Overview
Cross-system analysis of autoimmune biology has generated several testable hypotheses about drug response, disease connections, and treatment optimization. Approximately 30% of autoimmune patients fail first-line therapy—better prediction of response could transform care for hundreds of millions.
The Challenge
Autoimmune diseases share common mechanisms yet are treated as separate conditions. Patterns in drug response across diseases may reveal opportunities for optimization that single-disease studies miss.
The Hypotheses
1
Cross-Biologic Response Prediction
Observation: Etanercept, bimekizumab, and anifrolumab show correlated response patterns despite targeting different pathways (TNF, IL-17, Type I IFN).
Prediction: Patients who achieve excellent response to one of these drugs are more likely to respond to the others if switching is needed.
Testable: In biologic-switch cohorts, correlate prior drug response with subsequent drug response across these three agents.
2
PTPN22 as Universal Predictor
Observation: PTPN22 variants affect risk across multiple autoimmune diseases.
Prediction: PTPN22 genotype may predict response to immunomodulatory therapies across diseases.
Testable: Correlate PTPN22 R620W status with treatment response in RA, lupus, and T1D cohorts.
3
Interleukin Pathway Convergence
Observation: All interleukins share fundamental signaling characteristics.
Prediction: Blocking one interleukin pathway may partially compensate effects of blocking another.
Testable: In patients failing IL-17 inhibitors, test whether IL-23 or IL-12 blockade shows reduced efficacy compared to biologic-naive patients.
4
JAK Inhibitor Selectivity Clustering
Observation: Different JAK inhibitors show distinct response patterns despite similar mechanisms.
Prediction: Filgotinib (selective JAK1) may show a distinct responder population from tofacitinib (JAK1/3).
Testable: Compare responder characteristics between selective and non-selective JAK inhibitors.
5
B-Cell Depletion Hierarchy
Observation: Different anti-CD20 antibodies show varying potency.
Prediction: Obinutuzumab may show superior efficacy in autoimmune disease compared to rituximab.
Testable: Head-to-head trials in lupus nephritis or ANCA vasculitis.
6
Cross-Disease Drug Repurposing
Observation: Drugs effective in one autoimmune disease often work in others.
Prediction: Anifrolumab (approved for lupus) may show efficacy in Sjögren's syndrome and dermatomyositis.
Testable: Clinical trials of anifrolumab in interferon-driven autoimmune diseases.
7
Sequential Biologic Optimization
Observation: Certain biologics may share response predictors.
Prediction: The optimal sequence of biologics can be predicted by baseline characteristics.
Testable: Develop and validate a biomarker panel predicting optimal first-line biologic.
Research Priority Matrix
| Hypothesis |
Data Required |
Feasibility |
Impact |
| H1: Cross-biologic prediction |
Registry data |
High |
High |
| H2: PTPN22 predictor |
Pharmacogenomics |
Moderate |
Very High |
| H3: IL convergence |
Switch studies |
Moderate |
Moderate |
| H4: JAK clustering |
Trial comparison |
High |
Moderate |
| H5: B-cell hierarchy |
Head-to-head trials |
Low |
High |
| H6: Drug repurposing |
Phase 2 trials |
Moderate |
High |
| H7: Sequential optimization |
Registry + biomarkers |
Moderate |
Very High |
Potential Impact
300-500 million people have autoimmune diseases. Approximately 30% fail first-line therapy.
If these hypotheses improve treatment selection by 10%:
- 30-50 million patients with better outcomes
- Reduced time to effective therapy
- $10+ billion in reduced healthcare costs
Related: Microbiome & Autoimmunity
Dysbiosis, barrier dysfunction, and reduced regulatory T cells represent the gut-autoimmune axis. See our Microbiome & Immunity hypotheses for testable predictions on butyrate-Treg induction, early-life antibiotics, and fiber interventions.
Collaboration Invitation
We seek research partnerships with:
- Biologic registries (CORRONA, RABBIT, etc.)
- Pharmacogenomics databases
- Clinical trial networks
- Academic rheumatology centers