Case report

The patient presented at the age of 12 years with arthritis, myalgia, anemia and a low-titer ANA. Her uncle suffered from SLE but there was no other family history of autoimmune disease. Over the following years, the patient presented with recurrent episodes of pulmonary hemorrhage, thrombocytopenia, central and peripheral nervous system involvement, skin ulcers, and severely disabling diffuse calcinosis, mostly in the hip joints and pelvic muscles. She also exhibited dystrophic calcification of subcutaneous tissue around the face, chest wall and elbows. At the age of 15 years, she developed secondary anticardiolipin syndrome with pulmonary hypertension and recurrent episodes of digital ischemia. Repeated laboratory tests did not reveal the presence of autoantibodies (anti-DNA, anti-SM, anti-SSA, anti-SSB were negative) other than low titers of ANA and, later, rising titers of IgG and IgM anticardiolipin antibodies. The patient did not suffer from renal disease or myositis.

The disease responded only partially to corticosteroids, cyclophosphamide, azathioprine, methotrexate, plaquinill and thalidomide (which improved her skin ulcers). Despite vigorous immunosuppressive therapy, the child became bedridden, and an autograft was offered when she developed pulmonary hypertension and ischemic necrosis of the digits. The Ethics Committee of our hospital approved the procedure, and informed consent was obtained from the patient and her parents.

Peripheral stem cells were harvested after treatment with cyclophosphamide 4 g/m² and G-CSF. T-cell depletion was achieved by positive selection of CD34+ cells by immunomagnetic beads. The conditioning regimen included: BCNU 300 mg/m² IV once daily on day -7, etoposide 100 mg/m² IV twice daily on days -6 to -3 (total dose 800 mg/m²), cytarabine 100 mg/m² IV twice daily on days –6 to -3 (total dose 800 mg/m²) and melphalan 140 mg/m² IV once daily on day -2. On day 0, she received 4.4 10⁶ CD34 cells/kg. Neutrophil and platelet engraftment were prompt. No other significant complications were seen.

Gradually, the patient's mobility improved and she was able to perform daily activities, such as sitting, standing and walking, unaided. At 6 weeks after transplantation, the subcutaneous calcinosis nodules began to liquefy and calcium salts extruded through the skin. In parallel with the liquefaction of superficial calcinosis nodules, gradual improvement in the range of motion of her hips also occurred. The disappearance of deep calcinosis plaques was documented by serial bone scans (Figures 1 and 2). All skin ulcers healed completely without recurrence, and pulmonary blood pressure returned to normal (from 34 to 36 mmHg before to 21–23 mmHg after PBSCT). Her hemoglobin increased from 8.6 to 12.1 g/dl, and the ANA became negative. Anticardiolipin levels are still slightly above normal. The patient is presently 2 years after autologous transplantation and is free from clinical and laboratory evidence of disease activity.

Figure 1.

Anterior (left) and posterior (right) images of Tc99m-MDP bone scan prior to ASCT, showing abnormally increased uptake in multiple extraskeletal sites of calcinosis. Increased uptake is seen along the soft tissues of both thighs, most prominent in both hip joints, in soft tissues of the lateral pelvis region adjacent to the iliac crest, and in the postero-lateral aspect of the chest wall bilaterally.

Full figure and legend (105K)

Figure 2.

Anterior (left) and posterior (right) images of Tc99m-MDP bone scan 15 months after ASCT, showing resolution of abnormal uptake in most sites of soft tissue uptake demonstrated previously. Increased uptake is still seen in soft tissues along the left thigh and in the medical aspect of the distal thigh bilaterally.

Full figure and legend (120K)

Discussion

Refractory autoimmune diseases are a cause of a high degree of morbidity and mortality due to the disease and complications of intense immunosuppression. A report on 390 adults and children who underwent ASCT for autoimmune disease⁴ described clinically significant responses in two-thirds of the patients and in all disease categories. The reported transplant-related mortality was 9%. Results from current trials suggest that mobilization of hematopoietic stem cells, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells and post-transplantation follow-up need to be disease specific.⁵ Today, treatment-related mortality in patients with nonadvanced diseases is known to be 2–3%.

Our patient suffered from an ill-defined, progressive autoimmune disease that threatened her life expectancy. She also developed a severe form of calcinosis, namely tumoral calcinosis (also known as calcinosis universalis) which consists of large nodular deposits that extend to deeper tissue layers, including the muscles, that caused severe physical disability. Little is known about the pathophysiology of the calcinosis in juvenile dermatomyositis (JDM) or autoimmune diseases, but there is some evidence that calcinosis is associated with ongoing inflammation.⁶ In a recent report, macrophages and proinflammatory cytokines, including Il-6, Il-1 and TNF-, were present in the milk of calcium fluid examined from a patient.⁷ Calcinosis has also been more frequently associated with the TNF--308A promoter polymorphism, which is associated with increased TNF- production by peripheral blood mononuclear cells.⁸ Recent reports suggest that the early initiation of intensive anti-inflammatory therapy for JDM may be effective in preventing the future development of calcinosis.^6,9 Calcinosis is associated with a variable natural history, and spontaneous regression either through reabsorption or extrusion of the material may occur.¹⁰

There is no universally recognized treatment for patients who are actively depositing calcinosis. Many anti-inflammatory agents have been used, including hydroxychloroquine, intravenous immunoglobulin, cyclosporine and, most recently, infliximab, but unfortunately none of the many approaches to treatment has proven to be consistently effective.¹⁰

Our report contributes the first description of ASCT in a child with autoimmune disease and severely crippling, massive calcinosis that gradually disappeared starting 6 weeks after transplantation. From a bedridden girl, she became an active young adolescent involved in everyday activities. The mechanisms of action of PBSCT in severe autoimmune diseases are either simply debulking the autoimmune clones, with autologous stem cells as a hematopoietic rescue, or creating a new immunopoiesis that may ensure tolerance. Although the pathogenesis for the disappearance of the massive calcinosis is not clear, it is probably associated with vigorous anti-inflammatory and immunosuppressive therapy.

References

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Acknowledgements

The authors thank Mrs M Perlmutter for her help in the preparation of this paper.