Positive Anti-nuclear Antibody in Patients with Polyclonal Hypergammaglobulinemia Suggests the Presence of Multiple Distinct Comorbidities

Abstract

Objective Polyclonal hypergammaglobulinemia (PHGG) is a classic problem in internal medicine; however, its conditions and diagnostic procedures have not been well studied. We therefore conducted a retrospective study to characterize the PHGG disease spectrum. Methods We included all patients who underwent serum protein electrophoresis (SPEP) at a hematology tertiary referral center during a five-year period. For these patients, globulin clonality was determined and clinical data were extracted from the records. Results Out of 209 consecutive cases of hypergammaglobulinemia demonstrated by SPEP, 79 cases of PHGG were identified. A total of 46 diagnoses were associated with PHGG. Patients 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) than those with monoclonal hypergammaglobulinemia. Interestingly, out of 79 patients with PHGG, 15 were associated with more than one diagnosis, and a female predominance was observed in this specific subset of patients. PHGG cases with multiple diseases showed higher gamma-globulin levels than those with monoclonal hypergammaglobulinemia, in a disease-dependent manner. Additionally, positive anti-nuclear antibodies (ANAs) had a discriminative ability with an area under the curve of 0.81 (95% confidence interval, 0.65-0.96) and were highly sensitive to multimorbidity in PHGG (sensitivity, 92.3%). Conclusion These results establish a previously underappreciated unique immunological state of multimorbidity in PHGG and indicate that the gamma-globulin levels and ANAs could serve as markers for the clinical assessment of comorbidities in PHGG.

Keywords: anti-nuclear antibody; differential diagnosis; monoclonal hypergammaglobulinemia; multimorbidity; polyclonal hypergammaglobulinemia.

Figure 1.

Characteristics of hypergammaglobulinemia stratified by globulin clonality (monoclonal, n=130 and polyclonal, n=79). (A and B) Age (A) and gamma-globulin level (B) are plotted using boxplots. Males (blue dots) and females (red dots) are separately depicted. Patients with PHGG were younger [median 71.0 years old (yo) vs. 65 yo; p=0.002, Mann-Whitney U test] and had lower gamma-globulin level (median, 26.5 g/L vs. 24.8 g/L; p=0.03, Mann-Whitney U test). Age was statistically indistinguishable between male and female patients in both monoclonal (median, 71.5 yo vs. 70.0 yo; p=0.25, Mann-Whitney U test) and polyclonal (median, 65.0 yo vs. 66.0 yo; p=0.85, Mann-Whitney U test) patients. The gamma-globulin levels were also statistically indistinguishable between male and female patients in both monoclonal (median, 26.7 g/dL vs. 26.3 g/dL; p=0.47, Mann-Whitney U test) and polyclonal (median, 23.7 g/dL vs. 26.2 g/dL; p=0.14, Mann-Whitney U test) patients. (C) Gamma-globulin levels were indistinguishable between six disease groups (p=0.25, Kruskal-Wallis test). Diseases that coexist in a single patient were excluded from the analysis.

Figure 2.

Characteristics of PHGG associated with a single (n=49) or multiple (n=15) diseases. Iatrogenic and undiagnosed cases were excluded from the analysis. (A) The gamma-globulin levels of patients associated with a single or multiple diseases (median, 23.9 g/dL vs. 31.0 g/dL; p=0.01, Mann-Whitney U test). (B) When stratified further with the number of associated diseases, gamma-globulin levels tended to increase in a disease count-dependent manner (p=0.02, Kruskal-Wallis test. Post hoc test was not conducted due to the small number of patients). Note that patients with multiple diseases are mainly composed of females (red dots; 12 out of 15 patients). (C) An ROC curve describing the discriminative power of ANA titer (black curve) and CRP value (gray curve) for multimorbidity. Youden’s index was maximized at the ANA titer of 1:320, with sensitivity of 76.9% and specificity of 76.3%. (D) Gamma-globulin levels of patients associated with positive (i.e., ≥1:40) or negative ANAs. In positive ANA patients, the gamma-globulin levels tended to be higher in patients with multimorbidity (median, 25.8 g/dL vs. 31.0 g/dL; p=0.051, Mann-Whitney U test).