Hypergammaglobulinemia in Hidradenitis Suppurativa Patients: A New Emerging Association

Introduction

Hypergammaglobulinemia is an immunoproliferative disorder characterized by elevated levels of gamma globulins, proteins found in the gamma fraction of a serum electrophoretic trace. The increase in these proteins can be pathologically significant as it is associated with various diseases such as inflammatory conditions, cirrhosis, connective tissue diseases, acute hepatitis, mononucleosis, Hodgkin’s lymphoma, malignant neoplasms, plasmacytoma, parasitic infections, Hashimoto’s thyroiditis, burns, and sarcoidosis. Conversely, a decrease in their levels has been observed in immunosuppressive states such as AIDS, renal failure, Cushing’s syndrome, and with the use of immunosuppressive drugs and steroids.^1,2 Monoclonal gammopathy of undetermined significance (MGUS) occurs in 3.2% of persons 50 years of age or older and in 5.3% of those 70 years of age or older.²

The higher prevalence in older age is justified by immunosenescence, which is the physiological and gradual deterioration of the immune system because of aging. It is a multifactorial condition associated with advancing age. The factors that predispose to this condition are primarily age but also include chronic viral infections that cause antigenic stimulation, malnutrition and undernutrition (particularly protein deficiency), dysregulation of various hormonal pathways, and smoking.³

Materials and Methods

These concepts gave rise to our retrospective single-center, observational study designed to evaluate the potential association between hypergammaglobulinemia and hidradenitis suppurativa (HS) according to sex, age, disease severity according IHS4 score, and treatment with Adalimumab in HS patients. Hypergammaglobulinemia was evaluated by hematochemical tests. We evaluated the serum levels of IgG, IgM, and IgA in relation to disease severity, classified according to IHS4, at three-month intervals throughout the one-year study period. Only serum IgG levels, and not IgA or IgM, showed a significant correlation with severe IHS4. (Threshold values are detailed in Table 1)

Table 1 Clinical Features of Patients with Results of the Study

Results

Sixty patients were recruited for the study, including 32 women (54%) and 28 men (46%), mean age 47 years, observation period was 12 months. Clinical features of patients and results of the study are reported in Table 1.

Forty-one patients had hypergammaglobulinemia (68%), and thirty-four patients (57%) were on Adalimumab therapy. The results were as follows: the age range most affected by hypergammaglobulinemia was the youngest age group, namely 15 to 29 years (80%), after which the prevalence decreased in higher age groups (Figure 1).

Figure 1 Average Percentages Of Gamma Globulin In Relation To Age Ranges Of All Patients.

Correlation between IHS4 disease severity and frequency of hypergammaglobulinemia: disease severity was higher in the 15–29 age range, which is also the age range where hypergammaglobulinemia was more common (Figure 2). Finally, we observed a lower clinical response to Adalimumab therapy (mean 25% HiSCR difference) in young patients with HS and hypergammaglobulinemia compared to the rest of the study sample. The collected data were processed using Graph-Pad Prism software (GraphPad Inc., La Jolla, CA, USA). Paired t-test was used to compare data. P-value <0.05 with a 95% confidence interval was considered statistically significant in all analyses performed.

Figure 2 Average IHS4 Values.

Discussion

Inflammation parameters commonly monitored in HS, such as CRP and ESR, remain fundamental for therapeutic management.^4,5 However, our study has shown that hypergammaglobulinemia is increasingly frequent in HS subjects, particularly in young patients with moderate to severe forms of the disease. Typically, in patients without HS, gamma globulins are more frequently elevated in the elderly population, contrary to our findings. This discrepancy may be due to physiological immunosenescence in elderly patients, which in this pathology can result in more normal gamma globulin levels compared to younger patients, where the link between chronic inflammation and the disease is not well controlled.^6–8

Differently from the study conducted by Mintoff et al⁶ where the authors conclude that Serum IgG behaves as a marker of severe HS disease, our study explored this correlation in practice, in particular we noted a characteristic age range and correlated therapeutic response with Adalimumab.

We certainly agree with the authors with their findings that plasma cells and immunoglobulins may interact with the complement system, amplifying inflammation and contributing to the heavy inflammatory burden observed in HS.⁶

To expand on this conclusion, we could further explore the significance of these correlations and their potential implications for future research and clinical practice.

Conclusion

Firstly, the correlation between young patients with HS (Hidradenitis Suppurativa) and hypergammaglobulinemia suggests that immune dysregulation might play a substantial role in the onset or exacerbation of HS in younger demographics. Future studies could investigate whether hypergammaglobulinemia is merely a biomarker associated with the disease or whether it contributes causally to HS pathogenesis. Understanding this relationship could help refine diagnostic criteria, making it possible to detect HS at earlier stages or identify at-risk individuals based on immune markers.

Secondly, the link between hypergammaglobulinemia and the severity of HS underscores the possibility that increased immunoglobulin levels could serve as an indicator of disease progression or severity. If future studies confirm this relationship, monitoring hypergammaglobulinemia levels could become a tool for assessing disease activity and tailoring treatments to individual patients’ needs. Additionally, this could open avenues for therapeutic interventions targeting immune pathways, potentially reducing the severity or frequency of HS flares.^7–10

In summary, these findings not only suggest directions for further investigation into immune markers in HS but also raise the possibility of integrating immunological assessments into the management of HS, especially among younger patients.

Therefore, with larger datasets encompassing more patients, hypergammaglobulinemia could potentially be considered as a predictive factor for HS, especially for more severe or treatment resistant disease.