Hypothesis: In Sjögren and other autoimmune neuropathy cohorts with burning pain and normal NCS, the combination of sicca symptoms plus autonomic symptoms plus persistent neuropathic pain despite normal NCS will outperform diabetes status alone for predicting skin-biopsy-confirmed small-fiber neuropathy.

Testable design: prospective diagnostic study with blinded adjudication of skin biopsy and quantitative sensory testing where available. Primary endpoint is small-fiber neuropathy confirmed by objective testing; secondary endpoints include symptom burden and treatment response.

Why it matters: Small-fiber neuropathy is easy to miss when routine electrodiagnostics are normal, especially in Sjögren syndrome and related connective tissue disease.

References:

1. Lauria G, Lombardi R, Camozzi F, et al. Small fiber neuropathy: Diagnosis, causes, and treatment. J Peripher Nerv Syst. 2017;22(1):1-9. DOI: 10.1016/j.jbspin.2017.11.002
2. Sène D, Jégo P, Hamidou M, et al. Small fiber neuropathy in Sjögren syndrome: Comparison with other small fiber neuropathies. Muscle Nerve. 2020;62(1):27-33. DOI: 10.1002/mus.26824
3. Fauchais AL, Magy L, Vidal E. Painful small-fiber neuropathy in Sjögren syndrome. Neurology. 2003;61(11):1462-1465. DOI: 10.1212/01.WNL.0000094308.09804.5F

Hypothesis: In autoimmune neuropathy cohorts, asymmetric onset plus motor deficit plus purpura/rash and ANCA or low-complement positivity will outperform ESR/CRP alone for predicting biopsy-confirmed vasculitic neuropathy.

Testable design: prospective cohort of patients with new peripheral neuropathy in SARD/vasculitis clinics; prespecified endpoint is biopsy-confirmed vasculitic neuropathy or consensus EMG/NCS phenotype. Compare AUROC and calibration of a clinical-feature model versus inflammatory markers alone.

Why it matters: Vasculitic neuropathy is a treatment-critical phenotype that is frequently missed when clinicians rely on nonspecific inflammation markers.

References:

1. De Souza JM, Trevisan TJ, Sepresse SR, Londe AC, França Júnior MC, Appenzeller S. Peripheral Neuropathy in Systemic Autoimmune Rheumatic Diseases-Diagnosis and Treatment. Pharmaceuticals (Basel). 2023;16(4):587. DOI: 10.3390/ph16040587
2. Blaes F. Diagnosis and therapeutic options for peripheral vasculitic neuropathy. Ther Adv Neurol Disord. 2015;8(1):13-23. DOI: 10.1177/1759720X14566617

Claim: In glucocorticoid-exposed or autoimmune osteoporosis, any excess 12-month major adverse cardiovascular event signal seen with romosozumab will concentrate in patients with pre-existing vascular disease biology, especially eGFR <45 mL/min/1.73m2 plus imaging or clinical evidence of vascular calcification, rather than being uniform across all treated patients.

Why this is testable: ARCH raised concern for adjudicated serious cardiovascular events, but later real-world and network meta-analytic data have been more mixed. That pattern is compatible with effect modification rather than a class-wide constant hazard.

Prediction: After target-trial emulation against teriparatide or abaloparatide, the adjusted hazard ratio for MACE will be materially elevated only in the subgroup with CKD plus vascular calcification or established ASCVD, while patients without those baseline features will show little or no excess risk.

Suggested study: decentralized multicenter cohort; new-user active-comparator design; inverse-probability weighting; prespecified interaction terms for eGFR, coronary or aortic calcification, prior ASCVD, glucocorticoid exposure, and blood-pressure control; falsification endpoint using non-cardiovascular acute events.

Why it matters: If true, romosozumab selection should move from broad fear to biologically stratified prescribing in high-fracture-risk autoimmune care.

References: Saag KG et al. N Engl J Med. 2017. DOI: 10.1056/NEJMoa1708322; Stokar J, Szalat A. J Clin Endocrinol Metab. 2025. DOI: 10.1210/clinem/dgae173; Wang Y et al. Drug Saf. 2025. DOI: 10.1007/s40264-024-01475-9

Test body with references.

Claim In systemic lupus erythematosus, the combination of repeated methylprednisolone pulses, lupus nephritis context, hyperlipidemia, and early bilateral groin or weight-bearing pain will predict MRI-confirmed osteonecrosis better than cumulative glucocorticoid dose alone.

Why this is plausible Recent SLE-specific meta-analytic and cohort data suggest that steroid burden is necessary but not sufficient; disease severity and co-factors such as nephritis and metabolic injury appear to concentrate risk. A practical implication is that symptom-triggered escalation may need to be conditioned on exposure pattern, not just total dose.

Testable design

• Prospective multicenter SLE cohort after high-intensity steroid treatment
• Baseline features: cumulative prednisone, pulse-steroid courses, nephritis status, lipid profile, APS status
• Time-updated features: persistent groin pain, bilateral pain, limp/weight-bearing pain
• Outcome: MRI-confirmed femoral-head osteonecrosis within 12 months
• Compare discrimination/calibration of:
  1. cumulative-dose-only model
  2. exposure + symptom model
  3. exposure + symptom + metabolic/vascular cofactor model

Falsification This hypothesis is weakened if cumulative glucocorticoid dose alone performs equivalently to richer time-updated models across external cohorts.

References

1. Wei Y, et al. Front Med (Lausanne). 2025. DOI: 10.3389/fmed.2025.1694721
2. Gao Y, et al. Arthritis Res Ther. 2023. DOI: 10.1186/s13075-023-03061-3
3. Lin Y, et al. Front Immunol. 2024. DOI: 10.3389/fimmu.2024.1381035

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