Discussion
Immunity may be impaired in patients with thymoma. Thymoma-associated immunodeficiency is known as Good’s syndrome and includes hypogammaglobulinaemia, decreased or absent B lymphocytes, CD4+/CD8+ inversion and decreased T lymphocytes. In addition, autoimmune manifestations may occur4. The etiology of thymoma related PWCA is still unknown, but it appears to have an autoimmune background. Growth inhibition of granulocytic and macrophage colony-forming units exposed to different concentrations of serum from these patients has been observed. This finding suggests the presence of an immunoglobulin against immature myeloid cells, indicating an alteration of B cells and humoral immunity5. Conversely, the response to anti-calcineurin immunosuppressors in these cases, as in PRCA, points to an alteration in T cells and cellular immunity6. Thymus is the organ where T cell maturation and TCR gene rearrangement occurs. Besides, it is the place where negative selection of autoreactive T cells and positive selection of T cells capable of recognising MHC presented antigens take place7. In this sense, several causal mechanisms for the loss of self-tolerance in thymoma patients have been proposed: (1) Immaturity of neoplastic T cells that would allow the escape of autoreactive lymphocytes, (2) Neoplastic genetic alterations that would predispose to the appearance of autoimmunity such as decreased expression of HLA-DR and (3) Theory of combined dysregulation of cellular and humoral immunity, an autoreactive T cell would activate a B cell to produce autoantibodies8.
Surgery to resect tumour tissue is the standard treatment for patients with thymoma. Thymectomy appears to have a positive impact on the autoimmune clinic by removing the neoplastic tissue, which seems to provide the antigenic stimulus for autoreactive cells. It has been reported the case of a patient with thymoma and granulocytopenia in whom a decrease in anti-pANCA antibody titre and elevation of granulocytes in peripheral blood was observed after thymectomy9. However, in other cases neutropenia has not resolved after thymectomy and a second line of treatment is necessary10,11. The medical treatment of these patients is not established currently, due to low incidence of cases. Several strategies have been used to increase granulocyte counts (Table I) . GCS-F and IVIG normally have no impact in granulocytic count12. Of the 24 patients collected 13 survive, all of them receive some immunosuppressive treatment (CyA 6 patients, Azathioprine 2, Corticoid 2, Alemtuzumab 1, Chemoterapy 1 and plasmapheresis 1) which reinforces the idea of a combined surgical and immunosuppressive treatment for these patients.
CyA has demonstrated favourable responses in these patients. It has been used with target trough levels of 200-400 ng/mL and monitoring toxicities. Granulocytic recovery occurs within 7 to 10 days. Maintenance treatment has usually been applied, with CyA tappering until its total suspension after 4-6 months5,10. Others have used extended treatment with CyA and prednisone in decreasing doses for up to 20 months after thymectomy12.
Alemtuzumab has been successfully used as an immunosuppressor in autoimmune bone marrow failures. In two cases of PWCA Alemtuzumab has achieved complete response in the first month13. Alemtuzumab has been useful in the treatment of a patient with PWCA and thymoma, after failure of G-CSF and plasmapheresis, achieving granulocyte recovery in 12 days. However, agranulocytosis relapsed 5 months later and was treated with a new cycle of Alemtuzumab associated with CyA and maintenance mycophenolate14.
A case has been described of a paciente with MG thymectomised, who relapsed after 12 years with MG and de novo PWCA. In this case, plasmapheresis was started with improvement of the MG symptoms as diagnosis, but there was no change in the granulocyte count after 15 sessions. Azathioprine 2.5 mg and prednisone mg/kg were started, obtaining an increase in the granulocyte count 4 months later15. It suggests that plasmapheresis alone is not a good option for the treatment of PWCA and the use of concomitant inmunosupressor is needed.
Thymectomy is a major surgery with high complexity and infectious risks. We consider that the appropriate management would be the resolution of the PWCA prior to surgery. According to our review, treatments with immunosuppressive drugs are associated with better outcome. In our patient, we have obtained a good response with CyA, which supports the existing literature as the most successful therapeutic option. Furthermore, it is a drug with a known safety profile, extensive experience in its use and the possibility of measuring levels. Therefore, we suggest the use of CyA as a first-line drug with the concomitant use of G-CSF from granulocyte recovery onwards. Long-term follow-up of thymoma and immunological status is advisable because relapses have been observed in these patients.
Conflict of interest : Authors report no conflicts of interest associated with this publication.
Author contributions : Roberto Céspedes López is the main author, was involved in patient care, provided necessary data for the article, and was involved in manuscript preparation. Elena Amutio Díez is the main reviewer, was involved in manuscript preparation, checked grammatical and data errors, and patient care. Xabier Martín Martitegui was involved in patient care and provided data for the article. Amaia Balerdi Malcorra was invoveld in patient care. Lucía Insunza Oleaga was involved in patient care. Maite Moreno Gámiz was involved in patient care. Javier Arzuaga Méndez was involved in patient care. Juan Carlos García-Ruíz checked the manuscript for grammatical and secientific errors.
Ifrah Malik checked the manuscript for grammati-cal and scientific errors
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