Rheumatoid vasculitis (RV) is a rare, severe extra-articular manifestation of rheumatoid arthritis (RA), typically occurring after long-standing erosive disease. Advances in RA therapy have reduced its incidence; however, RV can occasionally present early in high-risk patients. We report a man in his thirties from Central India with a 3-year history of inadequately treated seropositive RA, who presented with progressive polyarthritis, neuropathy, and distal ischemic changes. Over five months, he developed worsening joint pain and swelling, followed by tingling, numbness, and subsequently dry gangrene of the 2nd-5th toes of the left foot. Examination revealed palpable peripheral pulses, normal ankle-brachial index, active synovitis in 24/28 joints, and sensorimotor deficits with weakness and absent ankle reflex. Laboratory evaluation showed anaemia, thrombocytosis, markedly elevated ESR and CRP, and high RF (288 U/mL) and ACPA (>300 U/mL). ANA and ANCA were negative. CT angiogram ruled out peripheral arterial occlusion, and echocardiography excluded cardiac emboli. Nerve conduction study demonstrated sensorimotor axonal neuropathy. Sural nerve biopsy confirmed vasculitis with axonal damage and perivascular inflammation. A diagnosis of rheumatoid vasculitis was made. Treatment with high-dose intravenous methylprednisolone, followed by oral prednisolone, rituximab, and methotrexate, led to rapid control of joint inflammation and halting of gangrene progression. At 6-month follow-up, the patient was asymptomatic on methotrexate 25 mg/week with steroids tapered off, and no further vascular events. This case highlights that RV may rarely occur early in seropositive RA with poorly controlled disease. Prompt recognition, biopsy confirmation, and aggressive immunosuppression are crucial for favourable outcomes.

Understanding the genetic regulation of circulating protein levels can provide new insights into disease mechanisms. Here, we present the largest proteogenomic study to date (n = 78,664 participants across 38 studies), identifying >24,000 protein quantitative trait loci (QTLs) associated with 1,116 proteins, acting near to (n = 5,040) or distant (n = 19,698) from the cognate gene. Using machine learning-guided effector gene assignment, we provide genetic evidence for pathways, cell types, and tissues that modulate circulating protein levels, highlighting N-linked glycosylation as an important regulatory pathway. We demonstrate that genetic instruments of protein production/function ("cis") versus modulation ("trans") reveal distinct phenotypic insights. We identify proteins as candidates for drug targets and engagement (e.g., plasma furin and cardiovascular diseases) by comparing cis-based genetic evidence with protein-disease associations. Systematic triangulation of trans-protein QTLs (pQTLs) with genetic and protein associations across many diseases highlights potential drug repurposing opportunities, e.g., tyrosine kinase 2 (TYK2) inhibitors for rheumatoid arthritis. Our multi-cohort meta-analyses generate proteogenomic insights into disease mechanisms and new treatment opportunities.

Women bear a disproportionate burden of knee osteoarthritis (KOA), yet global research systematically underrepresents sex-specific and context-sensitive analyses, limiting precision care and equitable interventions. We conducted a scoping review following PRISMA-ScR guidelines, systematically mapping studies on KOA in adults from 2000 to 2024 across PubMed, Embase, Scopus, Web of Science, and Cochrane Library. A predefined, version-controlled protocol was maintained with timestamped revisions and an independent audit to ensure methodological transparency. Dual independent screening, data extraction, and coding achieved high reliability (Cohen's κ = 0.87). A validated weighted gap scoring system assessed four equity domains: sex-disaggregated analysis, women's representation, contextual reporting, and geographic diversity. Integrated descriptive mapping and cross-tabulation quantified structural evidence gaps. Gray literature and non-English studies were excluded, acknowledging potential underrepresentation of low- and middle-income country (LMIC) data. Among 287 included studies, women were represented in 91%, yet only 22% were women-only cohorts, with high-income countries 2.4× more likely to conduct women-focused research than LMICs (χ2 = 29.4, p < 0.001). Sex-disaggregated analyses were reported in 38% of mixed-sex studies, with profound neglect of psychosocial, preventive, and mechanistic outcomes. Intersectional analyses combining age, socioeconomic status, and context were extremely rare. Weighted gap scores highlighted very high deficiencies in SES, education, occupation, and LMIC representation, with minimal improvement over 24 years. KOA's evidence base does not merely underrepresent women; it systematically fails to generate clinically validated knowledge for them. As a result, interventions are routinely applied without clear evidence of the effectiveness across the population most affected, without mandatory sex-aggregated, mechanistic, and context-specific research.

Systemic target engagement constrains the therapeutic index of many antibody drugs, particularly in inflammatory disease and immuno-oncology. Protease-cleavable masking can localize activity to disease sites, but existing approaches often tradeoff masking strength, reversibility, and developability. Here, we evaluated the insulin-like growth factor II (IGF-II) as a compact, structurally defined steric masking domain for protease-dependent conditional activation of therapeutic antibodies. IGF-II masking domains, including a receptor-silent variant (IGF-II-s), were engineered as N-terminal fusions to therapeutic antibodies via protease-cleavable linkers and characterized using antigen-binding and cell-based functional assays. IGF-II masking attenuated anti-TNFα binding and neutralization potency in a protease-dependent manner and activity was largely restored following cleavage. In vivo, an MMP2/9-cleavable masked anti-TNFα antibody retained efficacy comparable to adalimumab and infliximab in a collagen antibody-induced arthritis model, yet, unlike the reference antibodies, did not measurably reduce survival in a Listeria monocytogenes infection challenge model at the dose tested. IGF-II-s showed no detectable IGF receptor binding and provided stronger masking than native IGF-II. This generalized approach was demonstrated across multiple antibodies, enabling efficient protease-dependent conditional activation of trastuzumab (anti-HER2), an anti-IL-1β antibody, and bevacizumab (anti-VEGF). Together, these results established an engineered IGF-II-based masking domain as a versatile, IGF-II receptor-silent platform enabling protease-dependent conditional activation of therapeutic antibodies, with potential to improve safety and expand therapeutic windows.

With the recent rise in the numbers and diversity of astronauts and space travelers, health and prevention of illness in space are of primary importance. Changes in immune function among astronauts during spaceflight have been reported, but gaps remain in understanding how this may translate to increases in an in-flight risk of infection. To understand how immunity and infection are affected by microgravity, we used the nematode Caenorhabditis elegans as an animal host-pathogen model. Worms exposed to either space or simulated microgravity for several days exhibited increased Enterobacter gut colonization compared to normal gravity on Earth. Bacterial susceptibility was more severe in immunocompromised mutants of the pmk-1 gene, a conserved p38 MAPK ortholog that regulates innate immunity. RNA sequencing analysis identified several immune effector genes regulated by microgravity through MAPK/PMK-1. Silencing these genes via RNA interference identified specific immune effectors that protect C. elegans against increased Enterobacter gut proliferation, while transgenic expression of one of these effectors prevented increased colonization in immunocompromised C. elegans in microgravity. This study underscores the importance of the conserved MAPK/PMK-1 innate immune pathway in providing protection against possible infection during spaceflight.

GPCR therapeutics primarily target structured cavities formed by the seven transmembrane α-helices. However, amino acid sequence conservation in structured regions, especially among receptor subtypes, limits target selectivity. Here, we leverage the sequence divergence of the third intracellular loop (ICL3) of the receptor fold to derive a selective positive allosteric modulator for the β2 adrenergic receptor (β2AR). We repurpose the variable regions of a previously reported monoclonal antibody (Mab5) as single-chain (ScFv5) and single-domain (VhhL5) antibody fragments that enhance the maximal second messenger cyclic AMP signaling response downstream of the receptor. Despite ScFv5 binding a segment of ICL3 distinct to β2AR, it also non-selectively binds and modulates cAMP signaling downstream of β1AR and β3AR. We find that this lack of specificity stems from multiple redundant interactions that facilitate ScFv5-ICL3 binding. In contrast, VhhL5, derived from the Mab5 light chain, selectively modulates β2AR signaling over the β1/β3 subtypes. Mechanistically, VhhL5 enhances agonist-stimulated β2AR-G protein coupling through releasing autoinhibitory ICL3 conformational states. In parallel, VhhL5 decreases β2AR internalization promoting greater ligand-induced accumulation of cAMP. Our study demonstrates proof-of-concept for selective allosteric modulation of a GPCR by targeting a sequence divergent loop region within the receptor fold.