The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Figure 1) developed over the following 2 years.
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+0.8 SD) for a size of 92.5 cm (- 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Figure 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3x106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m²/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Figure 2.