A systemic sclerosis patient who has undergone autologous stem cell transplantation
Systemic sclerosis (SSc) can be a devastating disease, for which there are no US Food and Drug Administration or European Medicines Agency approved therapies. However, well controlled trials of cyclophosphamide (CYC) versus placebo, and mycophenolate mofetil (MMF) versus CYC have shown that both CYC and MMF can be effective in treating SSc [1,2]. When confronted with a patient with rapidly progressive SSc, physicians should also be aware of use of autologous hematopoietic stem cell transplantation (HSCT) as a treatment for this disease.
There are data from three controlled clinical trials supporting the use of autologous HSCT for early diffuse SSc.
1. American Scleroderma Stem Cell versus Immune Suppression Trial (ASSIST) 
This small trial compared 10 patients who received autologous HSCT with 9 patients given 1.0 g/m2 intravenous (IV) CYC once per month for 6 months. If improvement did not occur after 6 months of CYC, this group underwent HSCT. All 10 patients who received HSCT improved within the first 12 months of follow-up, compared with none of the 9 patients who received CYC during their 6 months of therapy. Seven patients randomly allocated to receive CYC did not respond and were given HSCT at 12 months (i.e. 6 months after their 6 month CYC therapy). As some patients in the CYC group received HSCT, the results were not definitive, but did support the use of HSCT. Adverse events were poorly documented, so it was not possible to discern if any adverse effects occurred in the CYC group, although 7 of 9 worsened. No deaths occurred in either treatment group during the follow-up period of up to 2 years.
2. The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial :
This randomized, multicenter trial compared 156 patients who received autologous HSCT (n=79), or 750 mg/m2 IV CYC monthly for 12 months (n=77). Conditioning included CYC (200 mg/kg over 4 days), and rabbit ATG (7.5 mg/kg over 3 days), IV methylprednisolone (1 mg/kg), and hyperhydration. The control group received 750 mg/m2 CYC monthly for 12 months (9 g/m2 over 12 months). Crossover was allowed from CYC after 2 years.
At 2 years, event-free survival and secondary outcomes were better in the HSCT group than the CYC group. At the end of the first year, 11 of the HSCT patients had 11 died (13.9%), including 8 treatment-related, versus 7 deaths (9.1%), none treatment-related, in the CYC group. After 4 years of follow-up, there were 13 deaths (16.5%) in the HSCT group vs 20 deaths (26.0%) in the control group (p=0.002). Patients in the HCST group experienced higher mortality rates in the first year, but had better long-term survival than those treated with CYC. Adverse events in the HSCT group included lymphoproliferative disease, and Epstein-Barr virus, cytomegalovirus and herpes zoster infections.
3. The Scleroderma Cyclophosphamide or Transplantation (SCOT) trial :
This randomized, controlled trial compared 36 patients given autologous HSCT, with 39 patients given monthly IV CYC over 12 months, with 54 month follow-up. Conditioning included 800 cGy fractionated total body irradiation with pulmonary and renal shielding, in addition to 120 mg/kg IV CYC and horse ATG, 90 mg/kg. After conditioning, patients received 5.6×106/kg CD34+ cells for transplantation. This was followed by granulocyte-colony stimulating factor and glucocorticoids. The CYC patients received 500–750 mg/m2 IV CYC over 12 months.
Despite the low numbers, the data demonstrated the efficacy of HSCT over CYC. At 54 months, the primary end point outcome was a hierarchical, composite global rank score, including, in order: death, event free survival, worsened forced vital capacity (FVC), worsened Disability Index of the Health Assessment Questionnaire (HAQ-DI) score, and worsened modified Rodnan skin score (mRSS). Pairwise comparisons favored HSCT over CYC: 67% versus 33% at month 54 (p=0.01) and 68% versus 32% at month 48 (p=0.008). In the per protocol population, event-free survival statistically favored HSCT at 48 and 54 months (79 vs 50%, P=0.02). The rate of serious adverse events in person-years was 0.38 in the HSCT group and 0.52 in the CYC group. Overall, like ASTIS, SCOT provided clear data supporting HSCT over IV CYC.
The patient was a 46-year-old female, who had 5 years of SSc, defined from the first non-Raynaud’s sign or symptom typical of SSc. She had been extremely tired for the last year, and had involuntarily lost 5.4 kg (12 lb), about 8% of her initial weight. She had finger ulcers, heartburn, nocturnal cough, and shortness of breath after walking up about 1.5 flights of stairs. She also had pain and swelling of both wrists, 2–3 metacarpophalangeal joints (MCPs) bilaterally, and the left knee.
The patient’s mRSS was 27 of a maximum of 51, with involvement of her face, chest, arms, forearms, hands, fingers and thighs, showing that she had moderately severe diffuse cutaneous disease. Her tender joint count was 4/28 and 4/68, while her joint swelling count was 3/28 and 3/66 (bilateral 2 MCPs, right wrist), indicating active arthritis. The patient’s visual analog scale for pain was 4/10, her patient global assessment score was 6/10, and her physician’s global assessment score was 5/10, thus her quality of life was significantly impacted. Her clinical disease activity index was 16, indicating moderate disease activity.
High resolution CT of the chest showed ground glass opacities and some reticulation but no honeycombing. Pulmonary function testing showed FVC was 74% and diffusing capacity for carbon monoxide of 55%, indicating mild–moderate early interstitial lung disease. On echocardiogram her left ventricular ejection fraction was 55–60% with E/A ratio of 1.2, tricuspid regurgitation velocity of 2.1 m/s and right ventricular systolic pressure of 27 mmHg, indicating that the patient probably had neither diastolic dysfunction nor pulmonary hypertension. Creatinine clearance was 82 ml/min with 1+ proteinuria (125 mg protein per 24 hrs), and there were no red cells or casts in the urine.
The patient received CYC orally (125 mg/day) for 4 months, which was then stopped as the patient did not feel there was any response, and her FVC had dropped by 10%. She could not tolerate MMF at 2 g/day due to gastrointestinal upset. Her mRSS then worsened from 27 to 31.
The patient failed two therapies which have been shown shown to be effective in well-controlled trials. Given her progressive disease and failure of the two most appropriate therapies for SSc, autologous HSCT was undertaken.
The treatment regimen was that of the SCOT trial (see above). Post therapy, she developed a urinary tract infection, which was treated successfully with amoxicillin/clavulanic acid for 10 days. No other significant adverse events occurred, although she did have some nausea and post conditioning regimen fatigue.
At 3 months after HSCT, her skin score had improved by 50%, her pain had improved by 40% and her global assessment of disease activity had improved by 50%. Her FVC worsened by 10%.
By 1 year following HSCT, her skin score had continued to improve and was now about 70% better (mRSS: 10), her global assessment of disease was 2/10, indicating good general health and her FVC had recovered to baseline.
Now, 2 years after HSCT, she is able to carry on her normal activities of daily living, although she cannot return to the active lifestyle of hiking and swimming that she had before her disease started.
Her therapy includes occasional ibuprofen plus ranitidine and hormone replacement therapy for her postmenopausal state.
This patient is illustrative of available treatments for diffuse SSc, as well as pointing to the data supporting the use of HSCT for the small percentage of patients who need this highly aggressive therapy. HSCT is best suited for patients with early, diffuse disease, and some but not a great deal of visceral involvement.
The basic concept for treatment using HSCT is to use it in patients with early disease in whom abrogation of the pathogenetic factors underlying the disease will allow the patient to heal.
Not all aspects of HSCT have been defined (e.g. what is the best regimen, who are the best patients for this treatment, can patients with lesser or later disease benefit) but this is a real step forward in the treatment of SSc.
This case study is illustrative in nature, and is based on data derived from a number of patients and the clinical experience of the author. All patients have given consent to publish their data.
- Tashkin DP, Elashoff R, Clements PJ et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354: 2655–2666.
- Clements PJ, Tashkin D, Roth M et al. The Scleroderma Lung Study II (SLS II) Shows That Both Oral Cyclophosphamide (CYC) and Mycophenolate Mofitil (MMF) Are Efficacious in Treating Progressive Interstitial Lung Disease (ILD) in Patients with Systemic Sclerosis (SSc). Arthritis Rheumatol 2015; 67 (Suppl 10): (Abstract).
- Burt RK, Shah SJ, Dill K et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet 2011. 378: 498–506.
- van Laar JM, Farge D, Sont JK et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 2014; 311: 2490–2498.
- Sullivan KM, Goldmuntz EA, Keyes-Elstein L et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med 2018; 378: 35–47.