Urogenital tuberculosis — epidemiology, pathogenesis and clinical features

Therapeutic Protein Offers New Hope For Inflammatory Lung Diseases

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Pulmonary sarcoidosis is a lung disease characterized by granulomas—tiny clumps of immune cells that form in response to inflammation. It's the most inflammatory of the interstitial lung diseases (ILDs), a family of conditions that all involve some level of inflammation and fibrosis, or scarring, of the lungs. In the U.S., pulmonary sarcoidosis affects around 200,000 patients. The cause is unknown, and no new treatments have been introduced in the past 70 years.

In a paper published in Science Translational Medicine on March 12, 2025, scientists at Scripps Research and aTyr Pharma characterized a protein, HARSWHEP, that can soothe the inflammation associated with sarcoidosis by regulating white blood cells. Reducing inflammation slows the disease's progression and results in less scarring. A phase 1b/2a clinical trial of efzofitimod, a therapeutic form of HARSWHEP, showed promising results.

"Taken together, these results validate a new way to approach immune regulation in chronic lung disease," says Paul Schimmel, professor of molecular medicine and chemistry at Scripps Research and the study's senior author.

The drug's power lies in its gentle nature. "It's not a hammer; it's not overly suppressing the immune system. It's just nudging the immune system in a certain way," explains Leslie A. Nangle, Vice President of Research at aTyr Pharma and the paper's first author. "And if you can quiet the inflammation, you can stop the cycle of ongoing fibrosis."

HARSWHEP is part of an ancient class of proteins known as aminoacyl-tRNA synthetases (aaRSs). Typically, aaRSs play a key role in protein synthesis. "They're in every cell in your body. They're in every organism on the planet," Nangle says. Over time, new versions known as splice variants have emerged that bind to receptors on the outsides of cells and initiate different events throughout the body.

One such variant, HARSWHEP, entered the picture about 525 million years ago. Nangle and Schimmel screened more than 4,500 receptors and were surprised to find that HARSWHEP will bind only to the receptor neuropilin-2 (NRP2). This receptor is known for its role in development of the lymphatic system—the circulatory system through which immune cells travel—not immune function. But the researchers found that when small, circulating white blood cells known as monocytes enter a tissue in response to inflammation and develop into larger, more specialized white blood cells known as macrophages, those cells start to express high levels of NRP2.

"We had a protein with an unknown function. We had a receptor that was doing something on immune cells that had never been characterized. So we had a couple things we had to match up," Nangle says.

The team found that HARSWHEP binding to NRP2 physically transforms the macrophage. "It's creating a new type of macrophage that is less inflammatory and actually helps to resolve inflammation," Nangle explains.

To characterize HARSWHEP's mechanism of action, the team administered the protein in mice and rats and found that it reduced lung inflammation and the progression of fibrosis.

In separately published clinical trial data, the team saw a positive impact on patients who were treated with efzofitimod while tapering off of oral corticosteroids. Long-term steroid treatment, currently the first-line option, is associated with significant weight gain and organ damage, and the immunosuppressive effects leave patients vulnerable to infection.

The team also characterized patients' circulating immune cells before and after efzofitimod treatment. They saw that it reduced key indicators of the inflammation that drives sarcoidosis, such as the concentration of macrophages and other inflammatory immune cells.

While they're exploring sarcoidosis first, efzofitimod is a potential treatment for many interstitial lung diseases, Nangle explains. The aTyr team plans to explore treating other ILDs and is running a clinical trial now for scleroderma-related ILD.

The work highlights macrophages as a possible target for treating ILDs, and the promise of HARSWHEP could foretell other aaRSs' therapeutic potential.

Nangle describes this work as moving "from concept to clinic." Schimmel has worked on aaRSs throughout his tenure at Scripps Research. ATyr Pharma spun out of Schimmel's lab; his former graduate student Nangle was the company's first employee upon opening their labs in 2006.

"Original work that happened at Scripps gave rise to the idea that this could be a new class of therapeutic molecules, Nangle says. "We have now moved it all the way to clinical development. It's a proof of concept for this whole class of molecules and the work Paul has done."

Reference: Nangle LA, Xu Z, Siefker D, et al. A human histidyl-tRNA synthetase splice variant therapeutic targets NRP2 to resolve lung inflammation and fibrosis. Sci Transl Med. 17(789):eadp4754. Doi: 10.1126/scitranslmed.Adp4754

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Biomarkers Forecast Interstitial Lung Disease In Rheumatoid Arthritis

A PROSPECTIVE cohort study has identified serum biomarkers that may predict the risk of progression in rheumatoid arthritis-associated interstitial lung disease (RA-ILD), offering valuable tools for clinical monitoring and early intervention.

Drawing on data from the Korean Rheumatoid Arthritis Interstitial Lung Disease (KORAIL) cohort, researchers analysed 136 patients with RA-ILD over a median of 3 years. Progression was defined using the 2022 international guidelines for progressive pulmonary fibrosis (PPF), encompassing both radiological and physiological changes.

One-third of patients (34.6%) experienced ILD progression during follow-up. Elevated baseline levels of Krebs von den Lungen 6 (KL-6) and human surfactant protein D (hSP-D) were independently associated with greater risk of progression, with adjusted hazard ratios (HR) of 1.37 and 1.51, respectively. Notably, matrix metalloproteinase 7 (MMP-7) was linked to progression only in its highest quartile (HR 2.60).

Among all biomarkers, the strongest predictor was a rising KL-6 level one year after baseline, which doubled the risk of progression (HR 2.00; 95% CI 1.29–3.11), even after adjusting for initial levels.

This is the first prospective study to apply the new PPF criteria to RA-ILD, and its findings suggest that routine serial monitoring of pulmonary biomarkers, particularly KL-6, could support earlier identification of patients at risk and inform more personalised treatment strategies.

Reference

Chang SH et al. Serum Biomarkers of Pulmonary Damage and Risk for Progression of Rheumatoid Arthritis–Associated Interstitial Lung Disease. J Rheumatol. 2025;52(4)323-33.

PAH Therapies Improve Outcomes In PH-ILD

Pulmonary hypertension is a common consequence of interstitial lung disease (PH-ILD), with the highest rate seen among individuals who have idiopathic pulmonary fibrosis. Overall, most cases of PH in the setting of ILD are mild.

Hemodynamic parameters—pulmonary vascular resistance and mean pulmonary artery pressure (mPAP), in particular—improved in patients with interstitial lung disease (ILD)–precipitated pulmonary hypertension (PH-ILD) who were treated with common pulmonary arterial hypertension (PAH) treatments. Levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were also significantly reduced, according to findings published in Journal of Clinical Medicine Research.

This new research has implications for future use of precision medicine to better identify who among these patients is likely to benefit from PAH-targeted therapy, as well as which method of therapy administration is most effective. Presently, the FDA only allows PAH-targeted therapies in patients with PH who have chronic thromboembolic PH.

PH is a common consequence of ILD because of vascular and parenchymal remodeling, with the highest rate seen among individuals who have idiopathic pulmonary fibrosis. Most of these cases are considered mild, with their mPAP measuring 25 and 35 mm Hg via right heart catheterization.

Thirty-seven patients from the University of Chicago Medicine PH registry were included in this retrospective review, from among 1507 patients living with PH and enrolled in the registry between January 1, 1997, and October 30, 2021; ILD diagnosis was classified by subtype and radiographic pattern. Outcomes were compared before and after treatment by looking at demographics, ILD type, PAH-targeted therapy, hemodynamics, and NT-proBNP.

These results warrant further clinical investigation, and call for the use of precision medicine to phenotype patients with advanced PH, such as that seen with ILD.Image Credit: © Uladzislau-stock.Adobe.Com

Before PAH-Targeted Treatment

At baseline, the mean (SD) patient age was 60.22 (10.54) years; most of these patients were female patients (78.4%), African American (54.1%) or Caucasian (40.5%), and had connective tissue disease–associated ILD (73%); and their most common comorbidity was connective tissue disease (73%). Usual interstitial pneumonia, in 46%, was the most common radiographic pattern.

Sixty-eight percent of patients had World Health Organization functional class (WHO FC) III disease and 19.4%, WHO FC II disease. The mean distance seen with the 6-minute walking distance (6MWD) test was 233 m among 10 patients, mPAP was 45 (11) mm Hg, PVR was 9 (4) Wood units, and median (IQR) NT-proBNP was 1498 (675-3208) ng/dL. Pulmonary function test (PFT) results were noteworthy, the study authors said, because of the numbers seen in relation to percent predicted for total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusion limitation of carbon monoxide (DLCO):

TLC: 68.9% (20.2%)

FVC: 59.9% (15.7%)

FEV1: 63.0% (16.2%)

DLCO: 34.5% (15.3%)

The most common type of PAH-targeted therapy was monotherapy with the phosphodiesterase-5 inhibitors (PDE5-Is; 51.4%), dual therapy with a PDE5-I and an endothelin receptor antagonist (ERA) was seen in 24.3%, and triplet therapy with a PDE5-I, ERA, and prostanoid was used by 2.7%.

After PAH-Targeted Treatment

Although significant improvements were not seen for WHO FC disease type or on exercise stress tests, PFT, and 6MWD tests, statistically significant improvements were seen in NT-proBNP, and hemodynamics.

After a mean 46-week follow-up, drops were seen in mean right atrial pressure (mRAP), mPAP, pulmonary capillary wedge pressure (PCWP), PVR, and in NT-proBNP:

mRAP: 6.71 (4.08) mm Hg from 9.93 (7.75) mm Hg

mPAP: 38.81 (12.62) mm Hg from 44.13 (10.87) mm Hg

PCWP: 10.67 (6.69) mm Hg from 11.83 (3.01) mm Hg

PVR: 4.50 (2.13) WU from 8.38 (3.76) WU

NT-proBNP: 842 (295-2329) from 1421 (675-2709)

Cardiac output and index both rose: 4.25 (1.31) to 5.17 (1.07) L/min and 2.11 (0.69) to 2.67 (0.65) L/min/m2, respectively.

The only adverse effect reported was a headache in 1 patient, but the authors attributed that to their study's retrospective nature.

Conclusions

Knowing that little data exist on the benefits of PAH-targeted therapy in a population who has PH-ILD, the present study authors highlight how their findings show improved hemodynamics—despite being "underpowered to detect associations between individual classes of PAH-targeted therapies and hemodynamics." Their results warrant further clinical investigation, and call for the use of precision medicine to phenotype patients with advanced PH, such as that seen with ILD.2

References

1. Selvan KC, Teerapuncharoen K, Bag R. Oral pulmonary arterial hypertension-targeted therapy in patients with pulmonary hypertension due to interstitial lung disease. J Clin Med Res. 2025;17(3):153-163. Doi:10.14740/jocmr6164

2. Singh N, Dorfmuller P, Shlobin OA, Ventetuolo CE. Group 3 pulmonary hypertension: from bench to bedside. Circ Res. 2022;130(9):1404-1422. Doi:10.1161/CIRCRESAHA.121.319970

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