Introduction
Polyclonal hypergammaglobulinemia (PHGG) results from the excessive production of immunoglobulins in response to diverse immunological challenges. In contrast to monoclonal hypergammaglobulinemia, whereby the monoclonal nature of immunoglobulin-producing cells is the central component of the pathophysiology ( 1 ), the etiologies of PHGG are manifold and not limited to hematological diseases, thus requiring clinicians to be well-versed with its diagnostic procedures and diverse differential diagnoses ( 2 - 6 ). While the diagnostic process of monoclonal hypergammaglobulinemia is relatively straightforward ( 7 - 9 ), it is often confounded when coincidentally encountered or consulted for PHGG, especially when some disease overlap is suspected. We therefore conducted a retrospective study of patients with PHGG to characterize the multimorbidity associated with PHGG.
Materials and Methods
We reviewed the medical records of all patients who underwent serum electrophoresis (SPEP) at the Department of Hematology and Oncology, The University of Tokyo Hospital between June 1, 2018, and May 31, 2023. We identified 209 patients with hypergammaglobulinemia, as defined by gamma-globulin levels ≥20 g/L ( 6 , 10 ). Gamma-globulin levels were calculated as (total protein×percentage of gamma globulin). For patients who underwent several SPEP examinations during this period, a value that exceeded 20 g/L for the first time was chosen for analysis. For these 209 patients, age, sex, globulin clonality, gamma-globulin levels, and associated conditions were extracted from the medical records. In patients with PHGG, laboratory data, including complete blood tests, biochemicals, and immunological markers, and imaging data with computed tomography (CT) obtained on the most immediate date within three months from the day of SPEP were extracted from the records. A fluorescent antibody test was used to detect anti-nuclear antibodies (ANAs). When SPEP revealed an M-peak in gamma-globulin regions, the result was interpreted as monoclonal, whereas when the protein had migrated to a broad range of gamma-globulin regions without an M-peak, the result was interpreted as polyclonal. In ambiguous cases, serum immunofixation was performed to determine clonality. Hepatomegaly, splenomegaly, and lymphadenopathy were detected by radiologists and confirmed by the physicians. In this study, the patients' medical conditions were organized into one of the following categories: hematological disorders, including hematological malignancies, autoimmune and autoinflammatory diseases, liver diseases, non-hematological malignancies, infection excluding viral hepatitis, other diseases, and iatrogenic states. Non-parametric tests were employed throughout this study to determine the significance of the data. Statistical tests and p values are mentioned in each figure legend and in the main text. Comparisons of continuous values between two groups were analyzed using the two-tailed-Mann Whitney U test, and comparisons between more than two groups were analyzed using the Kruskal-Wallis test. A receiver operating characteristic curve (ROC) was constructed to determine the predictive ability of biomarkers based on the area under the curve (AUC). p values less at p＜0.05. All statistical analyses and figure presentations were conducted and prepared using the Python software program.
Results
Globulin clonality and associated conditions
Of the 209 patients with hypergammaglobulinemia, 130 and 79 had monoclonality and polyclonality, respectively. Each of the monoclonal hypergammaglobulinemia cases was diagnosed with hematological disorders, such as multiple myeloma and Waldenström macroglobulinemia, except for five patients who did not have a confirmed diagnosis ( Table 1 ). Compared with patients with monoclonal hypergammaglobulinemia, those with PHGG were younger [median 71.0 years old (yo) vs. 65 yo; p=0.002] and had lower gamma-globulin levels (median, 26.5 g/L vs 24.8 g/L; p=0.03). Sex-dependent differences were not observed for age or gamma globulin levels ( Fig. 1A, B ). Among the 79 patients with PHGG, 46 different diseases were classified into one of the six predetermined disease categories (Tables 1 , 2 2 ). Thirteen patients had no definitive diagnosis. The gamma-globulin levels were similar between the disease categories ( Fig. 1C ).
Table 1.
Conditions Associated with Monoclonal and Polyclonal Hypergammaglobulinemia.
*In some of the conditions in PHGG, numbers in the parentheses represent the number of patients with multiple comorbidities associated also with the disease.
| Total patient count | 209 | ||||||
| Monoclonal patient count | 130 | Polyclonal patient count | 79 | ||||
| Hematological disorder (14 diseases) | Single disease patients | 49 | |||||
| Multiple myeloma | 49 | Multiple disease patients | 15 | ||||
| Monoclonal gammopathy of undetermined significance | 32 | Iatrogenic (IVIg) | 2 | ||||
| Waldenström macroglobulinemia/lymphoplasmacytic lymphoma | 20 | Undiagnosed | 13 | ||||
| Smoldering myeloma | 8 | Hematological disorder (22 diseases) | |||||
| Diffuse large B-cell lymphoma | 4 | Immune thrombocytopenia | 4 (3)* | ||||
| Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue | 3 | Erdheim-Chester disease | 3 | ||||
| AL amyloidosis | 2 | Myelodysplasic syndromes | 3 | ||||
| Erdheim-Chester disease | 1 | Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue | 2 (2)* | ||||
| Multicentric Castleman disease | 1 | Anaplastic large cell lymphoma | 2 | ||||
| B-cell lymphoblastic leukemia | 1 | Multicentric Castleman disease | 2 | ||||
| Hemophagocytic lymphohistiocytosis, Epstein-Barr virus associated | 1 | Hodgkin lymphoma | 2 | ||||
| Polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation, Epstein-Barr virus associated | 1 | Chronic myelomonocytic leukemia | 2 (1)* | ||||
| Clonal hematopoiesis of indeterminate potential | 1 | Myelodysplastic/myeloproliferative neoplasm, not otherwise specified | 1 (1)* | ||||
| Angioimmunoblastic T-cell lymphoma | 1 | Monoclonal gammopathy of undetermined significance | 1 (1)* | ||||
| Undiagnosed | 5 | Polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation, methotrexate associated | 1 (1)* | ||||
| Clonal cytopenia of undetermined significance | 1 | ||||||
| Acute myeloid leukemia | 1 | ||||||
| Acquired hemophilia | 1 | ||||||
| Plasmablastic lymphoma | 1 (1)* | ||||||
| Acquired aplastic anemia | 1 (1)* | ||||||
| Warm autoimmune hemolytic anemia | 1 (1)* | ||||||
| NK-large granular lymphocytic leukemia | 1 | ||||||
| Iron deficiency anemia | 1 | ||||||
| Polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation, posttransplant associated | 1 | ||||||
| Mantle cell lymphoma | 1 | ||||||
| Autoimmune pancytopenia, post-autologous HSCT | 1 | ||||||
| Autoimmune and autoinflammatory disorder (10 diseases) | |||||||
| Sjögren’s syndrome | 11 (8)* | ||||||
| Rheumatoid arthritis | 4 (2)* | ||||||
| Sarcoidosis | 2 (2)* | ||||||
| Scleroderma (including localized and systemic) | 2 (1)* | ||||||
| Systemic lupus erythematosus | 2 (2)* | ||||||
| Autoimmune thyroid disease (chronic thyroiditis) | 1 (1)* | ||||||
| Atopic dermatitis | 1 | ||||||
| Myasthenia gravis | 1 | ||||||
| Dermatomyositis | 1 | ||||||
| Immunoglobulin 4-related disease | 1 | ||||||
| Liver disease (4 diseases) | |||||||
| Primary biliary cirrhosis | 5 (4)* | ||||||
| Hepatitis C | 2 | ||||||
| Autoimmune hepatitis | 2 (2)* | ||||||
| Alcoholic cirrhosis | 2 | ||||||
| Malignancy (5 diseases) | |||||||
| Pancreas cancer | 2 | ||||||
| Cancer of unknown origin | 2 | ||||||
| Dedifferentiated liposarcoma | 1 | ||||||
| Odontogenic myxofibroma | 1 | ||||||
| Glottis cancer | 1 | ||||||
| Infection (3 diseases) | |||||||
| LTBI | 1 (1)* | ||||||
| Syphilis | 1 | ||||||
| Liver abscess | 1 | ||||||
| Others | |||||||
| Erythroderma | 1 | ||||||
| Cutaneous plasmacytosis | 2 |
Table 2.
Characteristics of Patients with PHGG. Undiagnosed Cases (13 Patients) are Excluded.
| Characteristics | Total | Single diagnosis (excluding iatrogenic causes) | >1 diagnosis | Iatrogenic | ||||||
| Total | Hematological | Autoimmune | Liver disease | Malignancy | Infection | Others | ||||
| (n=66) | (n=49) | (n=22) | (n=10) | (n=5) | (n=7) | (n=2) | (n=3) | (n=15) | (n=2) | |
| Median age (years) | 65 | 64 | 59 | 65 | 52 | 66 | 74.5 | 56 | 77 | 47 |
| Age range (years) | 28-87 | 29-87 | 29-87 | 35-83 | 34-84 | 33-83 | 72-77 | 49-65 | 28-87 | 23-71 |
| Female sex (%) | 56.3 | 51.0 | 50.0 | 80.0 | 20.0 | 57.1 | 0.0 | 33.3 | 73.3 | 0.0 |
| Hepatomegaly (%) | 1.6 | 2.0 | 0.0 | 0.0 | 20.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
| Splenomegaly (%) | 12.5 | 12.2 | 18.2 | 0.0 | 20.0 | 14.3 | 0.0 | 0.0 | 13.3 | 0.0 |
| Lymphadenopathy (%) | 28.1 | 28.6 | 36.4 | 20.0 | 0.0 | 28.6 | 50.0 | 33.3 | 26.7 | 50.0 |
Multimorbidity in PHGG
An illustrative case
Interestingly, 15 of the 79 patients (19.0%) with PHGG had more than one diagnosis. In patients with a single diagnosis, excluding iatrogenic and undiagnosed cases, the number of male and female patients was almost the same (24 males and 25 females), and patients with multiple diseases were mainly females (3 males and 12 females). Compared to PHGG patients with a single diagnosis, these patients with multiple comorbidities had higher gamma-globulin levels (median, 23.9 g/dL vs. 31.0 g/dL; p=0.01), which seemed to be dependent on the number of associated diseases ( Fig. 2A, B ). The clinical vignettes of the 15 patients with PHGG and multiple comorbidities are summarized in Table 3 . Several diseases were commonly found in these patients: eight patients were diagnosed with SS, four patients had primary biliary cirrhosis, and three patients had immune thrombocytopenia ( Table 1 ). As for the overlap among different disease categories, nine patients had diseases categorized as autoimmune and hematological diseases, and six patients had diseases categorized as autoimmune and liver diseases. All but two (Cases 6 and 12, Table 3 ) of the 15 patients with multimorbidity had diseases spanning more than one disease category. In 11 patients, the diseases were diagnosed sequentially, while in others, almost completely concurrent diagnoses were made (Cases 7, 13, 14, and 15). In one patient (Case 15, illustrative case ), as many as four diagnoses were made simultaneously. To characterize these unique populations of multimorbidity, we evaluated whether commonly performed immunological screening tests, namely ANAs and CRP levels, could distinguish patients with multiple comorbidities from those with a single disease. As shown in Fig. 2C and D , we found that the ANA titers, but not CRP values, have a discriminative ability with an overall AUC of 0.81 (95% confidence interval: 0.65-0.96). The presence of ANAs, regardless of titer (≥1:40), had a high sensitivity (92.3%), although with low specificity (42.1%). These results indicate that clinicians should suspect disease overlap when ANA is positive in patients with PHGG.
Table 3.
Clinical Vignettes of 15 PHGG Patients with Multiple Comorbidities.
AA: acquired aplastic anemia, Ab: antibody, AIH: autoimmune hepatitis, ANA: anti-nuclear antibody, CMML: chronic myelomonocytic leukemia, CT: computed tomography, SPEP: serum protein electrophoresis, ITP: immune thrombocytopenia, MALT lymphoma: extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, MDS/MPN-U: myelodysplastic/myeloproliferative neoplasm, not otherwise specified: MGUS: monoclonal gammopathy of undetermined significance, MTX-LPD: polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation, methotrexate associated, MuSK: muscle-specific tyrosine kinase, Nd: no data, PBC: primary biliary cirrhosis, PHGG: polyclonal hypergammaglobulinemia, RA: rheumatoid arthritis, RF: rheumatoid factor, SS: Sjögren’s syndrome, SSA: Sjögren’s syndrome-A, SSB: Sjögren’s syndrome-B, SSc: scleroderma, Tg: thyroglobulin, TPO: thyroid peroxidase, wAIHA: warm autoimmune hemolytic anemia, yo: years old
| Clinical vignettes | Gamma-globulin (g/L) | CRP (0-0.3 mg/dL) | Autoantibodies | Diagnosis when PHGG was detected | |
| Case 1 | 77-year-old woman with a 23-year history of RA treatment including methotrexate was referred to our department because of lymphadenopathy. PHGG was detected with SPEP. On biopsy, she was diagnosed with MTX-LPD. | 20.0 | 24.66 | RF | RA, MTX-LPD |
| Case 2 | 83-year-old man with a 50-year history of RA treatment showed progressing thrombocytopenia and PHGG. ITP was considered on scrutiny. | 23.4 | 0.79 | ANA (speckle), anti-SSA Ab, anti-glycoprotein IIb/IIIa Ab | RA, ITP |
| Case 3 | 46-year-old woman was diagnosed with MALT lymphoma on needle biopsy of the parotid gland. Two years prior to the diagnosis, she complained of dry eye, and was positive for anti-SSA/B Ab, highly suspicious of SS, of which she had declined further examinations. | 24.2 | 0.02 | ANA (speckle), anti-SSA Ab, anti-SSB Ab, RF | SS, MALT lymphoma |
| Case 4 | 81-year-old woman presented with normocytic anemia with PHGG. She was diagnosed with SS at 79 yo and PBC at 80 yo. Further examination showed deficiency of zinc and folic acid, of which supplementation normalized the blood count. | 24.3 | 0.44 | ANA (centromere), anti-SSA Ab, anti-mitochondria m2 Ab | SS, PBC |
| Case 5 | 77-year-old man was referred to our department for progressing multiple soft tissue enlargement. He showed PHGG, and needle biopsy of tumor in abdominal cavity showed fibrosis tissue with small lymphocytic infiltration. Immunostaining for lymphoma and IgG4-related disorder were negative. He had been diagnosed with PBC at 65 yo and SS at 75 yo. He died of massive pleural effusion without definitive diagnosis shortly thereafter. | 24.9 | 0.35 | ANA (homogenous, speckle, mitochondria), anti-dsDNA Ab, anti-SSA Ab, anti-mitochondria m2 Ab | PBC, SS |
| Case 6 | 43-year-old woman was referred to our department because of progressing leukocytopenia and anemia during treatment for SS, chronic thyroiditis and SLE. She had been diagnosed with SS at 30 yo and chronic thyroiditis at 36 yo. Although she did not meet the diagnostic criteria for SLE, she was treated accordingly from 42 yo because of progressing hair loss, cytopenia, and decrease of complement, and detection of anti-ssDNA Ab. She showed PHGG (27.9 g/L). Her blood count was stable thereafter. | 27.9 | 0.02 | ANA (speckle, nucleolar), RF, anti-TPO Ab, anti-Tg Ab | SS, chronic thyroiditis |
| Case 7 | 78-year-old woman was referred to our department because of PHGG. Liver function was exacerbating, therefore, ursodeoxycholic acid was initiated with clear response, making the PBC diagnosis highly likely. At the same time, she experienced sicca syndrome. On further inspection, she was also diagnosed with SS. | 30.3 | 0.51 | ANA (speckle, nuclear envelope, cytoplasmic), anti-SSA Ab, anti-SSB Ab, anti-mitochondria m2 Ab | PBC, SS |
| Case 8 | 66-year-old man was referred to our department for thrombocytopenia and PHGG. He had been treated for PBC and localized SSc. Bone marrow was mildly hypocellular, compatible with AA. He required no treatment. | 31.0 | 0.34 | ANA (speckle, centromere, mitochondria), anti-mitochondria m2 antibody, anti-dsDNA Ab, anti-ssDNA Ab, anti-centromere Ab | PBC, SSc, AA |
| Case 9 | 28-year-old woman with congenital genetic abnormalities of unknown significance showed PHGG on SPEP. She had been treated with romiplostim for refractory ITP. Shortly thereafter, she experienced dyspnea on exertion was diagnosed with lymphocytic interstitial pneumonia associated with SS. Blisters were also noted, and skin biopsy revealed anti-desmogrein 3 Ab positive, suggestive of pemphigus vulgaris. | 33.2 | 0.45 | ANA (speckle, cytoplasmic), β2 glycoprotein I IgG, anti-SSB Ab, anti-TPO Ab, anti TgAb, anti-desmogrein 3 Ab (skin biopsy) | ITP, SS |
| Case 10 | 54-year-old woman with a history of SLE and associated inclusion body myositis was referred to our department because of PHGG on SPEP. Immunofixation showed IgG-kappa monoclonal protein as well. Based on this result and other findings, she was diagnosed with MGUS. | 33.6 | 2.1 | ANA (nucleolar, cytoplasmic), anti-dsDNA Ab, anti-ssDNA Ab, anti-Sm Ab, anti-RNP Ab, anti-SSA Ab, anti-SSB Ab | SLE, MGUS |
| Case 11 | 77-year-old man was referred to our department for thrombocytosis. PHGG was detected, and bone marrow examination identified MDS/MPN-U. He had been diagnosed with sarcoidosis at 60 yo. Two years after the referral, he was diagnosed with chronic thyroiditis. At 80 yo, transformation to AML was revealed, and treated accordingly. | 33.7 | 1.5 | ANA (nucleolar) | MDS/MPN-NOS, sarcoidosis |
| Case 12 | 83-year-old woman presented with tumor arising at tongue base. Laboratory data revealed high soluble IL-2 receptor and PHGG. Plasmablastic lymphoma was detected on biopsy. She had been carefully followed for CMML for three years. With dementia, best supportive care was chosen. | 37.3 | 0.37 | Nd | CMML, plasmablastic lymphoma |
| Case 13 | 56-year-old man was hospitalized for liver transplant for AIH. Diagnostic criteria for SS and SLE were met at the preoperative screening. PHGG was also detected. | 38.6 | 1.03 | ANA (speckle), RF, anti-dsDNA Ab, anti-SSA Ab, anti-SSB Ab | AIH, SS, SLE |
| Case 14 | 82-year-old woman presented with thrombocytopenia and anemia with PHGG. She suffered from sarcoidosis for nearly 20 years. Laboratory as well as biopsy from an enlarged lymph node indicated sarcoidosis, but the disease activity seemed low. Eventually, she was diagnosed with ITP plus wAIHA (Evans syndrome). | 54.7 | 0.38 | ANA (centromere, cytoplasmic), β2 glycoprotein I IgG, anti-glycoprotein IIb/IIIa Ab | Sarcoidosis, ITP, AIHA |
| Case 15 (illustrated case, see text) | 50-year-old woman was referred to our department because of PHGG and liver function test abnormalities. Lymphadenopathy and gland enlargement were noted. She was diagnosed concurrently with SS, MALT lymphoma, and AIH. She was also diagnosed with latent tuberculosis infection because she was tested positive for interferon gamma release assay and for sputum polymerase chain reaction test for tuberculosis. | 56.4 | 0.88 | ANA (homogenous, speckle, cytoplasmic), anti-SSA/B Ab, anti-MuSK-Ab (equivalent to upper limit) | AIH, SS, MALT lymphoma, latent tuberculosis infection |
Discussion
PHGG is a classic problem in both clinical and basic internal medicine ( 11 , 12 ). The humoral arm of adaptive immunity and immunoglobulin production by plasma cells are dependent on various transcriptional factors, cytokines, and interactions with other immune cells during plasma cell differentiation ( 13 ). These processes of globulin production can occur in both inflammatory and non-inflammatory ways, triggered by endo- and exogenous stimuli associated with each disease condition ( 5 ). The seemingly incremental increase in the gamma-globulin levels irrespective of CRP level in multimorbidity in our cohort might reflect the cumulative effect of these different, but not always inflammatory, pathways that converge on the excessive activation of antibody-secreting plasma cells. Making an accurate assessment and diagnosis of these overlapping conditions is challenging; however, our analysis showed that the presence of ANAs is highly sensitive to multimorbid states. Clinicians observing PHGG and ANAs in patients should therefore be particularly alert to the presence of multifactorial conditions.
The underlying etiology of multimorbidity in PHGG is of special interest because it represents a unique immunogenicity in a subset of the population. In our study, multimorbidity was observed in 19.0% of our PHGG patients, which is in line with previous studies reporting 9.1 to 19.0% ( 2 , 3 , 10 ). These patients were associated not only with autoimmune diseases, but also with hematological diseases such as monoclonal gammopathy of undetermined significance and myelodysplastic syndromes. Indeed, 13 out of 15 patients with multimorbidity had disease spanning more than one disease category: nine patients had both autoimmune and hematological diseases, and six patients had autoimmune and liver diseases. The kaleidoscope of diseases in a single patient revealed in our study is thus not restricted to the state of ‘polyautoimmunity,’ defined by the presence of more than one autoimmune disease ( 14 ), but it extends to the potential interaction of autoimmune diseases with the development of hematological malignancies ( 15 - 17 ). In particular, SS was recurrently found in PHGG patients with multimorbidity (8 of 15 patients). The diagnosis was associated with extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue, primary biliary cirrhosis, chronic thyroiditis, aplastic anemia, immune thrombocytopenia, autoimmune hepatitis, and tuberculosis infection. The causative relationship between these myriad diseases is limited to speculations; however, it could be that patients with SS are highly immunogenic. The relationship to other autoimmune and hematological diseases of SS points to a common genetic background and immunological disturbances ( 18 ). The female predominance in multimorbidity might also be reflective of genetic and endocrine predispositions in this subset of patients.
This study is associated with some limitations inherent to a retrospective analysis conducted at a single hematology tertiary referral center. The sample size was relatively small, and some selection bias towards hematological disorders and rare diseases did exist. Uniform procedures were not employed for inspecting PHGG, and diagnoses were made solely at the discretion of the attending physicians. Consequently, it is possible that certain overlapping diseases may have been overlooked. The difference in the cutoff for gamma-globulin levels might explain the difference in the proportions of and gamma-globulin levels in disease categories from previous studies ( 2 , 3 ). Despite these limitations, this study established multimorbidity in PHGG patients and demonstrated the high sensitivity of ANAs to the multimorbidity state. Further studies are therefore warranted to validate these findings.
In summary, PHGG patients with multiple diseases showed higher levels of gamma-globulins than patients with monoclonal hypergammaglobulinemia in a disease-dependent manner, and the presence of ANAs was highly sensitive to multimorbidity in PHGG. These results indicate that the gamma-globulin levels and ANAs could be useful biomarkers of the host's intertwined immunological state and could aid in the clinical assessment of comorbidities in PHGG.
The authors state that they have no Conflict of Interest (COI).
Financial Support
This study was supported by grant 21H04805 to MK from the Japan Society for the Promotion of Science.
The authors would like to thank the patients and physicians, nurses, pharmacists, and other co-medical staff for their care of the patients involved in the study.
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