# Predictive Biomarkers for IVIG Response

## Clinical biomarkers predicting response to IVIG therapy

Predictive biomarkers for IVIG response are disease-specific: pre-treatment inflammatory markers (C-reactive protein, liver enzymes, bilirubin) predict resistance in Kawasaki disease, while post-treatment cellular immune markers (NK cells, regulatory T cells) predict response in chronic neurological autoimmune disorders.

## Abstract

Clinical biomarkers predicting IVIG response differ substantially by disease condition and reflect distinct pathophysiological mechanisms. In Kawasaki disease, pre-treatment inflammatory markers consistently predicted resistance: C-reactive protein (cut-offs 7-10 mg/dL), liver transaminases (AST ≥200 IU/L, ALT ≥80 IU/L), and total bilirubin (≥0.9 mg) demonstrated significant associations with non-response in multivariate analyses. Composite prediction scores combining multiple markers achieved 76-78% sensitivity and specificity. Post-treatment inflammatory markers measured 24 hours after infusion showed superior performance, with total leucocyte count >13.1×10⁹/L achieving 91% sensitivity and 89% specificity. In contrast, autoimmune neurological disorders demonstrated no predictive value for inflammatory markers. Instead, post-treatment cellular immune biomarkers proved informative: NK cell markers (CD56bright, KLRB1, KLRK1) measured 24 hours after IVIG initiation significantly discriminated CIDP responders from non-responders (p=0.007-0.027), while regulatory T cell frequency correlated with clinical recovery in Guillain-Barré syndrome. In dermatomyositis, higher baseline cutaneous disease activity predicted better response, whereas higher pulmonary activity predicted lower response. These divergent biomarker profiles reflect condition-specific IVIG mechanisms: acute inflammation suppression in Kawasaki disease versus immune cell modulation in chronic neurological disorders. Clinical consequences of non-response varied substantially, with Kawasaki disease non-responders experiencing coronary artery abnormalities at rates of 38-71% versus 1-5% in responders.

## Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 7 key aspects that mattered most to the research question.

## Results

### Characteristics of Included Studies

Ten studies investigating clinical biomarkers for predicting IVIG response were identified, spanning multiple autoimmune and inflammatory conditions. Five studies (50%) had full text available for detailed review.

| Study | Full text retrieved? | Medical Condition | Sample Size | IVIG Dose | Response Definition |
|-------|----------------------|-------------------|-------------|------------|---------------------|
| Y. Levy et al., 1999 | No | Systemic lupus erythematosus | 20 | 2 g/kg monthly over 5 days | Binary; clinical improvement with decreased SLAM score |
| A. Irgens et al., 2012 | No | Myasthenia gravis with worsening weakness | 51 | 2 g/kg divided over 2 days | Continuous; change in QMG Score at day 14 |
| C. Charles-Schoeman et al., 2025 | No | Dermatomyositis | 95 | 2.0 g/kg every 4 weeks | Continuous; total improvement score (TIS) |
| J. Hwang et al., 2010 | No | Kawasaki disease | 229 | Not specified | Binary; responder vs non-responder |
| M. Maddur et al., 2017 | Yes | Guillain-Barré syndrome | 10 | 0.4 g/kg for 3-5 consecutive days | Continuous; MRC and modified Rankin scores |
| T. Sano et al., 2006 | No | Acute Kawasaki disease | 112 | 2 g/kg within 2 days of onset | Binary; responsive vs non-responsive |
| Anne K. Mausberg et al., 2020 | Yes | Chronic inflammatory demyelinating polyneuropathy | 29 | Not specified, treatment up to 6 months | Binary; INCAT score decline ≥1 point over 6 months |
| K. Egami et al., 2006 | No | Kawasaki disease | 320 | 2 g/kg within 9 days of illness | Binary; resistance vs responder groups |
| J. Abe et al., 2008 | No | Kawasaki disease | Not specified | High-dose (not specified) | Binary; responsive vs nonresponsive |
| Mariko Fukunishi et al., 2000 | No | Kawasaki disease | 82 | High-dose (not specified) | Binary; defervescence within 5 days |

### Predictive Biomarkers by Disease Category

#### Kawasaki Disease

Five studies examined biomarkers predicting IVIG resistance in Kawasaki disease, demonstrating substantial heterogeneity in both biomarkers identified and their measurement timing. Pre-treatment inflammatory markers emerged as consistent predictors across multiple studies.

| Study | Pre-treatment Biomarkers | Cut-off Values | Performance Metrics | Post-treatment Biomarkers |
|-------|-------------------------|----------------|--------------------|--------------------------|
| T. Sano et al., 2006 | CRP, total bilirubin, AST, ALT, LDH, neutrophil count | CRP ≥7.0 mg, TB ≥0.9 mg, AST ≥200 IU/L | Multivariate p-values: CRP (p=0.009), TB (p<0.001), AST (p=0.002) | Not assessed |
| K. Egami et al., 2006 | Age, illness days, platelet count, ALT, CRP | Age <6 months, <4 illness days, platelet ≤30×10¹⁰/L, CRP ≥8 mg/dL, ALT ≥80 IU/L | Prediction score sensitivity 78%, specificity 76% | Not assessed |
| Mariko Fukunishi et al., 2000 | CRP, total bilirubin, LDH, gamma-glutamyltranspeptidase, hemoglobin | CRP >10 mg/dL, LDH >590 IU/L, hemoglobin <10 g/dL | Multivariate p-values: CRP (p=.006), LDH (p=.035), TB (p=.046) | Not assessed |
| J. Hwang et al., 2010 | Neutrophil differential, CRP | Pre-treatment: neutrophil >51% | Not specified | Total leucocyte >13.1×10⁹/L (sens 91%, spec 89%), neutrophil >51% (sens 91%, spec 76%), total protein <72 g/L (sens 64%, spec 78%) |
| J. Abe et al., 2008 | Polycythemia rubra vera 1, G-CSF measured by mRNA and protein levels | Not specified | Higher in nonresponders | Not assessed |

### Autoimmune Neurological Disorders

Three studies examined biomarkers in distinct neurological conditions, revealing markedly different predictive approaches.

1. **Guillain-Barré syndrome:** Maddur et al. investigated regulatory T cell (Treg) frequency as a post-treatment biomarker.
2. **Chronic inflammatory demyelinating polyneuropathy (CIDP):** Mausberg et al. identified natural killer (NK) cell markers measured 24 hours post-IVIG initiation as predictive.
3. **Myasthenia gravis:** Irgens et al. used the QMG Score for Disease Severity as both outcome measure.

### Other Autoimmune Conditions

In systemic lupus erythematosus, Levy et al. examined autoantibodies and complement levels as potential predictors. In dermatomyositis, a study identified higher cutaneous scores as predicting better improvement.

## Synthesis

The heterogeneity in predictive biomarkers across conditions reflects fundamental differences in disease pathophysiology, IVIG mechanisms of action, and optimal measurement timing. 
- **Disease-Specific Biomarker Patterns**: For Kawasaki disease, acute inflammatory markers consistently predicted resistance. Other conditions displayed distinct biomarker profiles reflecting divergent IVIG mechanisms.
- **Timing of Biomarker Measurement**: Variation in measurement timing was observed, with pre-treatment markers predicting response in Kawasaki disease.
- **Composite Prediction Scores**: Some studies developed scores combining multiple biomarkers.
- **Clinical Outcome Implications**: Non-responsiveness to IVIG varied by condition, illustrating the need for rapid biomarker prediction.