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].