Discussion:
Lymphoproliferative disorders are well known to be associated with autoimmune diseases (8% prevalence). MPNs are less commonly associated with autoimmune diseases (1.7% prevalence). U Dührsen et al. described the spectrum of autoimmune diseases in 346 patients with MPNs, including 76 patients with CML, 46 with idiopathic myelofibrosis (IMF), 35 with PV, 42 with unclassifiable myeloproliferative disorders, 14 with myelodysplastic syndrome, and 133 with acute myelogenous leukemia (AML). They found no instances of MG preceding or during any of the MPNs. Autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, and multiple sclerosis were associated with CML and pernicious anemia with IMF. They also described the spectrum of autoimmune diseases related to lymphoproliferative disorders, in which there was one case of MG associated with chronic lymphocytic leukemia (CLL) [7].
Paraneoplastic phenomenon in MPNs is rare. There are two case reports of patients who presented simultaneously with CML and MG [8,9]. Kumar et al. in 2007 reported the case of a 47-year-old male who presented with diplopia and was found to have leukocytosis on routine laboratory evaluation. He was diagnosed simultaneously with CML and MG. He had splenomegaly (6 cm), BCR -ABL1 gene fusion, and positive anti-AchR antibodies. He was started on steroids and pyridostigmine for MG and imatinib 400 mg daily for CML. Re-evaluation after 12 weeks showed regression of spleen with a complete hematological and cytogenetic response. There was a resolution of ptosis and ophthalmoplegia, and anti-AchR turned negative [8]. There are no cases of PV associated with MG reported so far. In our first case, both MG and PV presented simultaneously from the initial visit, whereas the second patient presented initially with PV, and MG manifested later, almost six months after initiation of treatment with hydroxyurea. There was no evidence of thymoma. Both patients were treated with hydroxyurea for their PV, but the second patient’s course was complicated with pancytopenia. Patient 1 had positive anti-MuSK antibodies, whereas patient 2 had positive anti-AchR antibodies. There is no clearly defined pathophysiology in the literature regarding the association between PV and MG. The closest possible hypothesis is that of paraneoplastic syndrome. It is postulated that the anti-AchR and anti-MuSK autoantibodies specifically target theα 3 subunit of nicotinic acetylcholine receptors (nAChRs), which are found in the thymus. It is proven that lung cancers and neuroblastomas can express the α 3 subunit of nAChR and thus cause MG without thymoma [10]. Patient 1 had a simultaneous presentation of both PV and MG. In patient 2, even though the MG was diagnosed six months after PV, there was a two-year history of diplopia, raising the possibility of simultaneous onset. Absence of thymoma, simultaneous onset, and positive anti-AChR or anti-MuSK antibodies are features suggesting possible paraneoplastic syndrome, in which PV expresses nAChRs.
Patients with PV who are more than 60 years of age and at high risk of thrombosis need cytoreductive therapy. The most common agent used for cytoreductive treatment in PV is hydroxyurea considering its cost-efficacy and safety profile. But there is no evidence of the benefit of hydroxyurea in patients with MG. One of our patients developed MG after six months of therapy with hydroxyurea. There are no other reports in the literature showing the onset MG after hydroxyurea therapy. Other non-traditional agents that could be used for cytoreductive therapy are busulfan and interferon-alpha. There are several case reports which link the onset of MG with busulfan therapy. Interferon-alpha is an upcoming agent in cytoreductive therapy for PV [11]. Some studies have shown that it is useful in the treatment of MG as well [12]. A few case reports have shown the onset of MG after interferon alpha therapy [13, 14]. It has been concluded that 6 months of IFN α  therapy seems to be safe in MG, though in patients with malignancy, IFN α  may cause increased autoimmunity, AChR positivity and MG [12].