As of December 2017, the US Food and Drug Administration (FDA) has approved 15 drugs considered as capable of modifying MS course: 5 interferon-beta preparations; two glatiramer acetate preparations; the monoclonal antibodies natalizumab, alemtuzumab, daclizumab and ocrelizumab (the first B-cell targeted therapy); the chemotherapeutic agent mitoxantrone; and small molecule oral agents fingolimod, dimethyl fumarate and teriflunomide. Dalfampridine (aminoperidine) has been approved as a therapy to treat and improve gait speed.21 However, none of these are curative therapies. They are partially effective in reducing relapse rates and disease progression. Furthermore, all disease-modifying therapies present safety concerns, with the risk increasing over time. Better treatment strategies are required for patients with relapsing MS, for those who present inflammatory activity despite the treatment used and for those with treatment side effects.27

Since the mid-1990s, with the first studies on animal models with subsequent clinical application, autologous transplantation (AHSCT) has been an important tool in inducing an “immunotolerant” immune reconstitution.2,3 Thousands of transplants for treating MS have been performed worldwide, with more than 700 evaluated in studies.6,28–46 Some studies showed progression-free survival of more than five years,39,43 with superior neurological improvement in patients with relapsing-remission type and in those with inflammatory activity observed on magnetic resonance imaging.43,47,48Table 2 shows the results of the main studies focused on the use of HSCT to treat MS: there are 8 retrospective studies and 6 single-arm clinical trials on AHSCT for MS, and only 2 randomized clinical trials focusing on the comparison of AHSCT versus disease-modifying therapies for MS. There are also 3 meta-analysis and systematic reviews and one position paper.6,9,10,39,49–57

These studies together support the efficacy of AHSCT in patients with relapsing form of MS. Although they differed in design, population, conditioning protocol and only two were randomized with a control group, many patients experience disease activity control for a long time. The largest retrospective study was a review from the CIBMTR/EBMT register in 2017 that analyzed 281 patients.53 Overall progression-free survival rate was 46%; among patients with RRMS or PRMS, progression-free survival rates were 82% at 3 years and 73% at 5 years; OS at 5 years was 93%. Factors associated with neurologic progression post AHCT was older age, progressive versus relapsing form of MS and more than two previous disease modifying therapies (DMTs).

All the single-arm35,58–63 clinical trials demonstrated high efficacy of AHSCT for RRMS or PRMS. The first reported was by Burt et al., with 21 patients with RRMS conditioned with cyclophosphamide plus rabbit ATG/alemtuzumab, showing a EDSS progression free survival at 3 years of 100% and EDSS improvements ≥1 in 81% and no change in 9.5%, OS of 100%.59 Recently Moore at al. reported 35 patients with RRMS and SPMS in a phase 2 study conditioned with BEAM and horse ATG showing a MS activity-free survival of 82% at one year 65% at 2 years and 60% at 3 years; looking at RRMS only the MS activity-free survival was 90% at one year and 70% at 3 years.63

Only two randomized controlled trials are available: in the ASTIMS study, Mancardy et al. compared AHSCT versus mitoxantrone; 9 out 21 were randomized to AHSCT.52 They were conditioned with BEAM plus rabbit ATG. Over 4 years, the median number of new T2-weighted MRI lesions was 2.5 in the AHSCT versus 8 in the mitoxantrone group (p=0.00016) and none of those who received AHSCT had new gadolinium-enhanced MRI lesions, but 56% of those on mitoxantrone had at least 1 MRI lesion (p=0.029); EDSS progression was 57% in AHSCT vs 48% in the mitoxantrone group (p=0.50). The phase 3 MIST trial55 compared the efficacy of AHSCT versus DMTs. The conditioning was non-myeloablative, with cyclophosphamide plus rabbit ATG and 110 patients were randomized 1:1. With a follow-up of up to 5 years, disability worsening occurred in 5.8% AHSCT versus 66.7% of DMT group. At 1 year, relapse occurred in 2% in the AHSCT and 68.2% in the DMT group 9; with p<0.001 and at 5 years, relapse occurred in 15.4% AHSCT vs 85.2% DMT group; no deaths or grade 4 toxicities related to transplantation were reported.

A meta-analysis of AHSCT for MS evaluated the safety and efficacy of transplant. Led by Somani at al., it evaluated 15 studies including more than 764 transplanted patients. A proportion of NEDA (no evidence of disease activity) was found in 2 years in 83% and in 5 years 67%; the transplant-related mortality was estimated in 2.3%, the rate of EDDS progression was 17.1% at 2 years and 23.3% at 5 years.54 Another interesting study done by Sormani et al.64 evaluated a comparison of NEDA status in studies of AHSCT (n=66) with various conventional e high-efficacy MS DMTs (n=216). The use of AHSCT led to NEDA rates of 78–83% at 2 years and 60–68% at 5 years. On the other hand, DMTs lead to reported NEDA rates of 13–46% at 2 years.

Transplant-related mortality (TRM) has improved over the past 20 years.14,54 The initial reports described TRM as high as 9.5% (37, revised in 65), which later decreased to 1.3%, according to EBMT data.6,9 The incorporation of less myeloablative regimens, center experience and center accreditation have contributed to the improved outcomes.8,59,65–68

Recently the American Society of Bone Marrow Transplantation50 has conducted a comprehensive literature review, including many of the papers already discussed here, and recommended autologous HSCT as “standard of care, clinical evidence available” for treatment-refractory relapsing MS.

Considering the results presented above, HSCT can be considered for patients with relapsing-remitting form of MS, with EDSS less than 6, who have not responded to conventional treatment or progressive MS with superimposed activity. Especially if disease activity continues despite treatment with high-efficacy DMTs and worsening disability. The treatment for other MS types should follow the guidelines proposed by SBMTO previously,69 shown in Box 1 and Box 2, and using the same reduced-intensity conditioning with cyclophosphamide (200mg/kg) and rabbit anti-thymocyte (4.5mg/kg). Intensive vigilance should be maintained for short and long-term post-transplant complications, especially fever, deep vein thrombosis, pulmonary embolism, urinary tract infections, falls, metabolic syndrome and coronary disease.65,70

Skin involvement is a hallmark of SSc, and its extent enables clinical classification into three subtypes: limited, diffuse and sine scleroderma (without cutaneous involvement). The extent of skin involvement correlates with disease presentation and severity. Patients with the diffuse form of SSc suffer from interstitial lung disease, cardiac and renal involvement more frequently.72 This subtype tends to progress faster and with greater severity, morbidity and mortality than other forms of the disease.72,76,77 On the other hand, limited systemic sclerosis patients tend to present pulmonary hypertension as a life-threatening manifestation.

The management of patients with systemic sclerosis (SSc) includes pharmacological and non-pharmacological approaches.78 Hand and extremity warming and protection against trauma, dietary and postural measures to reduce gastroesophageal reflux and treatment of skin and digital ulcers are recommended for most patients, given the high frequency of these manifestations.78

Conventional drug treatment is quite limited and ineffective in controlling the progression of the disease. There are no drugs that treat SSc globally, and therapeutic strategies are often organ or manifestation-directed. Currently, international rheumatology societies have developed recommendations for the treatment of patients with SSc, always according to individual manifestations.78,79 Randomized clinical studies have investigated synthetic and biological immunomodulatory agents, showing modest benefits and no repercussions on disease-related mortality, with exception of angiotensin-converting enzyme (ACE) inhibitors, which in the past significantly decreased the mortality of patients with scleroderma renal crises.59,78

Interstitial lung disease is a severe manifestation of SSc and the leading cause of death in this disease. The available treatments have modest and short-lived success rates on the control of interstitial lung disease.71,78–81 Best outcomes are described for cyclophosphamide and mycophenolate mofetil, with short-term benefit when compared with placebo.82,83 More recently, rituximab, tocilizumab, nintedanib and pirfenidone, among other therapeutic agents, have been investigated with promising results, yet to be confirmed.84–87 Isolated diffuse skin involvement, when severe and progressive, is also associated with high mortality rates and poor quality of life, with outcomes comparable to those of patients with visceral involvement.86 Thus, systemic immunosuppression is recommended for selected cases.87

In the past years 20 years, AHSCT has been indicated as treatment for patients with severe and rapidly progressive SSc.10 According to data from international transplant registries, the number of transplanted patients per year has progressively increased, reflecting the good outcomes of this therapeutic approach.14

The most recently adopted indication criteria for transplantation are the following10,88,89:

• •

  An established diagnosis of systemic sclerosis, according to the 2013 ACR/EULAR classification criteria90.

• •

  Patients with diffuse form of the disease, with a minimum modified Rodnan's score of 16, and worsening by at least 25% in the last 6 months, under immunosuppressive treatment.

• •

  Patients with interstitial lung involvement with a decline in predicted forced vital capacity (FVC) or carbon monoxide (CO) diffusion percentages greater than 10% in the preceding 6 months, while under immunosuppressive treatment.

The exclusion criteria for HSCT to consider based on available studies are the following10,88,89:

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  Age over 60 years;

• •

  Current pregnancy;

• •

  Inability to practice effective contraception;

• •

  Inability to accept infertility as a possible consequence after transplantation;

• •

  Severe psychiatric disorder;

• •

  Current acute or chronic infection;

• •

  Previous malignancy, except localized and treated cervical and thyroid cancer;

• •

  Major organ dysfunction, as follows:

  • •

    Liver – increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST), over three times the normal range; or increased serum bilirubin levels, over three times the normal range, except when Gilbert's syndrome present;

  • •

    Kidneys – creatinine clearance below 40ml/min; or creatinine levels above 2mg/dL;

  • •

    Lungs – forced vital capacity or hemoglobin-adjusted CO diffusion below 40% of predicted;

  • •

    Heart – left ventricular ejection fraction below 50%, constrictive pericarditis, ventricular arrhythmias, extensive myocardial fibrosis, systolic pulmonary artery pressure greater than 40mmHg or mean pulmonary artery pressure greater than 25mmHg, evidence of ventricular diastolic dysfunction, septal dyssynergia.

Historically, the initial studies were important to establish recommendations and guide currently adopted procedures. Phase I/II studies showed that autologous HSCT (AHSCT) improves skin involvement and at least stabilizes the pulmonary condition (Table 3).11,12,91–96 These studies also evidenced the importance of a proper heart assessment as a strategy to decrease transplant-related mortality. Cardiac dysfunctions that occur during transplantation accounted for many of the transplant-related deaths described in the initial studies.97 Currently, there are detailed cardiac assessment recommendations,98 aimed at identifying patients with previous cardiac lesions and, therefore, at a higher risk of cardiotoxicity.

The three randomized studies more recently published show that HSCT surpasses conventional treatment in SSc patients, promoting longer overall survival, longer disease-free survival and higher quality of life (Table 3).88,99,100 These results are essential to convince the community about the efficacy of HSCT. In fact, since 2017, AHSCT has been recommended by the European League Against Rheumatism (EULAR) guidelines, for patients with SSc at risk of organ failure.78

Treatment protocols have been refined and incorporated into the routine of several transplant centers. However, a few points of debate still remain. There is still no consensus among centers whether to adopt graft selection or to use non-selected grafts. While CD34+ graft selection may prevent reinfusion of autoreactive cells during transplant and potential disease reactivation, it adds costs to the procedure and increases the risk of contamination and cell death. A retrospective study from the European Blood and Marrow Transplant Group (EBMT) compared SSc patients transplanted with or without graft selection, showing similar clinical outcomes.101 Although not statistically significant, patients who received unselected grafts tended to have better overall and disease-free survival than patients treated with selected grafts. More recently, a second prospective observational study from the EBMT reported, conversely, higher disease improvement rates after HSCT with CD34+ graft selection, although there was no impact on the progression-free survival.102 A third, smaller, recent study has also shown better outcomes in patients transplanted with selected versus non-selected grafts (Table 3).103 In summary, the question shall not be settled without a prospective randomized trial.

Most transplant centers adopt non-myeloablative conditioning regimens, however a group of North American multicenter investigators, from 26 transplant sites, has consistently reported their experience with myeloablative protocols including full body irradiation.95,104 In this scenario, the most recently published randomized trial (SCOT trial) has shown good results in the myeloablative transplant group (Table 3).100

The experience with allogeneic transplantation for systemic sclerosis is limited to isolated case reports.14,105,106 Therefore, clinical evidence is insufficient to recommend this treatment modality for patients with SSc.

The three randomized studies already published provide solid evidence to recommend autologous hematopoietic stem cell transplantation for severe and progressive cases of systemic sclerosis. According to the Oxford Center for Evidence-Based Medicine's evidence table,107 we consider the evidence to have Grade A and Level 1B. Patients should be thoroughly evaluated for heart dysfunction and fibrosis before transplantation and the procedure should be performed in centers with experience in managing patients with systemic sclerosis during transplantation.

Hematopoietic stem cell transplantation (HSCT) has emerged as a potential treatment for Crohn's disease due to the chronicity of the disease and lack of further therapeutic options in refractory patients. Additionally, since 1993, there are several case reports in the literature of Crohn's disease patients with concomitant leukemia or lymphoma who improved from the former when transplanted for the latter.127–132

In 2003, investigators from the Northwestern University (Chicago, USA) published their successful experience with the first two patients treated with AHSCT for Crohn's disease as primary indication.133,134 A subsequent update from the same investigators described dramatic clinical remissions in 11 from a total of 12 transplanted patients, in 18 months of follow-up.135 In 2010, a last update described the long-term follow-up of 24 Crohn's disease patients transplanted in Chicago, showing high rates of disease progression over a five-year follow-up (Table 4).4

The European centers also reproduced the North-American protocol, with similar outcomes of low toxicity and high rates of short-term disease remission.136 Longer follow-up, however, confirmed the high relapse/progression rates.137–144 A European multicenter randomized study (Autologous Stem Cell Transplantation in Refractory Crohn's Disease, ASTIC) had a very strict study design and ambitious endpoints, and thus failed to show superiority of AHSCT versus mobilization only (Table 4).140 A later reassessment of the same results, with more traditional endpoints, enabled more optimistic conclusions; that AHSCT promotes clinical and endoscopic benefits, despite a high burden of adverse events.145 To date, the EBMT registry reports Crohn's disease as the third most frequent autoimmune disease indication for AHSCT.141

In Brazil, the first report of AHSCT for Crohn's disease was published in 2013.142 To date, at least 57 procedures have been performed in four Brazilian centers (unpublished data). A single institution Brazilian trial enrolled 14 Crohn's disease patients for AHSCT with high rate of disease remissions and improved quality of life at 30 days post-transplantation (Table 4).146 Longer follow-up of the quality of life in these patients, evaluated by the IBDQ (Inflammatory Bowel Disease Questionnaire) and SF-36 (Short Form-36) questionnaires show sustained benefit at four years post-AHSCT (data not published).

The field of AHSCT for Crohn's disease has advanced over time, in parallel to the learning curve in other autoimmune disease indications. Patient selection and disease stratification are important steps that precede AHSCT, and aim to improve safety and post-transplantation outcomes.46,143 Perianal disease, fistulas and intra-abdominal abscesses, as well as presence of ostomies, are not considered absolute exclusion criteria, but increase risks associated to the procedure and should be carefully considered before patient enrollment. Moreover, hematopoietic progenitor cells may be successfully and safely mobilized from the peripheral blood with low (2g/m2) doses of cyclophosphamide.147 Disease reactivation over time is still high (Table 4) and whether CD34+ graft selection has any effect on long-term control remains to be defined.4,136–140,142,143 Finally, there is evidence to suggest that after AHSCT, patients become more responsive to conventional therapy than before the procedure.140,141 These aspects should be explored in future studies.

The new ongoing protocols, ASTIC-Lite (ASTIC-low intensity therapy evaluation, EBMT), and the AutoCrohn2 (São José do Rio Preto, Brazil), include a more refined patient assessment and stratification with accurate clinical, immunological, magnetic resonance and microbiota studies. These studies aim for a better understanding of the therapeutic potential of AHSCT for patients with Crohn's disease.147–149

Autologous HSCT has the potential to induce clinical remission and improve quality of life in patients with Crohn's disease with poor prognosis or that are refractory to immunosuppressants or biologic agents. AHSCT is considered safe, but associated with a high number of adverse events, mainly infectious. Therefore, AHSCT for Crohn's disease should be performed by experienced centers, with specialized teams to manage gastrointestinal and infectious complications. Early referral is recommended to optimize clinical outcomes and minimize risks.