a permissive genetic environment is likely necessary for the initiation of disease. For example, there is an increased relative risk of SSc in first-degree relatives of patients with the condition, and a number of HLAs are associated with SSc, several of which correlate with specific ethnic populations or clinical features 1. Genomic analyses can differentiate normal from scleroderma skin and disclose associated fibroinflammatory and interferon (IFN)–associated gene signatures 2, 3. Among the chemokines, CXCL4 has been shown to predict the risk and progression of SSc 4. Epigenetic modification, including DNA methylation, histone modification, and microRNA expression, also appear to play roles in the pathophysiology of SSc. Phenotypic changes in SSc are driven by vascular damage, immune dysregulation, fibroblast activation, and collagen deposition 1. In a permissible genetic environment, increased circulating factors such as endothelin 1 (ET-1) promote vasoconstriction and injury to the endothelium. Vascular injury leads to a cascade of inflammatory cytokines, growth factors, and reactive oxygen species that propagate tissue damage. Platelet-derived growth factor can promote complement-directed endothelial cell injury, and aberrant transforming growth factor β (TGFβ) and ET-1 signaling appear essential for myofibroblast activation and profibrotic signaling. While SSc is a rare disease with an incidence of only 20 patients per million adults per year, it disproportionately impacts women in their 30s to 50s and is both debilitating and deadly. Independent risk factors for mortality in SSc include the presence of anti–topoisomerase I antibodies as well as pulmonary, renal, or cardiac organ involvement. Rapidity of progression of skin thickness has been shown to predict internal organ involvement and mortality 5. Meta-analysis of 40 years of publications comprising 2,691 patients with SSc has provided standardized mortality ratios (SMRs), the ratio of deaths compared to the expected deaths in the general population matched for age and sex, for the disease. Analysis showed that the pooled SMR for SSc was 3.5 (95% confidence interval [95% CI] 3.0–4.1) with little apparent change over the past 4 decades 6. Similarly, a 15-year follow-up of 398 patients with SSc enrolled between 1995 and 1999 at the Royal Free Hospital (London, UK) showed an overall SMR of 3.8 (i.e., 280% higher mortality than in the general population) 7. Patients with diffuse cutaneous SSc had a worse outcome than those with limited cutaneous disease, and women with diffuse cutaneous SSc had a remarkable SMR of 7.1. Organ (often lung) involvement denoted a much poorer prognosis compared to patients without organ complications 7. Scleroderma (either limited or diffuse) with organ involvement remains a progressively fatal disease without evidence of a survival plateau (Figure 1). Survival of patients with limited cutaneous systemic sclerosis (lcSSc) or diffuse cutaneous SSc (dcSSc) with internal organ complications enrolled at the Royal Free Hospital (London, UK). Adapted, with permission, from ref. 7. While multiple target tissues may be damaged, pulmonary involvement is the leading cause of death in SSc 8. Detection of scleroderma-associated interstitial lung disease (ILD) requires both pulmonary function testing (PFT) and high-resolution computed tomographic (CT) imaging of the lung 9. In a systematic review of 20 publications comprising 1,524 patients, diffusing capacity of the lung for carbon monoxide (DLCO) was the most consistent predictor of mortality in scleroderma lung disease, while the extent of disease on high-resolution CT imaging was an independent predictor for overall mortality and ILD progression 10. Pulmonary fibrosis on high-resolution CT and either a forced vital capacity (FVC) of <80% predicted or a decline of >10% in the FVC or a decline of >15% in the DLCO on serial measures constitute accepted indications for treatment 11. However, lung fibrosis is rarely reversible with conventional therapies. While uncontrolled case series have shown varying responses to several disease-modifying antirheumatic drugs (DMARDs) used alone or in combination, only CYC given for 1 year has been shown to be of benefit when compared to placebo administration 12. In the Scleroderma Lung Study (SLS) the degree of FVC benefit first conferred by CYC treatment was modest (2.5% mean difference in the adjusted 12-month FVC between the arms), peaked at 6 months off therapy, and was lost by 12 months off treatment 13. In a recently completed second SLS, there was comparable stabilization and improvement in FVC with a 2-year course of mycophenolate mofetil (MMF) when compared to a 1-year course of CYC 14. Moreover, MMF appeared better tolerated than CYC. Other, ongoing studies are exploring agents that inhibit fibrosis, TGFβ or Wnt signaling, and B cell activity. Several issues emerge in a review of the published literature on the treatment of scleroderma lung disease. Other than the aforementioned SLS, most trials are comprised of fewer than 30 participants and can suffer from selection and publication bias, while studies demonstrating ineffectiveness may be underreported. Most studies measure the change in percent predicted FVC, DLCO, and/or changes on high-resolution CT scans while others also include disease activity measures, such as the modified Rodnan skin thickness score (MRSS) and Health Assessment Questionnaire (HAQ) score. Few studies compare the treatment group with a control. Outside of CYC, MMF has been the next most commonly studied drug, and dosages of 2–3 gm daily were generally associated with the stability of PFT findings. However, many studies lasted only 6–12 months and a longer treatment course and follow-up may be necessary. Preclinical models of autoimmune disease published in the 1980s demonstrated a remarkable ability to prevent or reverse autoimmune disease following lymphomyeloablative conditioning and either allogeneic or autologous BMT. It was postulated that this efficacy was due to the effects of total body irradiation (TBI) ablating the host autoreactive immune repertoire, which was then replaced with normal allogeneic or autologous stem cells in the absence of the original antigenic trigger of the autoimmune disease. Genetic murine models of diabetes mellitus showed that TBI (which ablates both resting and dividing lymphoid immune cells) and allogeneic BMT could prevent subsequent development of the autoimmune disease 15. Importantly, established organ involvement in the genetic diabetes model (loss of islet cells in the pancreas) or in the lupus model (presence of immune complexes in the kidney) could be reversed after TBI and allogeneic BMT. Similar effects in a rat model of antigen-induced arthritis were observed after TBI and autologous BMT 16. In these animal experiments, myeloablative doses of TBI and CYC were significantly more effective than nonablative CYC alone in producing sustained elimination of the autoimmune disease following autologous BMT 17. By 1997, several teams had published clinical designs for HSCT for autoimmune disorders 18, 19. In the rare situation of an autoimmune disease co-existing with a hematologic malignancy, myeloablative allogeneic BMT appeared to offer long-term remission of both diseases 20. The first report of an individual undergoing successful autologous HSCT for SSc was published in 1997 21. Shortly thereafter, European registry experience showed dramatic improvement in dermal fibrosis after autologous HSCT in SSc 22. By 2009, the number of reported patients with SSc treated with autologous HSCT had reached 224 individuals in Europe 23 and 97 in North and South America 24. In these registry reports of transplants for autoimmune diseases, scleroderma was second only to multiple sclerosis as an indication for autologous HSCT. Spurred by research involving ionizing radiation following World War II, the first successful human autologous HSCT was performed in 1957. Once comprehensive worldwide registries of HSCT became available, records showed that more than 1 million individuals with malignant and nonmalignant diseases had received autologous (58%) or allogeneic (42%) hematopoietic cell transplants between January 2006 and December 2014 in 1,516 centers in 75 countries 25. During this 9-year period, there were 1,162 transplants for autoimmune diseases: 1,058 autologous and 104 allogeneic. HSCT is a multistep process involving: 1) hematopoietic cell mobilization and cell harvesting, selection, and cryopreservation, 2) preparative conditioning with chemotherapy with or without irradiation, 3) infusion of the stem cell graft, and 4) supportive care after transplantation 26-28. Mobilization of CD34+ hematopoietic stem cells from the marrow to the bloodstream is promoted by administration of hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF), with or without CYC priming. Circulating blood stem cells are then collected by leukapheresis, often in a 1-day collection. To further purify stem cells and remove differentiated lymphoid or other contaminating cells, positive stem cell selection by CD34+ isolation techniques (fluorescence or magnetic-activated cell sorting) can be used before cryopreservation of the autologous cells 28. Once thawed, cells are infused intravenously and home to the marrow. These hematopoietic stem cells are able to repopulate and differentiate into erythrocytes, megakaryocytes, and immune cells. Mediators of innate immunity, such as macrophages, granulocytes, and natural killer cells, repopulate and function early after HSCT. Adaptive immune cells, including effector and regulatory B and T cells, also recover early, while full function and immune memory return more gradually 29. Multiple regimens have been used to prepare patients to receive a transplant, ranging from nonmyeloablative conditioning (CYC 200 mg/kg) to fully lymphomyeloablative regimens (high-dose chemotherapy with or without TBI). For the less intensive regimens, most patients can be cared for in outpatient "day hospitals" while residing in apartments near the transplant center. Others remain inpatient until blood counts have engrafted. Sustained granulocyte recovery occurs 10–12 days after transplantation, and most patients return home shortly thereafter. While at the center, family or friends assist as accompanying caregivers, a vital role in the recovery of the patient. Complications associated with autologous HSCT include preparative regimen–related organ toxicity, opportunistic infections, infertility, recurrence of disease, and secondary malignancies 30. Autologous transplantation–related mortality is ∼3–5% for patients with myeloma and lymphoma and ∼5–10% for those with scleroderma 23, 28, 31, 32. Transplantation is an intensive procedure with significant side effects including nausea, vomiting, diarrhea, and oral mucositis, which usually resolve with blood count recovery. Organ toxicity may be due to the preparative regimen and any underlying organ damage from SSc. Reports of acute kidney injury led to the use of several scleroderma-specific renal protective regimens 33, 34. Gastrointestinal endoscopy has revealed gastric antral vascular ectasia (GAVE) in 22% of scleroderma patients screened before HSCT 35. Coagulation therapy of the GAVE lesions has been important in preventing hemorrhage during thrombocytopenia. All referred patients with scleroderma ILD will have diminished PFT findings. For safety, most centers exclude individuals with an FVC or DLCO of <45% predicted, although the lower limits are difficult to assess given other comorbidities 36. Conditioning regimens include varying doses of CYC, which can be associated with acute cardiotoxicity that appears to be dose- and schedule-dependent. At a normally tolerated CYC dose of 200 mg/kg given before transplantation, cardiac deaths have been reported, which raises the question of additional comorbidity from existing SSc-related heart disease 31. Opportunistic infections are the leading cause of mortality after HSCT for autoimmune diseases 23. While neutrophils recover within 2 weeks of transplantation, other components of immune recovery may take up to 6–24 months 29. That said, total infections and serious infections (i.e., those treated as an inpatient) cluster within the first month after autologous HSCT. In 4 time intervals (days 0–30, days 31–180, days 181–365, and days 366–730), the rates of total/serious infections were 5.75/4.90, 0.94/0.54, 0.29/0.05, and 0.16/0.08, respectively, among 56 individuals who were treated with CYC, TBI, and antithymocyte globulin (ATG) before autologous HSCT for autoimmune disease 29. Prevention of infection after transplantation is becoming increasingly refined since the introduction of sensitive polymerase chain reaction assays for a number of viral pathogens 37. While allogeneic HSCT for autoimmune disease has been reported, most centers have focused on autologous transplantation, where fewer complications are observed. Consensus conferences were held in Basel and Seattle to establish frameworks for clinical trials and reporting 18, 19. Follow-up studies refined the pretransplant conditioning regimens. Protocols enrolled high-risk scleroderma patients with internal organ involvement but for safety reasons excluded individuals with severely compromised organ function 38. Results of initial pilot trials demonstrated dramatic improvement in skin scores and quality-of-life measures with stabilization of pulmonary function 22, 23, 39. Figure 2 depicts outcomes in 34 patients with SSc with up to 8 years of follow-up after a phase II trial of myeloablative autologous HSCT 39. Before transplantation, mean measures for the cohort included an MRSS of 30.1, a modified HAQ score of 1.85, FVC of 71% predicted, and DLCO of 60% predicted. Over time, there were significant and durable improvements in the MRSS and HAQ, with stabilization of or modest improvement in FVC and DLCO. Results after total body irradiation, cyclophosphamide and antithymocyte globulin preparative conditioning, and CD34+ selected autologous hematopoietic stem cell transplantation in 34 patients with severe scleroderma 39. A, Modified Rodnan skin thickness score. B, Forced vital capacity. C, Diffusing capacity for carbon monoxide (DLCO). D, Quality of life measures (modified Health Assessment Questionnaire). Solid black lines show the mean; broken lines represent the generalized estimating equation; gray lines represent individual patient values. While encouraging, pilot studies underscored the need to control for potential selection or reporting biases by conducting prospective, randomized clinical trials comparing HSCT to CYC (the only DMARD shown to be of benefit in a controlled trial of scleroderma lung disease). Results from the randomized clinical trials the American Scleroderma Stem Cell versus Immune Suppression Trial (ASSIST) 40 and the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) 32 trial have been published, while the Scleroderma: Cyclophosphamide or Transplantation (SCOT) randomized trial results will be available in late 2016 after the last enrolled subject is evaluated at the 54th month primary end point. Table 1 details these 3 controlled studies. As shown, there are both similarities (inclusion and exclusion criteria) and differences (primary end points, preparative regimens, stem cell mobilization and selection techniques, and length of follow-up) across the trials. Most randomized subjects had scleroderma with internal organ involvement (predominantly lung), although the ASTIS trial enrolled high-risk subjects with only skin disease late in the study 5, 32. High-dose CYC was used for both stem cell mobilization and preparative conditioning in the nonmyeloablative ASSIST and ASTIS trials. In contrast, the SCOT trial mobilizes with G-CSF alone, uses a lower dose of pretransplant CYC, and uses TBI conditioning, which is fully lymphomyeloablative. A significantly higher dose of CYC before transplantation may account for reported cardiotoxicity in the nonmyeloablative scleroderma trials 31. In the single-center ASSIST trial, all patients in the CYC arm failed to respond to and all patients who received HSCT has been the number of patients, of and design Figure 3 depicts overall survival and survival of organ in the ASTIS As mortality was higher in the first year after transplantation. The at 2 years and HSCT was to CYC for both survival and overall survival 32. Table 2 morbidity outcomes in the ASTIS Rodnan FVC, total lung capacity and were all significantly after HSCT compared to and these improvements were to serial after CYC. to their HSCT had improvement over time in FVC and CYC had in pulmonary function over The differences in and DLCO for the 2 were As there were more 3 with but there were no significant differences in 4 Results from the Autologous Stem Cell Transplantation International Scleroderma trial comparing CD34+ selected autologous hematopoietic stem cell transplantation (HSCT) after conditioning with cyclophosphamide (CYC) and antithymocyte globulin to 12 months of CYC treatment 32. A, Survival of organ B, SSc is an aberrant activation of the and innate immune several factors have been in these outcomes with HSCT. In both allogeneic and autologous stem cell of doses of immunosuppression to patients with autoimmune disease. transplants a new immune from a normal stem cell 20. However, clinical experience with allogeneic transplants for autoimmune disease is limited to with autologous HSCT with to long-term control of the autoreactive disease. Autologous HSCT could the host immune to a in time when the antigenic of were of this is the that and often after autologous HSCT. In of TBI conditioning and autologous the T cell was shown to after and autologous transplantation in of autologous HSCT is also by on a of the among memory cells, and recovery of normal T cells. individuals who respond to autologous transplantation had less T cell early after immune recovery Patients with SSc have diminished cell of human cells has also been observed after autologous HSCT In a murine BMT model of the genetic of the bone marrow was between host and for the T cell cell of were shown to a immune human HSCT for arthritis and of cells was after autologous HSCT with evidence of a more and B this immune restoration after autologous HSCT. Immune following autologous hematopoietic stem cell transplantation A and B, T cell in cells after autologous HSCT in a patient with autoimmune disease and in 4 The number of per and where and 1 before and after transplantation are Adapted, with permission, from ref. and D, of autologous HSCT results in immune and immune C, of results in the death of autoreactive and after 1. The of regulatory T and B cells, both to or effector T and B cells, are increased D, of B cells and regulatory cells autoreactive during immune recovery. The in cell as immune is of and cell signaling in SSc are through studies associated with the SCOT For example, compared to and blood from SCOT patients showed of the signaling compared to their HSCT significant in the score at month In contrast, CYC had no change over time These could further the that autologous can be associated with restoration of immune B cell and of have been in patients with SSc Patients treated with autologous HSCT have B cell recovery associated with a decline in In to a B cell that can for regulatory B cells likely after autologous HSCT. cells have been to be for SSc in murine these that immune can be with HSCT. and a model of autologous HSCT results in immune and immune on the the following criteria as indications for referral for HSCT in patients with SSc. criteria include diffuse cutaneous SSc with internal organ age disease MRSS early pulmonary involvement by and FVC or DLCO between and predicted or a decline in FVC of >10% or DLCO of >15% on serial testing or to respond to initial therapy on serial PFT criteria include FVC or DLCO of <45% predicted, pulmonary cardiac with SSc, renal and CYC treatment of to the application of HSCT for autoimmune disease include in and referral Patients transplants for scleroderma fewer to more individuals have and published randomized trials have shown significant clinical benefit with HSCT referral can also be a as demonstrated by patients' for transplantation Patients to of the as well as the potential long-term with HSCT. However, may be with the details of a treatment their or be the associated for mortality in SSc is the individuals for stem cell transplantation. A new of in scleroderma lung disease can be to the evolution of arthritis Once mortality in was demonstrated of a autoimmune became an disease for the such has been in mortality rates greater than in the general then it is even more in scleroderma lung disease, which has mortality rates of greater than expected 7. While and agents may initial improvement on the for both patients and is the on the mortality associated with scleroderma lung disease. the ASTIS trial has demonstrated long-term survival and survival after for stem cell transplantation referral is a but requires PFT before pulmonary severe for transplantation. In such an and it is that the timely referral to a transplant for and of the techniques, toxicities, and outcomes of HSCT. patients will be without the and to this is a of and patient to the of treatment in of the situation and While there are often multiple manifestations of SSc, lung disease is the cause of conventional show modest the published literature on SSc a pooled SMR of 3.5 in with little change over decades of mortality remains of to patients and The for stem cell transplantation in SSc arose from animal that HSCT could prevent and reverse organ damage in genetic and antigen-induced models of autoimmune disease. studies have revealed that benefit in from the autologous stem cells of the repertoire, cells, and disease signatures of In the absence of the original antigenic immune is and can the of autologous HSCT the in autoimmune diseases with associated but for scleroderma lung disease the appear in multiple phase II reports from Europe and the dramatic and durable improvements in skin fibrosis and quality-of-life measures have been observed with stabilization of Three prospective, randomized clinical trials in patients with SSc and internal organ involvement have compared autologous HSCT treatment to high-dose CYC given for up to 12 The SCOT trial is following up all subjects through the primary end but as the ASSIST and ASTIS randomized trials have been completed and both showed significant clinical after stem cell transplantation. the morbidity and mortality in SSc patients with organ it appears to for HSCT and of scleroderma research and transplant centers are available and By to transplantation, patients will be more mortality risk for long-term be of and fully in the for referral to the HSCT are given but of pulmonary function is for timely During the transplantation the and are with the evidence HSCT as treatment for scleroderma lung disease. patients will transplantation and others will such as Thoreau can be reached as patients and look through each other's only for an We for All were in the and it for important and all the to be
Source: Arthritis & Rheumatology
DOI: 10.1002/art.39748
Authors: Keith M. Sullivan, Ankoor Shah, Stefanie Sarantopoulos, Daniel E. Furst
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,190
OpenAlex ID: W2395716661