Antibody-Associated Autoimmune Disease (AAD) in Children with Cancer in Immune Recovery Phase Following Cessation of Chemotherapy

(Introduction)

Outcome of pediatric cancer has improved dramatically by intensive chemotherapy, surgical treatment, radiotherapy, and stem cell transplantation (SCT). In children with cancer, immune system is damaged during treatment. Autoimmune diseases such as autoimmune hemolytic anemia (AIHA) during immune reconstitution were observed as complication after intensive chemotherapy in our institute. Although most of them recovered with supportive treatment, immunosuppressive agents including steroid were needed in some patients. Thus, we defined this complication as antibody-associated autoimmune disease (AAD), and we examined AAD in pediatric patients following cessation of treatment.

(Patients and Methods)

We reviewed medical records of patients who received intensive chemotherapy in Department of Pediatrics, Hokkaido University Hospital. Between January 2010 and December 2018, 130 patients with hematological malignancies, 127 patients with malignant solid tumor, 120 patients with brain tumor were treated in our institute. All of these patients were included in this study. The diagnoses of AAD were made by clinical criteria, combined with laboratory evidence of a definitive antibody in the serum of patients such as positive Coombs test, antineutrophil antibodies, antiplatelet antibodies, and thyroid-stimulating antibodies. In this study, apparent clinical GVHD and AAD associated with SCT were excluded.

(Results)

Among the 377 patients, 10 patients (2.7%) developed AAD. AAD was observed as ITP in 5 patients, AIHA in 2 patients, Hashimoto's diseases, multiple sclerosis, and neutropenia with antineutrophil antibody in one patient each. AAD developed a median of 4.0 months (range 2-27months) after cessation of treatment. At onset of AAD, the mean CD4 positive cell counts was 397 /ul and the mean serum IgG was 789 mg/dl.

Prednisolone was administered in 3 patients (AIHA and ITP) to treat AAD. The clinical symptoms of AAD regressed with supportive therapy only in the other patients. In 3 out of 5 patients who developed AAD with CD4 positive cell count over 500 /ul, autoimmune antibody in serum of the patients was detected continuously. On the other hand, in 5 patients who developed AAD with CD4 positive cell count below 500 /ul, both clinical symptoms and laboratory examinations regressed, synchronizing with the immune recovery. The mean duration of CD4 positive cell count <500/ul was significantly longer in patients with AAD (n=10) compared with that in patients without AAD (n=45) (p=0.013, 11.0±7.2 months vs 5.6±5.3 months), and the mean duration of serum IgG <500mg/dl was significantly longer in patients with AAD, compared to patients without AAD (p=0.002, 11.0±6.3 months vs 4.3±4.4 months).

(Discussion and Conclusion)

AAD was observed in immune recovery phase following cessation of chemotherapy, which mimicked immune reconstitution syndrome (IRS) after antiretroviral therapy in patients with HIV infection. It was reported that IRS was also observed in HIV-negative patients who were administered alemtuzumab, and in those who received stem cell transplantation. It was interesting that patients who had smaller number of CD4-positive cells at diagnosis of AAD had a faster recovery of the diseases in our study. We also speculate that AAD mimic autoimmune cytopenia such as ITP, AIHA, and autoimmune neutropenia in infancy because the diseases are caused by autoantibodies, occurring in immune-naive age, and they naturally recover in most cases although some patients need immunosuppressive treatment. Further studies are needed to clarify the pathogenesis of AAD in children.