Lower total serum Immunoglobulin G is associated with impaired patient-reported health-related quality of life in systemic sclerosis: a prospective cross-sectional study

Abstract

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune dysregulation, fibrosis, and vasculopathy, frequently resulting in substantial impairment in health-related quality of life (HRQoL). Total serum immunoglobulin G (IgG), a central component of adaptive humoral immunity, may reflect cumulative disease burden, yet has not been previously studied in relation to patient-reported outcomes (PROs) in SSc. In this prospective cross-sectional study, 64 patients fulfilling classification criteria for SSc were evaluated. HRQoL was assessed using the Systemic Sclerosis Quality of Life Questionnaire (SScQoL), Health Assessment Questionnaire Disability Index (HAQ-DI), and visual analog scales (VAS) for pain and global patient - reported disease activity (PGA). Lower IgG levels were significantly associated with worse HRQoL across all instruments: SScQoL (Spearman’s ρ = − 0.437, p = 0.0009), HAQ-DI (ρ = − 0.446, p = 0.0007), VAS pain (ρ = − 0.486, p = 0.0002), and PGA (ρ = − 0.584, p < 0.0001). These associations were consistent across major clinical subgroups, including those stratified by antibody status, interstitial lung disease, and skin involvement severity. In multivariable models adjusting for inflammation, fibrosis, and gastrointestinal symptoms, IgG remained an independent predictor of worse SScQoL (β = − 0.012, p = 0.003). Patients with gastrointestinal involvement had significantly lower IgG levels (p = 0.025). No differences in IgG or HRQoL were observed by immunosuppressive treatment status. These findings suggest that total serum IgG is inversely associated with patient-reported HRQoL in systemic sclerosis and may serve as a clinically relevant, treatment-independent biomarker of perceived disease burden.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00296-025-06048-2.

Introduction

Systemic sclerosis (SSc) is a rare connective tissue disease characterized by immune dysregulation, vasculopathy, and fibrosis, with heterogeneous multiorgan involvement and substantial impact on patients’ daily functioning [1]. Health-related quality of life (HRQoL) is often profoundly impaired in SSc, yet biologically grounded correlates of patient-reported outcomes remain limited [2–4].

Commonly used inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) are only weakly or inconsistently associated with patient-perceived disease burden [5]. Immunoglobulin G (IgG), the dominant isotype of adaptive humoral immunity, is measurable in routine clinical settings and has been studied in selected immunological and therapeutic contexts in SSc [6–8], including reports of intravenous immunoglobulin (IVIG) use [9–12]. Importantly, in other clinical settings - such as primary antibody deficiencies (PAD) and common variable immunodeficiency (CVID) - lower IgG levels have been associated with increased fatigue, reduced physical functioning, and impaired quality of life, supporting the plausibility of this relationship [13, 14].

However, to our knowledge, no previous study has examined total serum IgG as a correlate of multidimensional HRQoL in systemic sclerosis.

This prospective cross-sectional study aimed to explore whether total serum IgG levels are associated with patient-reported health-related quality of life in SSc. We evaluated correlations between IgG and four validated HRQoL instruments and analyzed potential differences across relevant clinical subgroups.

Methods

Study design and cohort

This was a prospective, cross-sectional analysis of 64 consecutively enrolled patients with SSc at a tertiary rheumatology center. Patients were consecutively enrolled between 20 February 2024 and 31 March 2025. Inclusion criteria were: (i) age ≥ 18 years, (ii) fulfilment of the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for systemic sclerosis [15], and (iii) availability of complete serum biomarker and HRQoL data. Exclusion criteria were: diagnosis of systemic sclerosis without skin involvement (ssSSc) or localized scleroderma (morphea); significant renal impairment (Cockcroft–Gault creatinine clearance < 45 ml/min); clinically significant hematologic, cardiovascular disease (New York Heart Association functional class III/IV), or investigator-assessed clinically significant hepatic insufficiency. All clinical, serological and health-related quality of life (HRQoL) data were collected during the same inpatient visit. The study was approved by the institutional ethics committee, and all participants provided informed consent.

Clinical and laboratory data

The dataset included

Demographics: age, sex, disease duration.

Autoantibodies: anti-centromere (ACA), anti-topoisomerase I (Scl-70), assessed by semi-quantitative immunoblot (0, 1+, 2+, 3+).

Organ involvement: ILD (High-Resolution Computer Tomography -HRCT- confirmed), gastrointestinal (GI) symptoms (documented reflux, dysphagia, malabsorption).

Biomarkers: total IgG, CRP, ESR, IL-6 (standardized hospital assays) Renal function and urinary protein loss: assessed using routine serum creatinine testing and dipstick urinalysis performed at admission. Serum creatinine was measured enzymatically, with a laboratory reference range of 0.7–1.2 mg/dL. Urinalysis was semiquantitative and proteinuria was recorded as negative, trace, or 1 + and above.

Skin involvement: modified Rodnan Skin Score (mRSS) [16],

Immunosuppressive therapy: current use of mycophenolate mofetil (MMF), methotrexate (MTX), or azathioprine (AZA) (yes/no); ever use of cyclophosphamide (CYC) (past or presen). Dose, duration, and cumulative exposure were not available.

IgG quantification and sampling conditions

Total serum IgG concentrations were measured using immunonephelometry (BN II System, Siemens Healthcare Diagnostics), according to the manufacturer’s instructions. The reference range was 700–1600 mg/dL. Samples were obtained from fasting patients in the morning hours during blood draws from peripheral venous access. The inter-assay coefficient of variation (CV) for this assay was < 5%.

Patient—reported outcome measures

Patient-reported outcomes (PRO) were assessed using four validated instruments:

Visual Analog Scale (VAS) for disease-related pain (0–100 mm).

VAS for global patient-reported disease activity (PGA) (0–100 mm).

Health Assessment Questionnaire Disability Index (HAQ-DI) [17].

Systemic Sclerosis Quality of Life Questionnaire (SScQoL), Polish-validated version [18].

All PRO instruments were administered on the same day as blood collection and clinical assessment, during inpatient hospitalization. The SScQoL was defined a priori as the primary endpoint, given its disease specificity, multidimensional structure, and availability of a validated Polish version developed through a cross-cultural European study. This instrument consists of 29 dichotomous items (0 = not affected, 1 = affected), yielding a total score from 0 to 29, where higher scores indicate worse health-related quality of life. Other PROs (HAQ-DI, VAS pain, and PGA) were included as secondary outcomes to assess convergent validity across different domains of health status. Other SSc-specific PRO instruments (e.g., ScleroID) could not be included due to licensing access problems and lack of Polish validated versions at the time of study design.

Bias minimisation

To reduce selection bias, patients were consecutively enrolled at a single tertiary rheumatology center between 20 February 2024 and 31 March 2025. All clinical, serological, and patient-reported outcome measures were obtained during the same inpatient visit, ensuring a uniform temporal relationship between serum IgG levels and HRQoL measures.

The order of study procedures was standardised for all participants. Modified Rodnan Skin Score (mRSS) assessment was conducted by experienced rheumatologists who routinely perform this examination in clinical practice; all assessors were trained according to EULAR recommendations and calibrated before study initiation to minimise inter-observer variability. Patient-reported outcome questionnaires (VAS Pain, PGA, HAQ-DI, and SScQoL) were administered by trained personnel who were not involved in laboratory testing, and the assessors were blinded to the IgG results at the time of data collection.

Serum IgG, CRP, ESR, and IL-6 levels were measured in the hospital’s laboratory using the same assays and protocols for all patients. Data were entered independently and cross-checked to ensure accuracy (double-data entry).

Study size

The study included 64 patients fulfilling the 2013 ACR/EULAR classification criteria for systemic sclerosis who were consecutively enrolled during the predefined recruitment period. All eligible patients meeting the inclusion and not meeting the exclusion criteria during this period were invited to participate and voluntarily agreed to participate.

No formal a priori sample size calculation was performed because the study was designed as an exploratory, hypothesis-generating analysis in a real-world clinical setting. However, a post-hoc power analysis was conducted for the main correlation of interest between serum IgG levels and SScQoL total score. With the obtained effect size (Spearman’s rho = − 0.41) and the available sample size (n = 64), the statistical power was estimated at > 80% (two-tailed α = 0.05).

The final sample size of 64 patients reflected the anticipated number of eligible and willing participants with clinical, laboratory, and PRO data who could be consecutively recruited during the defined 13-month enrollment period.

Statistical analysis

Spearman’s rank correlation (ρ) was used for all bivariate associations. 95% confidence intervals for Spearman’s ρ were calculated using Fisher’s z-transformation. Subgroup analyses were stratified by ACA status, ILD presence, and skin score severity (mRSS median split: lower ≤ 6, higher > 6). Mann–Whitney U tests were used to compare IgG concentrations between groups (e.g. GI involvement). No imputation was performed; all analyses were conducted on complete-case data. Additional exploratory multivariable regression, biologically informed regression, and partial correlation analyses were conducted and are described in the Results. Modified Rodnan Skin Score (mRSS) was treated as a continuous variable in multivariable models. Median-based subgrouping was applied only for descriptive stratification in exploratory analyses. Given the sample size and the exploratory nature of the study, we did not formally assess non-linearity. However, no visual evidence of substantial deviation from linearity was noted during preliminary inspection. Additional categorical comparisons were performed using Mann–Whitney U tests to evaluate differences in IgG and HRQoL outcomes between patients receiving immunosuppressive therapy and those untreated. Immunosuppressive therapy was defined as the presence of any current use of MMF, MTX, AZA, or past use of CYC. To assess whether treatment status influenced the IgG–HRQoL relationship, a supplementary multivariable linear regression model was constructed including “any immunosuppression” as a binary covariate. As only one patient had a history of rituximab use > 6 months prior to inclusion, three patients were receiving low doses of glucocorticoids (≤ 5 mg/day prednisone equivalent), and no patients received IVIG, no sensitivity analyses excluding such cases were performed. All statistical analyses were performed using GraphPad Prism (version 9.0, GraphPad Software, San Diego, CA) and IBM SPSS Statistics (version 28.0, IBM Corp., Armonk, NY).

Patient and public involvement

Patients or the public were not involved in the design, conduct, reporting, or dissemination plans of our research.

Results

Cohort characteristics

A total of 64 patients with systemic sclerosis were enrolled. The cohort was predominantly female (89%), with a median age of 57.5 years. Median disease duration was 4.2 years. Anticentromere antibodies (ACA) were present in 50% of patients, and anti-topoisomerase I antibodies (Scl-70) in 45%. Interstitial lung disease (ILD) was documented in 38% of patients based on high-resolution computed tomography, and 25% reported gastrointestinal (GI) involvement. The median modified Rodnan Skin Score (mRSS) was 6.0 (available for 62 patients). The median erythrocyte sedimentation rate (ESR) was 18 mm/h (interquartile range [IQR] 10–31). The median C-reactive protein (CRP) level was 3.5 mg/L (IQR 1.2–7.9). The median interleukin-6 (IL-6) concentration was 5.2 pg/mL (IQR 3.4–8.7). Serum IgG concentrations ranged from 603 to 1908 mg/dL, with a median of 1167 mg/dL, mean of 1126 mg/dL, and interquartile range (IQR) of 441 mg/dL. Normal distribution of IgG values was confirmed using the Shapiro–Wilk test (W = 0.970, p = 0.365). (Table 1). Immunosuppressive therapy at the time of assessment included mycophenolate mofetil (MMF) in 25 patients (39.1%), methotrexate (MTX) in 14 (21.9%), and azathioprine (AZA) in 3 (4.7%). Cyclophosphamide (CYC) had been used previously in 7 patients (10.9%). Overall, 49 patients (76.6%) had received at least one immunosuppressive agent. Routine urinalysis was available for all participants and showed no more than trace proteinuria in any patient. Serum creatinine results were available for 63 out of 64 patients, with a median value of 0.73 mg/dL (IQR: 0.67–0.88). Only 4 patients (6.3%) had creatinine levels above the institutional upper reference limit of 1.2 mg/dL, suggesting preserved renal function in the majority of the cohort.

Table 1.

Cohort characteristics, including demographics, serology, organ involvement, and IgG summary statistics

Characteristic	Value
Female sex—n (%)	57 (89%)
Age—years, median (IQR)	57.5 (48.8–63.5)
Disease duration—years, median (IQR)	4.2 (2.1–7.8)
ACA positivity—n (%)	32 (50%)
Scl-70 positivity—n (%)	29 (45%)
Interstitial lung disease (ILD)—n (%)	24 (38%)
Gastrointestinal involvement—n (%)	16 (25%)
mRSS—median (IQR)	6.0 (3.0–11.0)
Serum IgG—mg/dL, median (IQR)	1167 (947–1388)
ESR—mm/h, median (IQR)	18 (10–31)
CRP—mg/L, median (IQR)	3.5 (1.2–7.9)
IL-6—pg/mL, median (IQR)	5.2 (3.4–8.7)
Serum creatinine—mg/dL, median (IQR)	0.75 (0.66–0.89)
MMF use—n (%)	25 (39.1%)
MTX use—n (%)	14 (21.9%)
AZA use—n (%)	3 (4.7%)
Cyclophosphamide (ever use)—n (%)	7 (10.9%)
Any immunosuppressive therapy—n (%)	49 (76.6%)

Correlation between IgG and HRQoL

Total serum IgG was significantly and inversely correlated with all four health-related quality of life (HRQoL) instruments (Table 2; Fig. 1). The strongest correlation was observed with the patient global assessment of disease activity (VAS activity), with a Spearman’s rho of –0.584 (95% CI − 0.726 to − 0.395, p < 0.0001). Significant inverse correlations were also found with VAS pain (ρ = − 0.486, 95% CI − 0.654 to − 0.273, p = 0.0002), HAQ-DI (ρ = − 0.446, 95% CI − 0.623 to − 0.225, p = 0.0007), and SScQoL (ρ = − 0.437, 95% CI − 0.617 to − 0.214, p = 0.0009). These results indicate a consistent association between lower IgG levels and worse patient-reported outcomes.

Table 2.

Spearman correlation coefficients between total IgG and HRQoL outcomes

HRQoL Metric	Spearman ρ	95% CI for ρ	p-value
VAS Activity (PGA)	– 0.584	– 0.726 to − 0.395	< 0.0001
VAS Pain	– 0.486	– 0.654 to − 0.273	0.0002
HAQ-DI	– 0.446	– 0.623 to − 0.225	0.0007
SScQoL	– 0.437	– 0.617 to − 0.214	0.0009

Fig. 1.

Correlation plots between IgG and four HRQoL outcomes: (A) VAS Activity (PGA), (B) VAS Pain, (C) HAQ-DI, (D) SScQoL. Each metric shows a significant inverse relationship with IgG

Subgroup analyses

Stratified analyses confirmed that the inverse correlation between IgG and PGA was preserved across major subgroups. Among ACA-positive patients (n = 27), the correlation coefficient was − 0.712 (p < 0.0001, power = 0.964). In patients with ILD (n = 24), the correlation was − 0.679 (p = 0.0007, power = 0.932). When stratified by skin score severity, the association remained significant in both higher mRSS (n = 26, ρ = − 0.682, p = 0.0001) and lower mRSS (n = 26, ρ = − 0.528, p = 0.0056) subgroups. Additional associations showed that IgG was positively correlated with erythrocyte sedimentation rate (ESR) (ρ = +0.506, p = 0.0001, 95% CI +0.280 to + 0.678), weakly with C-reactive protein (CRP) (ρ = +0.275, p = 0.038, 95% CI +0.008 to + 0.506), and not significantly with IL-6 levels (ρ = +0.168, p = 0.215, 95% CI − 0.105 to + 0.417). Patients with gastrointestinal involvement had significantly lower serum IgG concentrations (p = 0.025).

Exploratory multivariable and partial correlation analyses

To further explore the independent relationship between IgG and HRQoL, additional statistical models were applied. In a multivariable linear regression including age and sex, total IgG was not significantly associated with SScQoL (β = − 0.0155, p = 0.665), and the model demonstrated low explanatory power (adjusted R² = − 0.046, power = 0.05) (Table 3).

Table 3.

Exploratory multivariable and partial correlation Analyses

Analysis Type	Outcome	Predictors	Effect Size / ρ	p-value	Model Fit / Power / 95% CI
Multivariable Regression	SScQoL	IgG, Age, Sex	β = − 0.0155	0.665	Adj. R² = − 0.046, Power = 0.05
Biologically Informed Regression	SScQoL	IgG, ESR, mRSS, GI involvement	β = − 0.012	0.003	Adj. R² = 0.132
Partial Spearman Correlation	SScQoL	IgG (adjusted for ESR, mRSS)	ρ = − 0.442	0.001	95% CI: − 0.620 to − 0.220

Summary of additional exploratory statistical analyses assessing the relationship between total serum IgG and health-related quality of life (SScQoL). multivariable regression models included standard and biologically informed predictors. partial correlation adjusted for systemic inflammation and skin involvement.

In contrast, a biologically informed regression model incorporating IgG, ESR, mRSS, and GI involvement revealed that IgG retained a statistically significant inverse association with SScQoL (β = − 0.012, p = 0.003), suggesting that this relationship was not fully explained by systemic inflammation or skin involvement. The model’s explanatory power improved (adjusted R² = 0.132), although multicollinearity and sample size limitations were noted (Table 3).

Partial Spearman correlation analysis controlling for ESR and mRSS further supported the robustness of the IgG–HRQoL relationship (ρ = − 0.442, p = 0.001) (Table 3).

Impact of immunosuppressive treatment

At the time of assessment, 49 out of 64 patients (76.6%) were receiving or had previously received immunosuppressive therapy. Median IgG levels and all HRQoL outcomes were comparable between receiving and not receiving immunosuppressive treatment patients (Table 4). Specifically, there were no significant differences in IgG concentrations (p = 0.56), SScQoL scores (p = 0.92), or other HRQoL domains (PGA, VAS pain, HAQ-DI), as assessed using Mann–Whitney U tests.

Table 4.

Comparison of serum IgG and HRQoL outcomes between immunosuppression-treated and untreated patients (n = 54)

Variable	Median (Treated)	Median (Untreated)	U-statistic	p-value
Serum IgG (mg/dL)	1167	1116	346.0	0.5637
SScQoL total	14.0	15.0	308.5	0.9183
PGA (0–100)	51.0	49.0	344.0	0.5890
VAS Pain (0–100)	50.0	41.0	348.0	0.5387
HAQ-DI	0.88	0.62	329.5	0.7859

All values are medians; p-values based on Mann–Whitney U tests.

Furthermore, to examine whether immunosuppressive therapy confounded the observed IgG–HRQoL relationship, a multivariable regression model was constructed including ESR, GI involvement, mRSS, and treatment status as covariates. In this model (Supplementary Table S1), total serum IgG remained a significant independent predictor of worse SScQoL (β = − 0.013, p = 0.005), while treatment status showed no significant effect (β = 0.135, p = 0.687). These findings support the interpretation that immunosuppressive therapy does not account for the inverse IgG–HRQoL association.

Table Legend: Values represent medians within each group. Comparisons were made using Mann–Whitney U tests (non-parametric). Treated group: patients receiving immunosuppressants (MMF, MTX, AZA, or CYC). Untreated group: patients not receiving these agents. There were no significant differences between the groups across any outcome (all p > 0.5).

Discussion

This study is the first to demonstrate a robust and consistent inverse association between total serum immunoglobulin G (IgG) levels and patient-reported health-related quality of life (HRQoL) across multiple validated instruments in systemic sclerosis (SSc) (Table 2; Fig. 1). Lower IgG levels were significantly associated with worse outcomes across functional (HAQ-DI), symptomatic (VAS Pain, PGA), and disease-specific (SScQoL) measures. These findings suggest that total IgG may reflect chronic disease burden more comprehensively than conventional acute-phase reactants.

Among the four PRO instruments analyzed, the SScQoL was designated as the primary outcome due to its disease specificity and comprehensive structure. While additional disease-specific instruments such as ScleroID are available, licensing and validation constraints precluded their inclusion in this study. The HAQ-DI, VAS pain, and PGA were pre-specified as secondary outcomes and provided convergent support for the observed associations.

Notably, the observed associations were present across a broad physiological range of IgG values (603–1908 mg/dL), with most levels falling within the conventional reference interval (700–1600 mg/dL) (Table 1; Fig. 2). This indicates that total IgG may function as a marker of relative immunologic burden even in the absence of overt hypogammaglobulinemia.

Fig. 2.

Distribution of total serum IgG (mg/dL)

Importantly, these associations were preserved across clinically heterogeneous subgroups, including ACA-positive and ILD-positive patients, as well as those with both lower and higher modified Rodnan Skin Scores. This phenotype-independent behaviour supports IgG’s potential role as a global marker of disease impact. The absence of correlation with IL-6 and CRP, alongside a positive association with erythrocyte sedimentation rate (ESR), further indicates that IgG captures a longer-term immunologic signal that may reflect slow-accumulating inflammatory or metabolic stress, rather than transient cytokine-driven activity.

From a mechanistic standpoint, total IgG is a stable immunological variable with limited circadian or treatment-induced fluctuation, unlike IL-6 or CRP. This makes it particularly suited for patient-centric endpoints such as HRQoL, which also evolve slowly over time.

Formal statistical comparisons showed no significant differences in total serum IgG concentrations or HRQoL outcomes between patients who were treated and those who were not treated with immunosuppressive therapy (Table 4). Specifically, IgG levels, SScQoL scores, and all secondary PRO domains (PGA, VAS pain, HAQ-DI) were statistically comparable between groups. Furthermore, when immunosuppressive therapy status was added as a covariate to a biologically informed multivariable regression model, total IgG retained a statistically significant inverse association with SScQoL (β = − 0.013, p = 0.005), while treatment status itself showed no significant effect (β = 0.135, p = 0.687) (Supplementary Table S1). These findings support the interpretation that the observed IgG–HRQoL relationship is not confounded by treatment effects and that serum IgG functions as a treatment-independent marker of disease burden in systemic sclerosis. Notably, this relationship remained robust after adjusting for inflammatory (ESR), fibrotic (mRSS), and gastrointestinal covariates, and was consistent across all analyzed PRO domains.

A detailed review of treatment history confirmed that no patients received intravenous immunoglobulin (IVIG) at any point, and only one had a history of B-cell depletion with rituximab (RTX), completed more than six months prior to study inclusion. No patients received cyclophosphamide (CYC) during the study period or within six months preceding inclusion, although “ever use” of CYC was recorded as a binary variable. Steroid use was minimal, limited to three patients (≤ 5 mg/day prednisone equivalent in each case). Two participants were receiving nintedanib, and two were in the pre-treatment evaluation phase for RTX. These findings suggest that concurrent or recent exposure to treatments known to significantly affect IgG levels was rare, supporting the interpretation that the observed IgG–HRQoL associations are unlikely to be treatment-driven.

While multivariable regression including only age and sex did not retain IgG as a significant predictor of HRQoL, updated analyses incorporating biologically meaningful covariates -namely ESR, mRSS, and GI involvement - revealed that IgG maintained a statistically significant inverse association with SScQoL (β = − 0.012, p = 0.003), as shown in Table 3. This biologically informed model demonstrated improved explanatory capacity (adjusted R² = 0.132) and confirmed that IgG acted in the cohort as a robust, non-redundant marker of patient-perceived disease burden. These results potentially position IgG not merely as a reflective biomarker, but as a clinically meaningful correlate of long-term systemic dysfunction in systemic sclerosis.

Partial Spearman correlation analysis demonstrated a statistically significant inverse association between total serum IgG and SScQoL (ρ = − 0.44, p = 0.001), independent of systemic inflammation (ESR) and skin involvement (mRSS). This supports the interpretation that IgG captures a broader dimension of disease impact beyond acute-phase reactants or localized fibrosis, aligning with patient-reported quality of life. This interpretation is further supported by prior findings in other clinical settings - such as primary antibody deficiencies and common variable immunodeficiency - where lower IgG levels have been associated with impaired physical functioning and fatigue [13, 14].

Importantly, the direction of correlation remained consistent throughout: lower IgG levels were systematically associated with higher (worse) HRQoL scores across all instruments. This reinforces the clinical interpretability of IgG as an inverse marker of perceived disease impact.

Our analysis also identified that patients with gastrointestinal (GI) involvement had significantly lower total IgG levels. This observation is consistent with mechanisms such as protein-losing enteropathy, impaired immunoglobulin synthesis due to hepatic dysfunction, or malabsorption related to small bowel dysmotility. Prior studies have shown that SSc-related GI pathology can result in immunoglobulin depletion and systemic nutritional stress [19, 20], and our findings suggest that IgG may serve as an indirect indicator of such hidden disease load. Importantly, this reinforces the need to interpret IgG contextually - not as a linear reflection of disease activity, but as a cumulative signal shaped by multiple systemic processes. These pathophysiological links are further supported by a recent systematic review published in Rheumatology International by Garrote-Corral et al., which found that intravenous immunoglobulin (IVIG) therapy may offer benefit in systemic sclerosis patients with cutaneous, muscular, and gastrointestinal involvement, reinforcing the clinical relevance of IgG modulation in SSc pathobiology [21]. Notably, as mentioned before, none of the patients in our cohort received IVIG therapy, and unlike that report, our study focused on total serum IgG levels in relation to patient-reported quality of life, a topic not previously explored in this journal.

This study was conducted in a single-center cohort with a cross-sectional design, which limits the ability to evaluate longitudinal trajectories or dynamic changes in IgG over time. The generalizability of our findings may be limited by the single-center design and characteristics of the recruited cohort. While the sample size was sufficient to detect robust and consistent associations with multiple HRQoL instruments, more granular modelling of phenotype - treatment interactions was beyond its scope. Although immunosuppressive therapies were recorded, the lack of detailed data on treatment duration, dosing, and small subgroup sizes limited further analysis of their relationship with IgG levels.

The study cohort represents consecutive patients with systemic sclerosis seen at a tertiary referral centre and the findings are therefore most directly applicable to similar European healthcare settings with comparable disease management protocols. As all participants met the 2013 ACR/EULAR classification criteria for SSc, the results are likely generalisable to adult patients fulfilling these criteria in other high-resource settings. However, the single-centre design may limit generalisability to populations with different ethnic composition, environmental exposures, or treatment practices. Replication of the findings in multi-centre, ethnically diverse cohorts, and in healthcare systems with differing access to specialist care, will be important to confirm the external validity of the observed associations.

Limitations related to inpatient-only recruitment

A potential limitation of this study is its inpatient-only recruitment strategy. However, this should be interpreted in the context of institutional model of care. The large majority of patients were admitted through the clinic’s outpatient department for routine, scheduled assessments, typically following a 2–3 month wait. These were short (1–4 day) hospitalizations, primarily intended for planned evaluation of disease activity, organ involvement, and treatment review or rheological treatment with prostacyclin infusions. These admissions were generally not prompted by acute deterioration. A minority of patients were hospitalized due to more urgent concerns, such as accelerated disease progression. Importantly, patients with overt infections were not admitted, and all clinical and laboratory procedures followed a standardized institutional protocol. While the inpatient setting may still introduce subtle biases compared to strictly outpatient samples, the clinical profile of most participants closely resembled that of stable ambulatory SSc patients, reducing the risk of systematic distortion in patient-reported outcomes or immunoglobulin G levels.

Although the study protocol did not include direct biomarkers of enteric protein loss, such as serum albumin, total protein, or fecal α1-antitrypsin, we examined available clinical data to assess this potential source of bias. Routine urinalysis revealed no more than trace proteinuria in any patient, and serum creatinine exceeded the reference range in only 4 of 63 cases (6.3%), suggesting preserved renal function in the vast majority of the cohort. Significant clinical features consistent with protein-losing enteropathy were noted in only one patient.

Even though these tests were not mandated by the study protocol, they were routinely ordered by treating physicians in cases with suspected renal or enteric protein loss, as part of standard hospital care. None of the available results revealed clinically relevant abnormalities. Gastrointestinal involvement was defined based on documented symptoms (reflux, dysphagia, or malabsorption), consistent with established observational practice. This symptom-based approach was deliberately chosen to maximize sensitivity, as strict reliance on documented diagnoses or laboratory-confirmed enteropathy may under - detect clinically relevant but subclinical GI disease in SSc. These findings argue against overt protein-losing conditions as major confounders of the observed IgG–HRQoL associations.

Although the study did not systematically collect detailed data on immunosuppressive dosing or duration, clinically relevant information on IVIG and steroid use as well as B-cell depletion history was available. Only one patient had a documented history of rituximab therapy, completed more than six months prior to inclusion. Glucocorticoid exposure was minimal and limited to low-dose regimens. Given their low frequency and intensity, these exposures are unlikely to have exerted a measurable impact on IgG levels in this cohort. While this precluded robust dose–response modeling, the risk of residual confounding by these factors appears minimal.

Nonetheless, the consistency and biological plausibility of our findings support their translational relevance. From a translational perspective, total serum IgG is a low-cost, reproducible, and widely available assay. Its consistent association with HRQoL across phenotypes, independence from immunosuppressive use, and superior performance over IL-6 or CRP make it a strong candidate for prospective biomarker development. It could serve, if our findings were confirmed in other cohorts of SSc patients, as a surrogate endpoint in longitudinal studies or trials assessing interventions aimed at improving systemic function or immune balance [3, 22].

Conclusions

This exploratory study identified a consistent inverse correlation between total serum immunoglobulin G (IgG) levels and patient-reported HRQoL scores in systemic sclerosis (SSc), suggesting that lower IgG may be associated with greater disease burden. These findings were preserved across clinically relevant subgroups and were independent of conventional inflammatory markers. Prospective studies are warranted to evaluate whether total IgG can serve as a reliable biomarker of patient-perceived disease burden and to explore its longitudinal dynamics in systemic sclerosis.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

All authors contributed substantially to the conception and design of the study. Jakub Trefler, Anna Pasierb, and Lidia Lech were responsible for data acquisition. Jakub Trefler performed the data analysis and wrote the first draft of the manuscript. All authors critically revised the manu-script, approved the final version, and agree to be fully responsible for the integrity and accura-cy of all aspects of the work.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

All data generated or analysed during this study are included in this published article. Additional de-identified individual data or analytical scripts are available from the corresponding author upon reasonable request.

Declarations

Conflict of interest

All authors declare no conflicts of interest.

Ethics approval

This study was approved by the Committee for Ethics and Oversight of Human Research at the National Medical Institute of the Ministry of the Interior and Administration (Warsaw, Poland) (approval date: 10 January 2024; protocol number: 25/BN/2023). All participants provided writ-ten informed consent prior to enrolment. The study was designed and initiated in accordance with the 2013 revision of the Declaration of Helsinki (adopted in October 2013), which was in effect at the time of ethics approval. Given that part of the study recruitment was conducted af-ter the release of the December 2024 revision of the Declaration, all procedures were reviewed for continued compliance with its applicable updates.

Questionnaire permissions

All necessary permissions for the use and re-use of the Health Assessment Questionnaire-Disability Index (HAQ-DI) and the Polish version of the Systemic Sclerosis Quality of Life Questionnaire (SScQoL) were obtained from the respective copyright holders prior to study initi-ation.