Background
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by clonal proliferation of myeloid cells, which leads to erythrocytosis in all patients and thrombocytosis and/or leukocytosis in half of patients [ 1 ]. Consequently, clinical manifestations include stomach discomfort caused by splenomegaly, minor or overt thrombosis and hemorrhage, vasomotor symptoms, and others. The median age at diagnosis is approximately 60 years, with no significant sex difference. More than 95% of PV patients have an activating Janus kinase 2 ( JAK2 ) gene variation. Therefore, patients who present with characteristic clinical features should be tested for JAK2 mutation, especially the most common V617F and exon12 mutations. The basic components of treatment are therapeutic phlebotomy and antiplatelet agents. Patients with history of thrombosis or who are over 60 years of age are classified as high-risk and should receive cytoreductive drugs, including hydroxyurea, interferon formulations, and ruxolitinib, a JAK1/JAK2 inhibitor [ 2 , 3 ]. Notably, the use of interferons should be avoided in patients with untreated autoimmune diseases. PV carries the risk of evolving into myelofibrosis or acute myeloid leukemia, and these risks are greater among patients with persistent leukocytosis and/or high JAK2 mutation burden [ 3 ].
Stiff-person syndrome (SPS), a rare autoimmune neuronal excitability disorder, occurs more often in the middle-aged and among women. The onset is insidious, and patients gradually develop persistent and intense muscle spasms particularly of the proximal lower limbs and lumbar paraspinal muscles, along with stiffness, task-specific phobias, and other unusual manifestations [ 4 ]. The majority of patients with SPS are positive for autoantibodies against glutamic acid decarboxylase 65 (GAD65). Other associated antibodies are targeted at the glycine receptor (GlyR), γ-aminobutyric acid (GABA) receptors, dipeptidyl peptidase-like protein 6 (DPPX), amphiphysin, and gephyrin [ 5 ]. Paraneoplastic varieties of SPS have been documented, usually in association with breast and lung cancer, and anti-amphiphysin and anti-gephyrin are the commonly responsible autoantibodies. However, research has indicated that SPS patients with anti-GAD65 are also 7 times more likely to have underlying cancer [ 6 ]. Treatments for SPS consist of GABA-enhancing drugs to relieve symptoms and immunotherapy to prevent disease progression. The most commonly applied immunotherapy is intravenous immunoglobulin, while studies have provided evidence that rituximab, plasmapheresis, and autologous hematopoietic stem cell transplantation also could be an option [ 4 , 5 ].
Here, we report possibly the first case of a patient suffering from PV and SPS simultaneously.
Case presentation
A 47-year-old male was hospitalized due to stiffness in the back, activity limitation, and erythrocytosis found incidentally. The patient had generally been in his usual state of health until early March 2024, when he developed stiffness in the back that became increasingly worse, making it difficult for him to bend and roll over. He also experienced paroxysmal stiffness and painful spasms in the abdominal muscles, which attacked at most 10 times a day and was more severe when stimulated by sound at night. The patient had been evaluated in the pain management department of another hospital. Laboratory data showed a red blood cell (RBC) count of 7.94 × 10 12 /L and a hemoglobin (HGB) level of 217 g/L (reference range, 120–160 g/L). His past blood count in August 2022 showed no abnormality. Magnetic resonance imaging (MRI) of the lumbar spine indicated mild degeneration of the intervertebral disks without cord or nerve-root compression and edema of paraspinal soft tissues at T6-7. Oral imrecoxib and baclofen did not relieve the patient’s symptoms. For further diagnosis and treatment, the patient came to the hematology center of our hospital. He denied any other accompanying symptoms or chronic diseases. His family history was negative for neurologic, autoimmune, or neoplastic diseases. His eating and sleeping habits, urination, and defecation were normal, but he had lost approximately 10 kg over the previous year.
Physical examination on admission was notable for a nearly violet face, red conjunctiva, and increased tone at both the back and abdomen, which aggravated when moving or touched. Mild lordosis of the lumbar spine was observed. No enlarged lymph nodes or sternal tenderness were found. The tone, strength, and deep reflexes of four extremities, higher cortical function, sensation, gait, and stance were normal; pathologic signs were negative. Repeated laboratory test results confirmed elevated RBC count, HGB level, and hematocrit level and a lowered erythropoietin (EPO) level of 1.46 mIU/mL (reference range, 2.59–18.50 mIU/mL), as shown in Table 1 . Abdominal ultrasound showed a slightly enlarged spleen. A bone marrow biopsy specimen was markedly hypercellular for his age (80–90% cells) with trilineage proliferation (Fig. 1 ). A molecular genetic study revealed a JAK2 V617F mutation burden of 60.36%. The rectus abdominis and paravertebral muscles exhibited action potentials in the resting state on electromyography. An SPS-relevant antibody profile was then evaluated, which provided a positive result for serum anti-GAD65 (cytometric bead array 1:1000+, Fig. 2 A). Positron emission tomography (PET)/computed tomography (CT) further suggested SPS with elevated uptake values in the cervicodorsal and intercostal muscles (Fig. 2 B). No signs of malignancy were observed.
Table 1 Laboratory tests results On admission 1.5 months before admission Reference range, adult men Red blood cell count (10 12 /L) 7.80 7.94 4.0-5.5 Hematocrit (%) 66.9 40–50 Hemoglobin (g/L) 212 217 120–160 Erythropoietin (mIU/mL) 1.46 2–21 White blood cell count (10 9 /L) 8.03 8.56 4–10 Platelet count (10 9 /L) 278 100–400 Serum ferritin (ng/mL) 18.10 15–200 Serum iron (µmol/L) 9.1 11–30 Creatinine (µmol/L) 43 53–106 D-dimer (µg/mL) 0.58 ≤ 0.5 Lactic dehydrogenase (U/L) 316 109–245 Erythrocyte sedimentation rate Negative - Antinuclear antibodies Negative - HLA-B27 Negative -
Table 1
Laboratory tests results
| On admission | 1.5 months before admission | Reference range, adult men | |
| Red blood cell count (10 12 /L) | 7.80 | 7.94 | 4.0-5.5 |
| Hematocrit (%) | 66.9 | 40–50 | |
| Hemoglobin (g/L) | 212 | 217 | 120–160 |
| Erythropoietin (mIU/mL) | 1.46 | 2–21 | |
| White blood cell count (10 9 /L) | 8.03 | 8.56 | 4–10 |
| Platelet count (10 9 /L) | 278 | 100–400 | |
| Serum ferritin (ng/mL) | 18.10 | 15–200 | |
| Serum iron (µmol/L) | 9.1 | 11–30 | |
| Creatinine (µmol/L) | 43 | 53–106 | |
| D-dimer (µg/mL) | 0.58 | ≤ 0.5 | |
| Lactic dehydrogenase (U/L) | 316 | 109–245 | |
| Erythrocyte sedimentation rate | Negative | - | |
| Antinuclear antibodies | Negative | - | |
| HLA-B27 | Negative | - |
Fig. 1 Hypercellularity observed in bone marrow biopsy specimen by hematoxlyin and eosin and periodic acid-Schiff staining
Fig. 2 A Immunofluorescence examination of Stiff-person syndrome antibody profile showed positive staining for anti-GAD65; B PET/CT showed high uptake values in the paraspinal and intercostal muscles
According to the diagnostic criteria for PV last updated by the World Health Organization (WHO) and International Consensus Criteria (ICC) in 2022 (Table 2 ) [ 1 , 7 ], this patient met al.l diagnostic criteria and was classified as low risk. Intermittent phlebotomy was performed, and low-dose aspirin was given, which failed to lower the patient’s HGB level. After adding hydroxyurea, the HGB remained as high as 200 g/L. Therefore, ruxolitinib was prescribed, and the patient was closely monitored due to the risk of thrombosis. The patient’s HGB level has been maintained at normal range ever since. The diagnosis of probable SPS was made mainly based on clinical manifestations [ 4 ]. Most SPS patients are seropositive, and a high titer of anti-GAD65 is strongly indicative of SPS [ 4 , 5 ]. No evidence of other neurological diseases was found that could explain the patient’s symptoms, and brain MRI also eliminated the possibilities of antibody-related encephalitis or encephalomyelitis. Therefore, he was diagnosed with non-paraneoplastic SPS. After a neurologic consult, diazepam was administrated, and the dose was gradually increased until the spasms improved. The effects later wore off, and diazepam was replaced with clonazepam and baclofen combined with mycophenolate mofetil. However, the patient’s stiffness and spasms worsened, and he developed tingling pain in the back. In addition to increasing the medication dosages, prednisone was added and human immunoglobin was given intravenously for 5 consecutive days, after which the patient’s symptoms resolved.
Table 2 Diagnostic criteria for polycythemia Vera according to WHO and ICC Major criteria 1. Hemoglobin > 165 g/L (men) or > 160 g/L (women), or hematocrit > 49% (men) or > 48% (women), or red blood cell mass elevation 2. Bone marrow biopsy showing age-adjusted hypercellularity with trilineage proliferation* 3. Presence of JAK2 V617F or JAK2 exon 12 mutation** Minor criterion 1. Subnormal serum erythropoietin level *However, initial myelofibrosis is present in approximately 20% patients and predicts rapid progression **In cases negative for these mutations, testing for non-canonical JAK2 mutations may be appropriate
Table 2
Diagnostic criteria for polycythemia Vera according to WHO and ICC
*However, initial myelofibrosis is present in approximately 20% patients and predicts rapid progression **In cases negative for these mutations, testing for non-canonical JAK2 mutations may be appropriate
| Major criteria |
| 1. Hemoglobin > 165 g/L (men) or > 160 g/L (women), or hematocrit > 49% (men) or > 48% (women), or red blood cell mass elevation 2. Bone marrow biopsy showing age-adjusted hypercellularity with trilineage proliferation* 3. Presence of JAK2 V617F or JAK2 exon 12 mutation** |
| Minor criterion |
| 1. Subnormal serum erythropoietin level |
Discussion and conclusions
PV is a clonal MPN that originates from hematopoietic stem cells, with an incidence rate of 0.4–2.8 cases per 100,000. It is pathologically characterized by bone marrow trilineage hypercellularity, which produces an excess of erythrocytes, leukocytes, and platelets. PV usually manifests as purple skin and mucosae, especially in the face and neck and extremities, splenomegaly, increased bleeding tendency, and atypical neurological symptoms, including tinnitus, dizziness, and blurred vision [ 2 , 3 ]. JAK2 is a non-receptor tyrosine kinase that participates in the signal transduction of growth factors such as erythropoietin and thrombopoietin. The JAK2 mutation that changes valine to phenylalanine at the 617 position renders it constitutively activate and increases the sensitivity of hematopoietic cells to growth factors [ 8 ]. Additionally, JAK2 mutation can influence coagulation and thrombosis through upregulation of proinflammatory cytokines [ 9 ]. The main treatment goals are to relieve symptoms and control the risk of thrombosis. Antithrombotic drugs and periodic phlebotomy to lower the hematocrit level to below 45% during plethora constitute the foundation of therapy. Cytoreductive drugs, including hydroxyurea, interferons, and JAK1 / JAK2 inhibitor ruxolitinib, should be given in high-risk patients and those with uncontrolled symptoms or intolerance of phlebotomy [ 3 ]. The selection of these agents should be individualized based on patients’ symptoms, preferences, response to treatment, and adverse events. Approximately 12% and 6% of PV cases transform to myelofibrosis and acute myelocytic leukemia, respectively. The risk factors for fibrotic transformation include persistent leukocytosis, a high JAK2 mutation burden, and the presence of additional gene mutations [ 2 ].
SPS is a rare autoimmune disease affecting the central nervous system, with an incidence rate of 1–2 per million. The symptoms vary, and stiffness and spasms of the affected muscles are nontypical in the early stage. SPS is commonly undiagnosed or misdiagnosed as Parkinson disease, myelopathy, dystonia, or spondylitis [ 4 , 5 ]. Therefore, clinical manifestations, abnormal electromyographic features, and serum or cerebrospinal fluid anti-GAD antibodies should be considered in combination to support accurate diagnosis [ 4 ]. GAD catalyzes the decarboxylation of glutamate to GABA and is the rate-limiting enzyme. Glutamate is the most abundant excitatory neurotransmitter, whereas GABA is the chief inhibitory neurotransmitter in the nervous system [ 10 ]. Anti-GAD antibodies disturb the balance between these two neurotransmitters and enhance neurological excitement, leading to simultaneous and constant contraction of agonist and antagonist muscles [ 6 ]. Nearly 80% of SPS patients are positive for high levels of anti-GAD65 antibodies. Because the pathogenesis of SPS remains unclear, treatments are mainly focused on symptom control. GABA receptor agonists are the most commonly used. Physical therapy and rehabilitation can also help maintain patients’ movement abilities. Immunotherapy has shown some effectiveness in slowing disease progression. Intravenous immunoglobulin (IVIg) and immunosuppressants like corticosteroids, azathioprine, and mycophenolate mofetil are first-line treatments, while the monoclonal antibody rituximab that depletes CD20 + B cells may be beneficial if IVIg is ineffective. Plasmapheresis is an adjunct therapy for patients with severe spasms, and when the above therapies fail, autologous hematopoietic stem cell transplantation or chimeric antigen receptor T cell infusion can be tried [ 5 ].
Very few cases of coexisting autoimmune disease and MPNs have been reported [ 11 , 12 ]. Through a literature review, we found only one case report of the co-occurrence of SPS positive for anti-GAD65 and multiple myeloma, and whether the two conditions were related in that patient remains unknown [ 12 ]. The present case is the first reported case of PV with concurrent SPS, and it is difficult to determine whether these conditions were related to happened incidentally. Because PV was found by chance, the chronological order of the occurrence of the two diseases is not definite. A previous study implied that autoimmune diseases are associated with an increased risk of MPNs, and the researchers proposed that autoimmune conditions cause inflammation-driven tumorigenesis [ 13 ]. Recent studies also suggested that the JAK/STAT pathway plays a role in rheumatic arthritis and cardiovascular events via its proinflammatory activity [ 14 , 15 ]. A genome-wide association study identified a possible link between JAK2 and Crohn’s disease, an inflammatory bowel disease [ 16 ]. These collective findings suggest that constitutive activation of JAK2 may regulate autoimmunity through chronic inflammation, and further research is needed to determine the underlying molecular mechanism.
The initial treatment goals for the present case were to control the patient’s risk of thrombosis, relieve the patient’s muscle discomfort, and preserve the patient’s movement ability. Importantly, the use of interferons should be avoided in patients with autoimmune diseases. The present case highlights the importance of precision medicine. Multi-disciplinary treatment, close follow-up, prompt adjustment of medications, and supportive care are crucial to improving the quality of life of patients with complicated rare diseases.
Abbreviations
Polycythemia vera
Myeloproliferative neoplasm
Janus kinase 2
Stiff-person syndrome
Glutamic acid decarboxylase 65
Glycine receptor
γ-aminobutyric acid
Dipeptidyl peptidase-like protein 6
Red blood cell
Hemoglobin
Intravenous immunoglobulin
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Authors' contributions
Haixia Mu: Conceptualization, Data curation, Investigation, Writing - original draft; Fengxia Ji, Rongfeng Du and Lingyan Hou: Data curation, Investigation, Writing - original draft; Yanni Li, Xiujun Yang, Chunxiao Shao and Kaijuan Hou: Formal analysis, Investigation, Writing - review & editing; Yanping Wang: Conceptualization, Investigation, Resources, Supervision, Validation, Writing - review & editing.
Funding
This study was not supported by any sponsor or funder.
Data availability
All data generated or analyzed during this study are included in this published article. Further enquiries can be directed to the corresponding author.
Declarations
Ethics approval and consent to participate
This study was reviewed and approved by the Ethics Committee of Laizhou People’s Hospital. All procedures were conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from the individual participant included in the study.
Consent for publication
Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Competing interests
The authors declare no competing interests.
References
1. Thiele J Kvasnicka HM Orazi A Gianelli U Gangat N Vannucchi AM The international consensus classification of myeloid neoplasms and acute leukemias: myeloproliferative neoplasms Am J Hematol 2023 98 166 79 10.1002/ajh.26751 36200127 Thiele J, Kvasnicka HM, Orazi A, Gianelli U, Gangat N, Vannucchi AM, et al. The international consensus classification of myeloid neoplasms and acute leukemias: myeloproliferative neoplasms. Am J Hematol. 2023;98:166–79. 36200127 10.1002/ajh.26751
2. Tefferi A Barbui T Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management Am J Hematol 2023 98 1465 87 10.1002/ajh.27002 37357958 Tefferi A, Barbui T. Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98:1465–87. 37357958 10.1002/ajh.27002
3. Tremblay D Kremyanskaya M Mascarenhas J Hoffman R Diagnosis and treatment of polycythemia vera: A review JAMA 2025 333 153 60 10.1001/jama.2024.20377 39556352 PMC11921015 Tremblay D, Kremyanskaya M, Mascarenhas J, Hoffman R. Diagnosis and treatment of polycythemia vera: A review. JAMA. 2025;333:153–60. 39556352 10.1001/jama.2024.20377 PMC11921015
4. Chia NH McKeon A Dalakas MC Flanagan EP Bower JH Klassen BT Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria Ann Clin Transl Neurol 2023 10 1083 94 10.1002/acn3.51791 37212351 PMC10351653 Chia NH, McKeon A, Dalakas MC, Flanagan EP, Bower JH, Klassen BT, et al. Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria. Ann Clin Transl Neurol. 2023;10:1083–94. 37212351 10.1002/acn3.51791 PMC10351653
5. Dalakas MC Stiff-person syndrome and related disorders - diagnosis, mechanisms and therapies Nat Rev Neurol 2024 20 587 601 10.1038/s41582-024-01012-3 39227464 Dalakas MC. Stiff-person syndrome and related disorders - diagnosis, mechanisms and therapies. Nat Rev Neurol. 2024;20:587–601. 39227464 10.1038/s41582-024-01012-3
6. Ariño H Höftberger R Gresa-Arribas N Martínez-Hernández E Armangue T Kruer MC Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies JAMA Neurol 2015 72 874 81 10.1001/jamaneurol.2015.0749 26099072 PMC4838033 Ariño H, Höftberger R, Gresa-Arribas N, Martínez-Hernández E, Armangue T, Kruer MC, et al. Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies. JAMA Neurol. 2015;72:874–81. 26099072 10.1001/jamaneurol.2015.0749 PMC4838033
7. Khoury JD Solary E Abla O Akkari Y Alaggio R Apperley JF The 5th edition of the world health organization classification of haematolymphoid tumours: myeloid and Histiocytic/Dendritic neoplasms Leukemia 2022 36 1703 19 10.1038/s41375-022-01613-1 35732831 PMC9252913 Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the world health organization classification of haematolymphoid tumours: myeloid and Histiocytic/Dendritic neoplasms. Leukemia. 2022;36:1703–19. 35732831 10.1038/s41375-022-01613-1 PMC9252913
8. Morgan KJ Gilliland DG A role for JAK2 mutations in myeloproliferative diseases Annu Rev Med 2008 59 213 22 10.1146/annurev.med.59.061506.154159 17919086 Morgan KJ, Gilliland DG. A role for JAK2 mutations in myeloproliferative diseases. Annu Rev Med. 2008;59:213–22. 17919086 10.1146/annurev.med.59.061506.154159
9. Perner F, Perner C, Ernst T, Heidel FH. Roles of JAK2 in Aging, Inflammation, hematopoiesis and malignant transformation. Cells. 2019;8. 10.3390/cells8080854 PMC6721738 31398915
10. Koh W Kwak H Cheong E Lee CJ GABA tone regulation and its cognitive functions in the brain Nat Rev Neurosci 2023 24 523 39 10.1038/s41583-023-00724-7 37495761 Koh W, Kwak H, Cheong E, Lee CJ. GABA tone regulation and its cognitive functions in the brain. Nat Rev Neurosci. 2023;24:523–39. 37495761 10.1038/s41583-023-00724-7
11. Clow EC Couban S Grant IA Stiff-person syndrome associated with multiple myeloma following autologous bone marrow transplantation Muscle Nerve 2008 38 1649 52 10.1002/mus.21153 18932204 Clow EC, Couban S, Grant IA. Stiff-person syndrome associated with multiple myeloma following autologous bone marrow transplantation. Muscle Nerve. 2008;38:1649–52. 18932204 10.1002/mus.21153
12. Schiff D Dalmau J Myers DJ Anti-GAD antibody positive Stiff-Limb syndrome in multiple myeloma J Neurooncol 2003 65 173 5 10.1023/B:NEON.0000003754.34527.f2 14686738 Schiff D, Dalmau J, Myers DJ. Anti-GAD antibody positive Stiff-Limb syndrome in multiple myeloma. J Neurooncol. 2003;65:173–5. 14686738 10.1023/b:neon.0000003754.34527.f2
13. Kristinsson SY Landgren O Samuelsson J Björkholm M Goldin LR Autoimmunity and the risk of myeloproliferative neoplasms Haematologica 2010 95 1216 20 10.3324/haematol.2009.020412 20053870 PMC2895049 Kristinsson SY, Landgren O, Samuelsson J, Björkholm M, Goldin LR. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica. 2010;95:1216–20. 20053870 10.3324/haematol.2009.020412 PMC2895049
14. Baldini C Moriconi FR Galimberti S Libby P De Caterina R The JAK-STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms Eur Heart J 2021 42 4389 400 10.1093/eurheartj/ehab447 34343257 PMC8572559 Baldini C, Moriconi FR, Galimberti S, Libby P, De Caterina R. The JAK-STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms. Eur Heart J. 2021;42:4389–400. 34343257 10.1093/eurheartj/ehab447 PMC8572559
15. Virtanen A Spinelli FR Telliez JB O’Shea JJ Silvennoinen O Gadina M JAK inhibitor selectivity: new opportunities, better drugs? Nat Rev Rheumatol 2024 20 649 65 10.1038/s41584-024-01153-1 39251770 Virtanen A, Spinelli FR, Telliez JB, O’Shea JJ, Silvennoinen O, Gadina M. JAK inhibitor selectivity: new opportunities, better drugs? Nat Rev Rheumatol. 2024;20:649–65. 39251770 10.1038/s41584-024-01153-1
16. Barrett JC Hansoul S Nicolae DL Cho JH Duerr RH Rioux JD Genome-wide association defines more than 30 distinct susceptibility loci for crohn’s disease Nat Genet 2008 40 955 62 10.1038/ng.175 18587394 PMC2574810 Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for crohn’s disease. Nat Genet. 2008;40:955–62. 18587394 10.1038/NG.175 PMC2574810