robert thoburn

Rheumatologist, immunologist. Audaciously curious. Proud father of 4, grandfather of 11. Latest book: Spacetime: The Fabric of Forever.

[robert thoburn @thoburn_robert]

interesting case. Do auto-Ab-positive hosts infected with zoonotic IAVs show higher peak viral loads, prolonged shedding, or elevated secondary attack rates compared with auto-Ab-negative hosts with equivalent exposure? Do rare inborn errors of type I IFN production or signaling (TLR3, IRF7, etc.) play an analogous role in facilitating zoonotic adaptation, or are auto-Abs the dominant acquired defect in adults? ty

[robert thoburn @thoburn_robert]

Universities Are Cooked: Ten Years to Reinvent Higher Education—Revision https://t.co/WxcvvpMFjH

[robert thoburn @thoburn_robert]

Fascinating case report. How frequently is TLR8-GOF (or other innate-sensor GOF disorders) the underlying driver in patients labeled “primary HLH” when conventional HLH and bone-marrow-failure panels are negative? What is the precise pathway from myeloid TLR8 hyperactivation to full-blown HLH? Is the IFN-γ/CXCL9 axis the dominant effector, or do other cytokines (IL-1, IL-6, TNF, type I IFNs) contribute substantially? Is IFN-γ blockade with emapalumab broadly useful in TLR8-GOF, or mainly when HLH criteria and high CXCL9 are present? What is the optimal duration, and can it be used as a bridge or steroid-sparing strategy outside of frank HLH? ty

[robert thoburn @thoburn_robert]

Vasculitis in 2031: When AI Begins Discovering Cures https://t.co/9k1JuedfAs

[robert thoburn @thoburn_robert]

Peer Review Was Built for Yesterday’s Science https://t.co/Y0db5jMUef

[robert thoburn @thoburn_robert]

Peer review was built for yesterday’s science. It’s time to reinvent it.

Why should two or three reviewers determine the fate of a scientific discovery when 100 specialized AI agents could simultaneously examine its statistics, genetics, molecular mechanisms, clinical implications, and reproducibility?

Imagine these agents debating competing hypotheses, exposing hidden biases, challenging scientific orthodoxy, and designing experiments to resolve disagreements.

Then take the next step: connect these agents to automated laboratories that can test their hypotheses.

Human scientists remain essential, but their intellectual capabilities could be dramatically amplified.

By 2031, peer review could evolve from a system that judges completed research into one that actively accelerates discovery.

The revolution isn't faster publication. It's closing the gap between asking a scientific question and finding the answer.

Science needs fewer gatekeepers and more discovery engines.

[robert thoburn @thoburn_robert]

Memory Before Neurons https://t.co/JIfKsY5MQI

[robert thoburn @thoburn_robert]

Universities Are Cooked: Ten Years to Reinvent Higher Education https://t.co/8J4AoomLDe

[robert thoburn @thoburn_robert]

How should a rheumatologist respond? A rheumatologist would most likely encounter this patient as “unusual lupus,” refractory autoimmune cytopenias, or recurrent hyperinflammation. The crucial clue is the combination of autoimmunity and impaired host defense beginning early in life.

The new report makes that overlap concrete: patients had ANA/anti-SSA positivity, immune complex renal disease, cytopenias, and neurologic involvement alongside substantial immune abnormalities.

How the patient might arrive:

These are illustrative clinical scenarios:
Referral Features that should prompt an IEI evaluation: “childhood lupus” with cytopenias and proteinuria; severe infections or low immunoglobulins predating treatment; recurrent ITP, autoimmune hemolysis, or Evans syndrome; persistent neutropenia, lymphopenia, or additional organ involvement; suspected MAS/HLH, recurrent inflammatory episodes; liver dysfunction, and infection susceptibility; young adult with longstanding “undifferentiated autoimmunity”; childhood infections, growth abnormalities, visual problems, or fever-associated liver injury.
None individually identifies NBAS deficiency. Together, they lower the threshold for genetic investigation. Absence of the classical liver or skeletal phenotype should not end that investigation.

How I would approach the evaluation
My clinical approach would be to establish three things in parallel: what is damaging organs, whether infection is contributing, and whether an inherited immune defect explains the whole trajectory.
Reconstruct the pretreatment history. Obtain childhood blood counts, infection records, growth history, previous liver abnormalities, and family history. Were infections and cytopenias present before corticosteroids or other immunosuppression?

Characterize both immune activation and immune deficiency. Alongside CBC/differential, smear, reticulocytes, and hemolysis studies, obtain quantitative immunoglobulins and T-, B-, and NK-cell subsets. Clinical immunology can assess antibody responses and, when indicated, NK-cell function. Earlier NBAS research showed impaired humoral immunity and defective NK-cell function, providing a biological reason to evaluate host defense even when autoimmunity dominates. PMC

Define organ involvement and urgent threats. Assess urine sediment/protein, creatinine, liver tests, and synthetic function; pursue renal biopsy when indicated. fever with worsening cytopenias warrants simultaneous investigation for infection and HLH/MAS. New neurologic deficits require urgent evaluation rather than attribution to “neurolupus.”

Bring genetics in early. With immunology and hematology, request an appropriate IEI panel or exome/genome analysis that includes NBAS. Confirm pathogenicity and the expected biallelic inheritance; uncertain variants alone do not establish the diagnosis. RNA studies may help resolve suspected splice defects.

How the diagnosis changes treatment:
The aim becomes controlling damaging inflammation while preserving—and supporting—host defense.
Treat urgent organ disease promptly. Proceed with genetic testing alongside necessary treatment.
Address immune deficiency directly. Immunoglobulin replacement and antimicrobial prophylaxis may be appropriate according to the documented defect and infection history.
Consider pathway-directed therapy cautiously. The report describes improvement with ruxolitinib plus corticosteroids in one patient. That supports specialist consideration of JAK inhibition for severe inflammatory disease, but does not establish its efficacy, safety, or superiority. Baseline cytopenias and infection susceptibility make monitoring particularly consequential.

Establish a fever emergency plan with hepatology/metabolic specialists. Fever can precipitate acute hepatic deterioration; early assessment and measures to avoid catabolism matter even beyond childhood.
An IFN gene-expression score could support mechanistic assessment at a specialist center. It is neither diagnostic of NBAS deficiency nor sufficient on its own to guide treatment selection. Single-cell sequencing is presently a research tool, not a prerequisite for clinical care.
One scientific qualification matters: the transcriptomic findings support IFN-I pathway activation, but the proposed link from defective trafficking to STING activation remains a hypothesis. Ruxolitinib also inhibits signaling beyond IFN-I, so its apparent benefit does not prove which pathway caused improvement.
Confidence is high in the clinical value of recognizing this autoimmune–immunodeficiency overlap; preliminary confidence in NBAS-specific JAK treatment. For rheumatology, the practical opportunity is to recognize when a familiar autoimmune presentation deserves a molecular diagnosis and a coordinated rheumatology–immunology–hematology–genetics team.

[robert thoburn @thoburn_robert]

Autoimmune Disease: Five Years to Change What We Expect https://t.co/fbMgwnAE7k

[robert thoburn @thoburn_robert]

Vasculitis in 2031: How AI Could Transform Understanding, Treatment, and Remission https://t.co/ficp2BxHFK

[robert thoburn @thoburn_robert]

Autoimmune Rheumatology in 2031: How AI Could Rewrite the Course of Disease https://t.co/FiiXCYTUk0

[robert thoburn @thoburn_robert]

Where the Relapse Hides: Vasculitis in 2031 Oct 24, 2026 · @robert thoburn https://t.co/V141vGENxN

[robert thoburn @thoburn_robert]

For a rheumatologist, the value lies mostly in recognizing an immunodeficiency that presents in rheumatology clothing and avoiding the treatment mistakes that come with missing it.

Recognizing the pattern. These patients often reach a rheumatologist before an immunologist, because their first visible problem is autoimmune or autoinflammatory: refractory ITP or Evans syndrome, atypical Behçet-like disease with oral ulcers, periodic fevers, alopecia areata, or unexplained lymphoproliferation. Onset can be as late as the seventh decade, so adult age doesn’t exclude the diagnosis. Suspicion should rise when that picture is accompanied by low immunoglobulins, recurrent sinopulmonary infections, or a family history of either. NFKB1 is the most common monogenic cause of CVID, so it belongs on the differential.

Screening before immunosuppression. The most practical lesson is to measure IgG, IgA, and IgM, and ideally switched memory B cells, before starting rituximab, high-dose steroids, or other B-cell-depleting therapy in a patient with cytopenias or atypical inflammatory disease. Giving rituximab to someone with unrecognized antibody deficiency can cause prolonged, severe hypogammaglobulinemia and serious infection. Poor vaccine responses are another clue.

Choosing therapy by mechanism. Loss of p50 removes a transcriptional brake on canonical NF-κB signaling, so TNF and IL-1 drive the inflammatory arm. That gives a rational basis for anti-TNF or anti-IL-1 agents in the autoinflammatory features, rather than escalating broad immunosuppression. Immunoglobulin replacement often treats both infections and some immune dysregulation. Stem cell transplantation is reserved for severe, refractory cases.

Setting expectations after a genetic result. The specific variant doesn’t predict course, severity, or which autoimmune complication will appear. A carrier who is well today can become affected later, so surveillance is open-ended. Surveillance should include vigilance for lymphoma and monitoring for new cytopenias, lung disease, or enteropathy. Relatives need cascade testing and counseling that emphasizes variability.

Interpreting reports carefully. Many NFKB1 variants on commercial panels are of uncertain significance. This paper shows that published cases are biased toward sick carriers, so a variant of unknown effect in a patient with a common autoimmune disease shouldn’t automatically be treated as causal. Functional testing or immunology input helps. GenIA (https://t.co/msWFhAXOvp) is a useful place to check whether a variant has been reported and, if so, with what phenotype.

Conceptually, NFKB1 haploinsufficiency is a natural human model of how a partial defect in one transcription factor produces antibody failure and autoimmunity together. That is the same paradox rheumatologists see in CVID-associated autoimmunity, IgA deficiency with lupus, and similar overlaps. The unexplained penetrance is a reminder that monogenic labels still leave much of the disease to modifiers we don’t yet understand.

[robert thoburn @thoburn_robert]

Thank you for bringing this to our attention.
A twin study (Danish, n=3,270, ages 65–96) detected neutralizing anti–type I IFN autoantibodies in 1.5% of older adults. Concordance was very low: only 1 monozygotic pair was concordant versus 35 discordant pairs. This argues against strong germline genetic etiology for the sharp post-65 rise in prevalence and favors individual-specific nongenetic drivers (progressive thymic involution reducing AIRE-mediated tolerance, stochastic germinal-center affinity maturation, or unique infectious/inflammatory “second hits”). A slight, nonsignificant mortality association was observed.

Experiment to evaluate causes
Longitudinal multi-omics study in a large aging cohort (or existing biobanks with serial samples):
Track anti-IFN-I neutralizing titers and specificities (α2, ω, β) every 1–2 years from age 55–85.

Pair with thymic function proxies (TREC levels, recent thymic emigrant markers), peripheral T-reg/B-cell repertoire sequencing, and plasma IFN/ISG signatures.

Capture infection history (serology + electronic records) and test for temporal association between viral exposures/high IFN periods and subsequent autoantibody emergence.

In discordant twin or sibling subsets, compare somatic mutation burden and B-cell epigenetic profiles at the time of conversion.

Outcome: distinguish pure age-driven thymic decline from trigger-dependent stochastic events by measuring whether autoantibody appearance clusters after documented high-IFN episodes independent of shared genetics.

[robert thoburn @thoburn_robert]

The Tutor That Never Tires https://t.co/WTRZVfbU0o

[robert thoburn @thoburn_robert]

Where the Disease Lives https://t.co/wpiN0mXUmI

[robert thoburn @thoburn_robert]

@mrxuniverseus 93

[robert thoburn @thoburn_robert]

When Inflammation Stops, Has the Tissue Recovered? https://t.co/FYc5oQ1kZR

[robert thoburn @thoburn_robert]

From Rituximab to CAR-T—and Beyond https://t.co/5iOsIPkkl8