Wegener granulomatosis (WG) is a multisystemic necrotizing granulomatous vasculitis of small- and medium-sized vessels, primarily involving the respiratory tract and the kidneys. Involvement of other organ systems such as eye, subglottis, joints, skin, nervous system and liver has been reported. Pediatric WG is rare, shares many features with the adult disease, but shows a predominance of female patients, a higher incidence of subglottic stenosis and of generalized disease. In total, 80–95% of pediatric patients are positive for classical anti-neutrophil cytoplasmic antibodies (ANCA) and 5–20% are positive for perinuclear (P)-ANCA. By treatment with steroids and CY, a remission rate of 75% can be achieved. However, the relapse rate is high (about 75%) and significant chronic organ damage is observed. In children, a survival rate between 85 and 100% is reported.1, 2, 3
Marmont and VanBekkum were the first to discuss the potential role of allo-SCT for refractory autoimmune diseases.4 Here, we report the successful treatment of a pediatric WG by allo-SCT following reduced-intensity conditioning.
A 9-year-old girl, with no history of autoimmune disease, came to our clinic with recurrent fever, weight loss, arthralgia, epistaxis and dacryocystitis. Chest X-ray and computed tomography scan revealed pulmonary nodular infiltration. She presented with hematuria and proteinuria, elevated renal parameters with kidney enlargement and diffuse infiltration.
Diagnosis was established according to the criteria of the American College of Rheumatology and was proven by tissue biopsy from lacrimal gland, kidney and bronchoalveolar lavage. Histological changes showed granulomatous inflammation, necrotizing vasculitis, pauci-immune crescentic glomerulonephritis and alveolar hemorrhage with neutrophilic alveolitis. Five out of six required criteria, as defined by the European League Against Rheumatism and the Pediatric Rheumatology European Society, were fulfilled.5 P-ANCA were detectable by indirect immunofluorescence and were determined by ELISA against myeloperoxidase, but other autoimmune antibodies were negative.
Primary therapy consisted of i.v. prednisolone (2 mg/kg/day), followed by pulse-therapy (20 mg/kg/day for 3 days). Supportive care consisted of fluconazole and co-trimoxazole. The pulmonary function deteriorated quickly with acute respiratory distress syndrome and the girl was on mechanical ventilation for 4 weeks. Despite additional i.v. therapy with CY (1000 mg/m2/biweekly) and high-dose Ig, the girl developed multiorgan dysfunction requiring intensive care with catecholamines, surfactant and inhaled nitric oxide. Further manifestations such as keratoconjunctivitis, sinusitis, pericarditis and mitral insufficiency maximum grade IV evolved. Severe infectious complications included pneumonia with methoxycillin-resistant Staphylococcus epidermidis, sepsis due to Pseudomonas aeruginosa and recurrent CMV reactivations. Resistant pancytopenia required regular erythrocyte and plt transfusions. She developed hypothyroidism, increasing hepatobiliary disease and renal impairment resulting in a Birmingham vasculitis score of 21. Additional MTX (20 mg/m2 i.v.) had to be discontinued because of liver toxicity. Biopsy showed focal fibrosis with reactive bile duct proliferation.
Following partial response after 8 months, CY was switched to oral dose of 2 mg/kg/day.
During steroid tapering, she experienced disease flares with worsening of liver, lung and kidney function, paralleled by an increase of P-ANCA titers and infectious complications. With a vasculitis damage index of 14, a persistent Birmingham vasculitis score of 6 and a Lansky score of 65% and persistent severe pancytopenia, allo-SCT from her HLA-identical brother was considered.
Reduced-intensity conditioning consisted of fludarabine (90 mg/m2 total dose), 2 Gy TBI and 2.5 Gy total lymphoid irradiation. On day 0, unmanipulated BM with 3.6 × 106 cells per kg CD34+ cells and 6.4 × 107 cells per kg CD3+ cells were infused. GVHD prophylaxis consisted of CYA at 2 mg/kg/day (day 0 till day +300) and mycophenolate mofetil at 30 mg/kg/day (day −1 till day +40). Supportive treatment included oral amphotericin, co-trimoxazole, gancyclovir and i.v.Ig (400 mg/kg). No serious toxic or infectious complications and no acute GVHD occurred.
Hematological engraftment (ANC >500 cells per μL) occurred on day +22. Engraftment was monitored by FACS and FISH analysis for sex chromosomes from sorted cell populations of both BM and peripheral blood. Mixed donor chimerism was present until day +78, followed by complete donor chimerism thereafter. Prolonged thrombocytopenia without thrombocyte or other autoantibodies was then associated with hypersplenism and resolved after splenectomy, 8 months after SCT. Histology showed an enlarged spleen with dilatated sinusoids, fibrotic sinusoidal walls and deposits of hemosiderin, and was interpretated as congestive splenomegaly.
Limited de novo chronic GVHD of skin and oral mucosa occurred 18 months after SCT and was successfully treated with oral prednisolone and topical therapy. Delayed immunoreconstitution for the first 3 years was complicated by recurrent infections and GVHD. Finally, cellular immunity has nearly normalized. Mild IgG2-deficiency has no clinical correlation with regular specific Ab responses after revaccination. She is off immunosuppression since 3 years without GVHD (disease course: Figure 1). Residual organ damage comprises mitral insufficiency grade III, cardiomyopathy, stable hepatopathy without portal hypertension and mild nephropathy. Liver biopsy showed fibrosis with no signs of autoimmune hepatitis or GVHD. Late effects include mild osteopenia and compensated hypogonadism. At 8 years after SCT, the patient is leading a nearly normal life with a Lansky score of 90% and vasculitis damage index of 5 with good pulmonary and renal function. P-ANCA and myeloperoxidase-Abs are constantly negative since day +78.
Wegener granulomatosis in children can be treated successfully, but relapses, chronic organ damage and infectious complications still limit the outcome of patients treated conventionally.1, 2 Kidney or lung involvement at diagnosis is associated with a threefold increased mortality, and up to 30% of patients with WG requiring intensive care die within the first month.3, 6
Immunoablative chemotherapy with subsequent auto-SCT has become an accepted therapy for severe autoimmune diseases,7 but disease recurrence remains a major obstacle.4 Auto-SCT for WG has been associated with persistence of ANCAs and new autoimmune phenomena.8 In the presented patient, transfusion- and G-CSF-resistant pancytopenia was a limiting factor for auto-SCT. Other immunomodulatory approaches such as anti-CD20 moAb have been successfully used, but may be restricted to non-granulomatous lesions and responses may be temporary.9
Reduced-intensity conditioning may prevent additional toxic organ damage, but the incidence of GVHD and late complications are still a matter of investigation.10 In our patient, HLA-identical allo-SCT resulted in 100% donor chimerism, was effective in controlling resistant WG and ensured long-term disease-free survival. However, outcome and quality of life depend on preexisting organ damage, potentially aggravated by GVHD and recurrent infections.
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We thank Professor Gerhard Fritsch, Professor Winfried Pickl and Professor Gerhard Zlabinger for providing data about immunoreconstitution.
The authors declare no conflict of interest.
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Lawitschka, A., Peters, C., Seidel, M. et al. Long-term remission in pediatric Wegener granulomatosis following allo-SCT after reduced-intensity conditioning. Bone Marrow Transplant 46, 462–463 (2011) doi:10.1038/bmt.2010.126
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