Adult Stem Cell Treatment of Scleroderma

Alan Tyndall; Daniel E. Furst


Curr Opin Rheumatol. 2007;19(6):604-610. 

In This Article

Results of Phase I/II Studies

All studies have used autologous hematopoietic stem cells.

The first 65 transplanted patients reported to the EBMT/EULAR database showed an improvement of 25% or more in the skin score (measured by the modified Rodnan method) in 70% of the patients, with a transplant-related mortality (TRM) of 12.5%.[6] Several protocols were used, mostly either cyclophosphamide based (4 g/m2 cyclophosphamide mobilization and cyclophosphamide 200 mg/kg body weight conditioning) or radiation (8 Gy/cyclophosphamide 120 mg/kg body weight). With further patient recruitment and longer term follow up, the TRM of the EBMT-registered patients fell, considered to be related to more careful patient selection and appropriate changes in the treatment regimens. Lung function tended to stabilize and renal function generally remained stable, but some factors were identified as potentially hazardous for HSCT (see below). A long-term follow up of this cohort showed an overall TRM of 8.5%, no further transplant-related deaths and trend to durable remissions (Fig. 1).[7] Within controlled trials, the TRM has thus far been 2.5%. For this subset of SSc there is so far no proven disease-modifying therapy capable of controlling the disease.

Clinical outcome in 57 systemic sclerosis patients followed up to 60 months following transplant

Between 1997 and early 2005, 34 early, poor prognosis SSc patients enrolled in a pilot North American study. After an early protocol in eight patients (which had probable radiation-related toxicity) was modified, the next 25 patients underwent conditioning with 800 cGy total body irradiation (with lung shielding to 200 cGy), 120 mg/kg cyclophosphamide and 90 mg/kg equine ATG. After a median follow up of 4 years, an approximately 70% improvement in skin and 55% improvement in function were noted (P <0.0001). Transplant-related mortality occurred in five patients [two from pulmonary toxicity before protocol modification - none have died of pulmonary toxicity since - one of Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder, one with myelodysplastic syndrome, and one of multiorgan failure (15%)].[8,9]

Initially, most groups followed the consensus guidelines of 'life or organ threatening autoimmune disease refractory to conventional therapy and with sufficient reversible pathology to allow a decent quality of life after cessation of inflammation'. Such SSc patients have a 50% 5-year survival[10] and were therefore considered suitable candidates for such an aggressive treatment. The phase I/II experience showed that particular clinical features are associated with potential toxicity, for example patients with a mean pulmonary artery pressure above 50 mmHg by right heart catheterization tended not to tolerate neutropenic fever well due to circulatory compromise, and advanced cardiac or pulmonary disease was prone to deteriorate. This is due to a combination of direct organ toxicity, for example cyclophosphamide cardiac toxicity, and the hyperhydration required during mobilization and conditioning.

Cardiac assessment and monitoring is particularly important in HSCT for SSc,[11••] since subclinical myocardial involvement is more frequent than suspected[12] and fatal ventricular tachyarrhythmia may occur. In general, it is thought that an ejection fraction above 40% is necessary to cope with a doubling of cardiac output over several days, as may occur with sepsis-associated pyrexia, and sufficient diastolic reserve to tolerate a 30% expansion of intravascular volume typically seen in hyperhydration. This is analogous to the reserve required to survive pregnancy.[11••] SSc as well as amyloidosis are both conditions associated with diastolic dysfunction and which may be treated with HSCT.

All patients with SSc who are potential HSCT candidates should undergo screening consisting of a standard 12-lead ECG, 24 h Holter monitor and, if coronary artery disease is suspected, coronary artery angiography or pulmonary hypertension, and right heart catheter exam. In addition, echocardiography should always be performed, and if the results suggest pulmonary artery hypertension, a right heart catheter study is required. This should include measuring the pulmonary capillary wedge pressure, which reflects the left ventricular function and should be less than 15 mmHg. This procedure may need to be repeated prior to conditioning in the European protocol in which cyclophosphamide is used during mobilization, as the patient may experience a deterioration after taking this drug. Based on one experience,[11••] an implantable defibrillating device is suggested if nonsustained ventricular arrhythmias are present, since antiarrhythmic drugs are considered as adjunct therapy and will not prevent sudden cardiac death on their own.

Thoracic high-resolution computer tomography (HRCT) should be performed to assess interstitial lung disease, with a 'ground glass' pattern suggesting active alveolitis.[13] In addition, HRCT excludes unsuspected pulmonary emboli as the cause of pulmonary artery hypertension. This is particularly relevant if significant pulmonary artery hypertension is present, and in fact, most patients are anticoagulated for this reason.

The routine use of angiotensin converting enzyme (ACE) inhibitors during the transplant period has been subject to debate, but several reports of acute renovascular crises in patients not taking these agents have prompted some groups to routinely use them. In the Autologous Stem cell Transplantation International Scleroderma (ASTIS) trial it is mandatory during the treatment period and generally continued indefinitely afterwards. In the Scleroderma Cyclophosphamide Or Transplant (SCOT) trial, ACE inhibitors are required during the 2 months when steroids are utilized. The combination of hyperhydration and pulses of glucocorticosteroids during the ATG infusion may increase the risk of scleroderma renal crisis.

There are now significant numbers of SSc patients followed for 10 years in which major regression of skin thickening has occurred as well as stabilization of lung function. All groups have noted that the first positive impact on disease is often improved quality of life and scleroderma health assessment questionnaires, which include parameters such as physical function, vitality and fatigue. Studies of immune reconstitution have been few, with one study up to 1 year following transplant confirming the known prolonged impairment of the nave T-cell compartment with no significant difference between responders and nonresponders. A similar study in multiple sclerosis patients in remission 2 years following transplant showed a rejuvenation of the T-cell repertoire, with no relapse.[14] This indicates that the clinical benefit is not simply dependent on prolonged immunosuppression through lymphopenia.

Similar data are evolving concerning morphological changes induced by HSCT. One group has reported remodelling and reduction of skin collagen following autologous HSCT in eight of 10 patients[15••] and another following both autologous and allogeneic HSCT.[9,16] Several reports of improvement of nail fold capillaroscopy changes following autologous HSCT indicate a more profound impact on tissue and matrix function than simply transient antiinflammatory and immunosuppressive effects (M. Matucci-Cerinic, personal communication).


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.