Appendices

Basic Research Investments Lead to Therapeutic Targets

NIAMS supports a robust portfolio of basic research studying the mechanisms underlying health and disease. Many of these basic research projects help to identify potential therapeutic targets. Here are a few examples of such discoveries from across the NIAMS mission areas:

• Specific types of voltage-gated sodium channels, which are mostly found on the membranes of cells such as neurons that can create tiny electric currents between their interior and exterior (i.e., excitable cells) but also appear on other cell types that are considered unable to be excited, were found to be present in human chondrocytes. Furthermore, they exist in greater numbers in chondrocytes from people who have OA.⁴
• Advances in understanding the fundamental biology of the aberrantly expressed DUX4 in facioscapulohumeral muscular dystrophy from studies of human cells and animal models have introduced targets for both gene therapy and small molecule therapies.⁵
• Several groups studying cachexia in the context of cancer using human cells and animal models produced breakthroughs in understanding the roles of certain micro-RNAs and specific proteins in muscle wasting.⁶
• Researchers uncovered new insights into the pathophysiology of juvenile fibromyalgia, including the pain mechanisms that are impacted by the disease in patients.⁷
• The loss of an enzyme in the endoplasmic reticulum—the cellular transportation system—might play a protective role in a rat model of spondyloarthritis.⁸
• In the field of SLE, investigators are understanding the underlying mechanisms and signaling pathways that influence age-associated B cell differentiation and function and have found that the cells’ activities can be controlled in a sex-specific manner in mice.⁹
• Investigators exploring the mechanisms underlying T cell function in the development of inflammation in people who have RA determined that mitochondrial dysfunction is a key aspect of T cell-induced autoimmunity.¹⁰
• Mouse studies suggest that topical squaric acid dibutyl ester (SADBE)-based immunotherapy may result in novel treatment strategies for children with giant congenital nevi, which cannot be treated surgically, to prevent their transition to melanoma.¹¹
• In mice, the so-called “contagious itching” phenomenon is controlled through a visual pathway that operates independently of the visual cortex.¹²
• Researchers have identified disease-associated proinflammatory pathways in human skin that could be targeted in people with chronic acne.¹³

NIAMS-Funded Genetic and Genomic Studies Advance Knowledge of a Broad Range of Diseases

Over the past five years, the NIAMS-supported research community has made considerable advances in understanding genetic components of various rare and common diseases. For example:

• A collaborative effort led by the NIAMS IRP uncovered a cause of melorheostosis—a rare, progressive disease that affects the growth and development of bone and soft tissue. The researchers discovered a genetic mutation in a crucial pathway for skeletal development that causes human bone cells to display increased growth and hardening.¹⁴ The finding also has far-reaching implications for related diseases that impact broader populations.
• Within the limb-girdle muscular dystrophies, a group of rare progressive genetic muscle wasting disorders, upwards of 29 disease-causing genes have been identified and characterized in patients, opening the door for gene-specific treatments.¹⁵
• A comparison of genetic differences between mice, which walk on four legs, and humans, which walk on two, provided insights into the development of OA.¹⁶ Researchers identified a non-coding regulatory sequence likely important for controlling leg bone length and identified a variant in this sequence as a potential genetic risk factor for human OA.
• In genetics studies regarding bone mineral density (BMD), a measurement used to diagnose bone health and osteoporosis, researchers determined that only three of a panel of known BMD-associated genetic markers from people of European descent were also present in those of African ancestry. Furthermore, they identified novel genetic markers in their African ancestry populations not previously known as BMD-associated genetic markers in studies of populations of European descent.¹⁷
• In vitro studies of human skin cells led to the identification of eight genes that impact melanin levels and modulate human skin color. These findings broaden the understanding of human evolution and the genetics underpinning contemporary human skin color diversity.¹⁸
• In Sjögren’s disease, NIAMS-supported researchers performed the largest genome-wide association study to date in individuals of European ancestry, increasing the total known genetic risk loci.¹⁹
• Researchers conducting large-scale genome-wide studies focusing on RA and SLE examined diverse populations from different ancestral groups and geographic locations and identified new genetic loci associated with RA and novel rare genetic variants in SLE.²⁰
• Other investigators have furthered the understanding of the role of human leukocyte antigen genes in autoimmune and rheumatic diseases.²¹

Studies of Bacteria and Viruses Provide Numerous Insights Into NIAMS-Relevant Topics.

Over the past five years, the research community has gained an ever-growing appreciation for the roles bacteria play in health and disease. Some examples are provided here:

• Investigators leveraging large cohort studies partially funded by NIAMS have linked the gut microbiome with BMD, bone microarchitecture, and bone strength.²²
• Changes in different microbiome niches are related to the onset of OA in mice.²³ This identification of specific groups of microbes or immunological pathways influenced by the microbiome opens avenues for potential targets in the prevention and treatment of OA.
• Many surgical site infections begin with microbes that patients brought with them prior to hospital admission.²⁴
• Specific microbial signals promote skeletal muscle regeneration following injury in mouse models.²⁵
• Knowledge of the role of microbiota in triggering RA and oral inflammation has increased, with NIAMS-funded researchers providing evidence of mucosal immune responses in RA initiation and perpetuation of systemic autoimmunity in patients.²⁶ This finding directly supports the mucosal origins hypothesis of RA, which suggests that mucosal immune responses are key in the initiation or perpetuation of systemic autoimmunity.
• The research community has made considerable progress in understanding the role of the bacterial microbiome and SLE. Evidence suggests that gut microbiota plays a role in SLE, and NIAMS researchers not only identified a causal relationship between the two but also potential pathogenic properties of the microbiota in people who have SLE flares.²⁷
• In the skin portfolio, results from NIAMS-funded research using human tissue and animal models reveal that synergistic interactions between bacteria and a specialized subset of dendritic cells critically support establishment of tolerance to commensal bacteria at barrier surfaces early in life, providing insights into which cell types and pathways instruct unique early life immunity.²⁸
• Skin bacteria also play a role in inhibiting the development of acne. Staphylococcus capitis was found to selectively inhibit growth of Cutibacterium acnes, which is known to promote acne vulgaris. This inhibition, observed when studying human skin cells and animal models, is mediated by factors known as antimicrobial peptides, which are released by Staphylococcus capitis and are nontoxic for human skin.²⁹
• NIAMS intramural researchers in collaboration with investigators from the National Human Genome Research Institute and international colleagues cataloged a broad analysis of the human skin microbiome into the Skin Microbial Genome Collection. The collection is thought to identify about 85 percent of the microorganisms present on healthy skin from 19 body sites and serves as a valuable resource for studying how microbes interact with the human host to elicit or ameliorate disease.³⁰

Beta Blocker Use Influences Bone Health

Two related papers show that use of a class of blood-pressure drugs called beta blockers is associated with BMD values of the hip and spine.³¹ Using multidisciplinary approaches for these studies, investigators also have identified two microRNA molecules that are significantly increased with beta blocker use, increased BMD, and an associated decrease in fracture risk. Since microRNAs are small, noncoding pieces of RNA that regulate gene expression, the researchers were able to leverage this finding to discover possible gene targets and pathways that point to potential mechanisms for why beta blocker use affects bone health. If subsequent studies validate these mechanisms, the findings may provide potential drug targets and possibly lead to use of the microRNAs as biomarkers of bone health.

NIAMS-Supported Research Lays Groundwork for U.S. Food and Drug Administration (FDA)-Approved Drug for Fibrodysplasia Ossificans Progressiva (FOP)

Research funded by NIAMS is bringing therapies into reach for the rare condition FOP while also uncovering clues into fundamental biology. In FOP, bone forms in places that it does not belong, such as muscle and other connective tissue. The research supported by NIAMS has provided the foundation for developing the first FOP drug treatment to be FDA approved. The drug, palovarotene, received FDA approval in August 2023. Other FOP research has revealed more biological processes and mechanisms of FOP, which are being explored to develop additional therapies for this genetic disease.³² The research has also provided insight into complicated biology related to other forms of abnormal bone growth.

Three-Dimensional (3D) Printing Leads to Safer Joint Prostheses

Total joint replacements are effective treatments for degenerative joint diseases such as OA, with more than 2.8 million hip and knee replacements performed in the United States over the past decade.³³ However, these popular surgeries carry the risk of life-threatening infections around the implants. Using 3D printing technology and previous findings about the biocompatibility and wear properties of various materials, NIAMS-supported investigators studying orthopaedic implant science have improved existing implant technology. The investigators identified modifications to enhance resistance to wear and bacterial infection, significantly improving the properties of titanium implants commonly used for joint replacement.³⁴ Although 3D-printed devices are not yet available for patients, the approach shows promise for overcoming a potentially devastating complication from a common surgery.

Leveraging Muscle Biology Knowledge May Lead to Better Gene Therapies

Researchers pursuing treatments for muscle disorders have uncovered a potential new therapy by studying how muscles work. They discovered that they could make viruses more effective at targeting muscle cells and promoting muscle maturation in mice by adding certain muscle proteins to viruses used in gene therapy.³⁵ Because the added proteins play a crucial role in the fusion of individual muscle cells, this new approach may prevent off-target expression that is often seen with some of these approaches and thereby make them safer.

Expanded Genotypic and Phenotypic Study Leads to Improved Understanding of Immune Dysregulation and a New Form of a Disease Known as PLAID

Pathogenic variants of the PLCG2 gene cause two related forms of autosomal dominant immune dysregulation: PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammatory PLAID (APLAID). NIAMS intramural researchers characterizing the effects of 60 additional PLCG2 variants found that over 70 percent of the variants resulted in PLCG2-dependent altered immune function, and most of the variants lead to reduced PLCG2 activity.³⁶ These findings define both a new class of PLCG2 mutation and a novel form of PLAID.

Discovery of Novel Rheumatic Disease Provides Hope for Previously Undiagnosed Patients

Since its discovery in 2020 by researchers at NIAMS, NHGRI, and their international team of collaborators, researchers are making great strides in understanding the population prevalence and molecular underpinnings of VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome. VEXAS syndrome is a rheumatologic and hematologic disease commonly associated with UBA1 gene somatic variants; it manifests during adulthood and is often fatal.³⁷ There has been considerable progress in this area of research, including a deeper understanding of the clinical spectrum of VEXAS.³⁸ Studies focused on therapeutic targets may also improve treatment for people who have VEXAS syndrome as well as those with many other diseases ranging from autoimmune conditions to cancer.³⁹

Immune Reaction to Chromosome Regulatory Molecule Partially Explains Why Autoimmune Diseases Are More Common in Women

Autoimmune diseases occur in women at a rate much higher than in men; for example, SLE has a 9:1 female-to-male ratio, and Sjögren’s disease has a 19:1 female-to-male ratio. Most studies into this discrepancy have focused on differences in hormonal background and in gene dosage in response to altered chromosome expression. The latest evidence, however, suggests that some people launch an autoimmune reaction to a ribonucleoprotein complex that includes the X-inactive specific transcript (Xist), a long noncoding RNA. The XIST RNA molecule helps control the inactivation of one of the two X chromosomes in female cells.⁴⁰ While XIST and the complex of proteins it binds to do not single-handedly cause an autoimmune response, these findings imply that the ribonucleoprotein complex can help to trigger autoimmunity in susceptible women and girls.

Neutrophil Biology and Function Differ for Women and Men

NIAMS intramural researchers discovered that female neutrophils have striking upregulation of type I interferon stimulated genes, suggesting an enhanced response to this group of antiviral cytokines.⁴¹ The difference appears to be driven by sex hormones, such as estradiol. Their findings suggest that sex differences in neutrophil function might contribute to sex differences observed in autoimmunity, cancers, and infections, and implicate sex hormones as potential therapeutics in infectious and autoimmune diseases.

Neutrophil Extracellular Traps (NETs) Induce Loss of Immunologic Tolerance and Acceleration of Organ and Vascular Damage in Autoimmune Diseases

Some researchers in the NIAMS IRP study neutrophil abnormalities and seek to understand the role of NETs in systemic autoimmune disorders. In addition to their exploring the role of NETs in lupus, they discovered that NETs trigger pathogenic inflammation and bone loss in gum disease⁴²; promote bone erosion and the formation of osteoclasts—the cells that degrade bone tissue—in rheumatoid arthritis⁴³; and are partially responsible for the extensive vascular injury, multisystem inflammatory syndrome, and a phenomenon referred to as “COVID toes” seen during COVID-19 infection.⁴⁴

Basic Research Holds Promise for People With Severe Form of Scleroderma or Localized Fibrosis

Systemic sclerosis (SSc), a form of scleroderma, is an autoimmune disease characterized by vasculopathy, inflammation, and fibrosis affecting the skin and multiple internal organs. Several NIAMS-funded investigators have used human cells and animal models to elucidate mechanisms and pathways that drive fibrosis, with the aim of being able to therapeutically slow down and ideally reverse the fibrosis.  They have used various approaches, including single-cell RNA sequencing and bioinformatics analysis techniques, to further understand the role of fibroblasts and their crosstalk with immune cells and adipocytes in fibrosis. ⁴⁵ Other researchers made advances in understanding morphea, or localized scleroderma, by studying pediatric and adult patients.⁴⁶ They discovered molecular signatures unique to the disease as well as risk factors for musculoskeletal manifestations in both age groups.

Research Into Viruses Elucidates Their Role in SLE

Viral infections have long been proven to induce and exacerbate SLE. Specifically, Epstein-Barr virus (EBV) and human endogenous retroviruses are known to be associated with SLE pathogenesis. Because the specific mechanisms of viral-host interactions and the impact of viruses on disease course are unknown, NIAMS-supported researchers have looked deeper into the role of EBV in SLE. The investigators have provided evidence supporting a molecular mimicry model for the generation of SLE, starting with an EBV infection.⁴⁷ Researchers also focused on retrotransposon expression in patients with SLE, with several studies demonstrating a significant association between human endogenous retroviruses and SLE as well as other rheumatic diseases.

High-Resolution Three-Dimensional Tool Allows for Direct Observation of Platelet Deformation Following SARS-CoV-2 Infection

The virus SARS-CoV-2 is highly pathogenic because of the way its spike protein interacts with host-cell receptors. The disease it causes, COVID-19, is often associated with low platelet counts and excessive blood clotting, leading to myocardial infarction in severe cases. Investigators in the NIAMS IRP employed electron cryotomography—an imaging technique used to produce high-resolution three-dimensional views of biological macromolecules and cells—to observe how the interaction triggers human platelet deformation, which leads to irreversible platelet activation in some cases and can even cause the excessive blood clotting seen in severe COVID-19 cases.⁴⁸

Nervous System Influences Skin

NIAMS-supported researchers discovered a novel neuroimmune mechanism indicating that interactions between the nervous and immune systems help regulate the immune cells that interact with the skin. They found that, in mice, the presence of a subset of sensory neurons is reduced when the skin immune regulator Langerhans cells are absent, resulting in increased mast cell degranulation and cutaneous inflammation.⁴⁹ Other results from NIAMS-funded research help uncover the role of peripheral nerves in regulating skin stem cells and their niche, revealing novel potential approaches in regenerative medicine. Researchers discovered that a population of basally located stem cells in the interfollicular epidermis interacts with nerves to regulate their fate and participate in wound healing in mice.⁵⁰ Another team, also studying mice, found that release of the neurotransmitter noradrenaline, also known as norepinephrine, in response to stress can cause hair to gray prematurely by affecting the stem cells that are responsible for regenerating hair pigment.⁵¹

Research Provides Insights Into the Immunobiology of Leprosy

NIAMS has a longstanding research investment in leprosy, an infectious and inflammatory skin disease. Over the past five years, investigators have gleaned insights into how the disease occurs and how it limits itself in certain cases. For example, researchers studying patients characterized the role of myeloid derived suppressor cells in suppressing immunity against the disseminated/progressive form of the disease.⁵²  Another group focusing on self-limiting tuberculoid leprosy identified a set of human genes responsible for the antimicrobial response to Mycobacterium leprae, which in turn allowed them to gain insight into the structural, cellular, and molecular signatures characterizing this form of the condition.⁵³

Delivery of Alkaline Phosphatase Promotes Bone Regeneration in Mice

NIAMS intramural researchers studying the bone consequences of periodontal disease showed that regulating the levels of phosphate and pyrophosphate can restore cementum and bone growth in mice.⁵⁴  This research was the first to show that administration of tissue-nonspecific alkaline phosphatase could enhance cementum growth in a periodontal disease model with a mineralization deficiency. These results may lead to new treatment options for periodontal disease.

Improvements in Bone Morphogenic Protein-2 (BMP-2) Delivery Methods for Repairing Bone Are on the Horizon

Although recombinant BMP-2 is an FDA-approved therapeutic for fracture healing, its use has been limited by several different adverse side effects that result from the high doses needed to stimulate formation of enough bone to fill large gaps. Many NIAMS-funded research teams are exploring approaches to improve BMP-2 delivery and its ability to promote bone repair in animal models. Approaches include removing cells and modifying them to overexpress BMP-2 before reimplanting them,⁵⁵ chemically modifying messenger RNA to deliver BMP-2,⁵⁶ and implanting a sponge embedded with BMP-2 and wrapped in a dehydrated amniotic membrane.⁵⁷

Mechanical Stimulation Combined With Cell Repair Approaches Has Many Applications

As scientists learn more about how to regenerate or repair musculoskeletal tissues, they are integrating mechanical stimulation into their studies. One group of researchers has successfully generated live cartilage tissue that can produce an anti-inflammatory molecule in response to mechanical stimulation.⁵⁸ This novel class of drug-producing cartilage constructs could enhance the therapeutic potential of engineered tissues and promise a new treatment for cartilage defects and osteoarthritis. In addition, the site-specific, mechanically controlled drug release could be applied to the treatment of a wide range of acute and chronic diseases. Other investigators report the synergistic effects of a tissue engineering strategy and exercise rehabilitation in the treatment of volumetric muscle loss injuries in a mouse surgical model.⁵⁹ These researchers used in situ 3D bioprinting for controlled release of a myogenic growth factor that, when combined with exercise treadmill running, led to improved muscle healing that was better than either intervention when provided separately.

Cellular Technologies Hold Promise for Informing Musculoskeletal Tissue Repair Strategies

Single-cell and lineage-tracing technologies are elucidating the role of stem and progenitor cells in musculoskeletal tissues as well as aiding in the development of iPSC differentiation pathways. Using lineage tracing, researchers discovered the overarching molecular programs that govern tendon healing and bone fracture healing, including the programs governing bone and muscle crosstalk.⁶⁰ Understanding how resident stem cells are activated and their role in musculoskeletal tissue repair will allow for the design of better regenerative therapeutics. Additionally, advancements in understanding iPSC differentiation protocols could inform methods of generating musculoskeletal tissues such as bone cells.⁶¹ Researchers used bulk RNA sequencing, single-cell RNA sequencing, and bioinformatic analyses to identify the gene networks regulating iPSC differentiation into chondrocytes.⁶² These results show great promise for the future of cell therapy applications for musculoskeletal conditions.

Muscle Stem Cell Research Offers Potential Therapeutic Applications

Muscle stem cells help to repair muscle fibers after injury. These cells stay mostly inactive, but have different functions: some renew themselves, while others differentiate into more mature forms. Researchers have made many advances related to muscle stem cell behavior, including discovering proteins that maintain these inactive states in stem cells from adult mice or determine the number of stem cells in young animals.⁶³ Others characterized a fusion protein that helps stem cells merge with muscle fibers and showed that its levels increase in damaged muscles but are reduced after repair.⁶⁴ Use of adult muscle stem cells for potential therapies is a growing field, underscoring the importance of efforts to understand how to maintain these cells in culture; a molecule that is being studied as a treatment for other conditions was found to keep these cells inactive, and when transplanted into muscle, they act like new stem cells.⁶⁵ Elsewhere, researchers found a way to transform fibroblasts into muscle-like stem cells that might be used for treatments.⁶⁶

New Protocol Is the First Step Toward Patient-Specific iPSC-Derived Replacement Tissue for Recessive Dystrophic Epidermolysis Bullosa (RDEB)

NIAMS-supported researchers developed a streamlined protocol to generate gene-corrected autologous skin transplants for people suffering from RDEB, a severe blistering skin disease caused by mutations in the collagen 7 gene.⁶⁷ Their one-step protocol to generate patient-derived iPSC uses CRISPR/CAS-mediated homology-directed repair to correct the disease-causing mutations. Using a cell culture system that did not rely on any animal products to feed the human cells, they generated multilineage skin organoids that contain multiple components resembling human skin. Further, they showed that these organoids can reconstitute skin in a mouse model. The team’s accomplishment provides an excellent starting point for establishing the commonly acceptable quality control criteria that must be established to generate iPSC-derived replacement tissues such as skin for people.

Bioprinted Skin Substitutes May Serve as a Promising Alternative to Traditional Skin Grafts

Researchers incorporated six human skin cell types into a multilayered skin construct through extrusion bioprinting.⁶⁸ In in vitro preclinical studies, this construct maintained a three-layer structure as expected in healthy human skin and matured appropriately. The researchers confirmed that in animal models, their bioprinted skin implants successfully integrated into regenerated skin to speed healing.

NIAMS and NIA Encourage the Leveraging of Existing Databases and Cohorts to Better Understand the Risks and Benefits of Long-Term Osteoporosis Therapy and Drug Holidays

To address unmet research needs identified as part of a 2018 workshop, NIAMS and NIA issued a NOFO to encourage investigators to conduct analyses of existing large datasets to provide evidence about appropriate strategies for long-term osteoporosis therapies, including drug holidays, and to better understand their risks and benefits.⁶⁹ The institutes were particularly interested in supporting interdisciplinary studies using innovative analytical approaches such as modeling studies or causal inference methods using data sources from large cohort studies, health care systems, and other public, private, or commercial datasets. In response to this NOFO, NIAMS-funded investigators are pooling international cohort and datasets of long-term bisphosphonate use and atypical femoral fractures, a rare but serious adverse event associated with these drugs.⁷⁰ Their goal is to develop predictive tools that can guide clinical decisions regarding length of treatment, drug holidays, and re-initiation of bisphosphonates or other anti-osteoporosis medications.

Natural Language Processing Can Detect Infections After Total Joint Replacement

Infection following total joint replacement and similar procedures is a common complication. The ability to automate the identification of patients who have prosthetic joint infections by scanning unstructured text of electronic health records will enable clinicians and researchers to use this algorithm as a real-time screening tool. Investigators developed and validated a new natural language processing algorithm, compared it to the gold standard of manual chart review for accuracy, and found that the automated processes were highly accurate for detecting periprosthetic joint infections.⁷¹ This initial attempt at creating a new algorithm and its validation at a single institution holds promise for advancing diagnostic decision-making by orthopaedic surgeons and could be of further use in clinical research by other investigators.

Technology Helps Evaluate and Treat People Who Have Knee OA

Over the past five years, NIAMS-funded researchers have applied new technology to improve the quality of care for knee OA patients. Prior to the development of sensor technologies to assess patients with knee OA, functional assessments were limited to in-person evaluations during clinician visits. Now, these advances have proven the capabilities of wearable sensor technologies for telehealth and at-home functional testing in patients.⁷² Other researchers used deep learning risk assessment models to predict the progression of knee OA to total knee replacement.⁷³ Deep learning models were found to provide superior diagnostic performance compared to traditional models and hold significant potential for shaping the future landscape of clinical practice and clinical drug trials.

Computational Biology Approaches Identify Novel and Conserved Gene Programs in Systemic Juvenile Idiopathic Arthritis (sJIA) and Other Inflammatory Disorders

The etiology of sJIA is multifaceted and obscure, and heterogeneous clinical manifestations include active sJIA, inactive sJIA, sJIA macrophage activation syndrome, and sJIA lung disease. Accordingly, treatment response is highly variable. Recent advancements in single-cell genomics have provided an understanding of genomic associations in patients compared to those in control groups. However, this strategy does not reveal the regulatory gene programs that link to disease states that have not manifested yet among healthy individuals. Also, it does not identify novel conserved gene programs among distinct patient subsets. To address these gaps, investigators used newly developed computational approaches to discover novel common and unique autoimmune gene clusters that are functionally associated with phenotypes of patients with sJIA.⁷⁴ Moreover, they found certain groups of genes, or programs, that may be shared among patients with other autoimmune diseases such as SLE and even healthy individuals. These findings highlight the value of these computational approaches for understanding the pathogenesis of highly heterogeneous autoimmune and autoinflammatory diseases.

Researchers Develop Algorithm for Integrating Single-Cell Datasets

While the ever-increasing diversity of single-cell RNA-seq datasets allows for the full transcriptional characterization of cell types across a wide variety of biological and clinical conditions, combining them for analysis is challenging, especially when the datasets are produced from different technologies. To address this need, investigators developed an algorithm called Harmony that accounts for multiple experimental and biological factors.⁷⁵ Over six analyses, the researchers demonstrated that Harmony generated superior results while requiring fewer computational resources than similar products.

AI Approach for Assessing Mpox Lesions Using Patient Photographs Correlated With Manual Counting

Mpox (formerly known as monkeypox) is predominantly a skin disease, resulting in substantial morbidity. As per current World Health Organization guidelines, the severity of mpox disease is determined by the number of skin lesions present on the body. The number of lesions is also a key parameter in mpox therapeutic trials. Counting skin lesions manually is time-consuming and logistically challenging, particularly in remote areas prone to mpox outbreaks. Researchers in the NIAMS IRP and extramural domestic and international collaborators developed an artificial intelligence algorithm to count mpox skin lesions in patient photographs that correlates closely with manual counts.⁷⁶

Vitamin D Supplements Do Not Prevent Fractures in Healthy People but May Lower Autoimmune Disease Risk

As part of the Vitamin D and Omega-3 Trial (VITAL), researchers studying more than 25,800 men and women for more than five years concluded that supplemental vitamin D₃ did not offer any protection against fractures compared with placebo.⁷⁷ Because the study was designed to test the supplements’ effects against heart disease and cancer, participants were generally healthy and had not been selected for characteristics that would put them at risk of fracture such as low bone mineral density, vitamin D deficiency, or fracture history. Nevertheless, the study was large enough that investigators could compare the effects of supplementation on those with lower and higher vitamin D levels at the beginning of the study and found no differences in fractures. This—combined with other results from VITAL showing no effects on cancer, heart disease, fall risk, migraines, stroke, age-related macular degeneration, and knee pain—calls into question the necessity of vitamin D supplements, which are taken by one-third or more of U.S. adults 60 years of age or older. However, study findings did suggest that daily supplementation with either vitamin D or a combination of vitamin D and fish oil reduces autoimmune disease incidence.⁷⁸

Differences in Diet Affect Bone Health in Puerto Ricans

Modifying a person’s diet is a simple way to lower their osteoporosis risk. There are a variety of diets across the many diverse populations, and these differences may contribute to some of the disparities found in bone-related outcomes. Investigators assessed associations between BMD and how well people’s diets resembled any of three diets known to be associated with health benefits in a large cohort of older Puerto Ricans. Overall, all diets were associated with a lower likelihood of osteoporosis and protective of bone health in postmenopausal Puerto Rican women.⁷⁹ Specifically, the findings suggested that for postmenopausal women not taking estrogen, the Dietary Approaches to Stop Hypertension (DASH) diet most positively influenced bone health.

High Fat Diet Directly Promotes Dermatitis in Mice Before Substantial Weight Gain

Researchers now have experimental evidence supporting the notion that environmental cues, such as a high fat diet, directly influence skin health.⁸⁰ When mice were fed a “western” diet that is high in fat and simple sugars, they experienced skin inflammation even before appreciable body weight gain occurred. The investigators identified the molecules responsible for the inflammation, but do not yet know how these molecules are activated.

Weight Loss Is an Effective Knee OA Treatment

Over the last decade, NIAMS-funded clinical trials have measured the efficacy of weight loss through intensive diet and exercise interventions for the management of knee OA. The research suggests that weight loss achieved through these interventions represents an effective nonpharmacologic treatment for older adults with knee OA. These findings are reflected in recent updates to clinical practice guidelines, which strongly advocate for weight loss and exercise in patients with OA who are overweight or obese.⁸¹ Moreover, evidence shows that weight loss due to diet and exercise can be sustained over the long term. In one of the longest follow-ups of a behavioral therapy clinical trial for knee OA, investigators demonstrated that older adults with knee OA who underwent an 18-month diet or diet-plus-exercise intervention experienced partial weight regain 3.5 years later but maintained statistically significant changes in weight loss and knee pain reduction relative to baseline.⁸²

Studies Provide Evidence Supporting Exercise for People With or Interested in Preventing Knee OA

Although it is well known that exercise has numerous health benefits, people at risk of developing knee OA or who already have advanced disease are often concerned that exercise may cause knee damage. However, OAI data demonstrated that long-term strenuous exercise did not increase a person’s risk for developing knee OA.⁸³ Other OAI data suggest that walking volume and intensity did not accelerate a person’s risk of knee replacement over five years, and walking at a moderate intensity was related to a small decrease in knee replacement risk.⁸⁴ These findings support the recommendation to employ daily walking for exercise and reassure people that moderate increases of both walking volume and intensity are unlikely to accelerate the need for future knee replacement in patients with advanced knee OA.

On the other hand, a randomized controlled trial demonstrated that high-intensity strength training does not reduce pain and joint compressive forces more than low-intensity strength training or counseling about lifestyle changes but was associated with greater risks of falls, pain, and muscle strain.⁸⁵

Studies Elucidate Molecular Connections Between Exercise, Diet, and Healthy Muscle

Researchers identified a cell surface protein in skeletal muscle that, when deleted in mice, improves exercise capacity and resistance to fatigue. Loss of this receptor also inhibits some types of muscle atrophy, suggesting a new avenue for treatment development.⁸⁶  An additional research group identified a cellular biosensor within the mitochondria of skeletal muscle that responds to exercise by modulating mitochondrial quality control through degradation.⁸⁷ A third group seeking to understand the paradoxical finding that a diet high in protein can increase the risk of certain metabolic and age-related diseases in some, but not all, people showed that resistance exercise protects against the fat gain seen in sedentary mice fed a diet high in protein but not the diet’s deleterious effects on glucose metabolism.⁸⁸ Exercised mice on the high protein diet also gained more muscle mass and strength than those on low protein diets, but the effect on strength was transitory.

NIAMS Leads NIH-Wide Effort to Understand How Environmental Exposures Affect Autoimmune Diseases

Many large studies have addressed the genetic contributions to autoimmune diseases, but how exposures and the exposome contribute to their development and progression has not been addressed in a large-scale, systematic manner. In 2023, NIAMS partnered with the National Institute of Environmental Health Sciences and other institutes and centers to support conceptual stage research projects for an exciting future national, interdisciplinary, collaborative, team science research network that will advance the study of the exposome in autoimmune diseases (Exposome in Autoimmune Diseases Collaborating Teams, EXACT).⁸⁹ The future EXACT Network will conduct research to discover the environmental exposures such as diet, the microbiome and social determinants of health that influence disease susceptibility, onset, and outcomes and will develop a system-level approach to understanding the mechanisms underlying how exposures perturb cellular, organ, and tissue function across autoimmune diseases, many of which affect women disproportionally.

Better Mobility Is Associated With Higher Incomes and Longer Working Life in Older Adults

Analysis of decades of data on health and income showed that better walking speeds and mobility are strongly associated with higher income.⁹⁰ Specifically, people who maintained their mobility level were able to work longer and had higher incomes as they aged. This finding underscores the importance of remaining physically active throughout the lifespan, as regular exercise was associated with improved mobility for people of all income levels.

Brittle Bone Disorders Consortium Continues to Provide Hope for Patients Who Have Osteogenesis Imperfecta (OI)

A clinical trial conducted as part of the Brittle Bone Disorders Consortium, a NIAMS-led component of the National Center for Advancing Translational Sciences’ Rare Diseases Clinical Research Network, confirmed findings from previous mouse studies showing that excessive signaling through a molecular pathway controlled by the molecule TGFβ is possibly a key factor causing bone defects for people with OI.⁹¹ The clinical trial also suggests that the anti-TGFβ antibody is safe to be used in OI patients and might be able to increase bone density for people who have type IV OI. Other research from the Consortium could influence the design of future clinical trials, as it showed that a 12-question survey accurately assesses physical aspects of OI patients’ health-related quality of life.⁹² The finding suggests survey results could be a surrogate marker to measure changes in physical function in response to interventions as a secondary outcome in future clinical trials of adults who have OI.

High Dose Teriparatide Followed by Denosumab Leads to Large Gains in BMD

After the Denosumab and Teriparatide Administration (DATA) study demonstrated greater increases in hip and spine BMD in post-menopausal women treated with combination therapy of standard doses of teriparatide (an anabolic drug that promotes bone formation) and denosumab (an anti-resorptive drug that inhibits bone resorption) than either treatment alone, investigators sought to determine if a higher dose of teriparatide would lead to even larger increases in BMD. Over the course of 15 months, the women who received the higher teriparatide dose followed by a standard denosumab dose had significantly higher BMD in the spine and hip than those who received the standard dose of both drugs.⁹³ This suggests a treatment protocol that might benefit women with rapid bone loss at the menopause transition who are at a high risk of fragility fractures.

FDA Approves Bridge-Enhanced Anterior Cruciate Ligament (ACL) Restoration (BEAR) Implant

In December 2020, the FDA approved the first-ever implant to stimulate ACL healing. NIAMS supported the development of the BEAR implant and a clinical trial of the implant that is now monitoring highly active recipients who are at greater risk of ACL re-tear due to lifestyle post-surgery. As this device continues to be used, other NIAMS-funded researchers are looking into post-operative care and its impact on the risk of re-injury.⁹⁴

The NIH Helping to End Addiction Long-term^® (HEAL) Initiative Advances Understanding of Pain Mechanisms

NIAMS plays a major role in the NIH HEAL Initiative^®, an NIH-wide effort focused on improving prevention and treatment strategies for opioid misuse, addiction, and overdose. As part of this effort, researchers are working to understand, manage, and treat pain. NIAMS leads two programs under the NIH HEAL Initiative focused on the mechanisms of pain. The Restoring Joint Health and Function to Reduce Pain (RE-JOIN) Consortium focuses on generating maps of sensory neuron innervation in the different tissues that collectively form the joint, to understand the key players in pain activation in both preclinical animal models and humans. The Back Pain Consortium (BACPAC) Research Program takes a patient-centered approach to address the need for personalized therapies for chronic low back pain. Under BACPAC, the Biomarkers for Evaluating Spine Treatments (BEST) clinical trial measures the effectiveness of existing chronic low back pain treatments to determine what patient characteristics are associated with the best outcomes for each treatment. These programs will continue to elucidate the mechanisms underlying pain and provide novel targets for therapeutics.

Breakthroughs in Duchenne Muscular Dystrophy (DMD) Result in Better Research and Care

The 2023 FDA approval of the first gene therapy, delandistrogene moxeparvovec, for young boys with DMD is just one of many recent advances relevant for this population. The FDA also approved the steroid vamorolone as a treatment for DMD based on evidence demonstrating that it is a better tolerated alternative to the current standard of care—corticosteroids—particularly for long-term use.⁹⁵ Furthermore, a research group meticulously studying fat distributions in individuals with and without DMD and other muscular dystrophies uncovered a consistent progression of muscle deterioration in various upper and lower leg muscles in DMD patients.⁹⁶ Their insights present a promising avenue for clinical trials when developing and testing therapeutic interventions for managing DMD-related complications.

Janus Kinase (JAK) Inhibitors Used as Treatment for Autoimmune Diseases

NIAMS IRP basic research on the immune system led to the development of JAK inhibitors—a class of drugs routinely used to treat a wide range of autoimmune disorders. To date, 10 JAK inhibitors have been FDA approved for treatment of a range of disorders, including RA and alopecia areata.⁹⁷ The recent approval of baricitinib was the first time the FDA specially approved an oral drug as a treatment for alopecia areata.

Tocilizumab Prevents Progression of Interstitial Lung Disease Associated With Early Systemic Sclerosis

The FocuSSced trial, a phase III randomized placebo-controlled trial that tested the safety of tocilizumab and its effects on skin and lung manifestations among patients with SSc and progressive skin manifestations, demonstrated that 48 weeks of treatment stabilized lung function in patients with scleroderma-associated interstitial lung disease (SSc-ILD).⁹⁸ Importantly, lung preservation by tocilizumab treatment is effective regardless of baseline lung function and fibrosis severity before the treatment. For patients with early stage diffuse cutaneous SSc, a form of the disease associated with a high prevalence of interstitial lung disease, early intervention with tocilizumab is expected to have a significant benefit by delaying disease progression even in SSc patients with mild lung involvement. This study highlights the importance of screening patients for SSc-ILD using radiographic modalities such as high-resolution computed tomography of the chest. Tocilizumab received FDA approval as a treatment for patients who have SSc-ILD in 2021.

Commensal Bacteriotherapy Could Treat Atopic Dermatitis

A NIAMS-funded phase 1 clinical trial documented the safety of a bacterium isolated from healthy human skin as a topical therapy for atopic dermatitis.⁹⁹ Staphylococcus hominis A9 (ShA9) cleared some strains of Staphylococcus aureus, a skin pathogen that promotes skin inflammation in patients with atopic dermatitis. Furthermore, ShA9 treatment significantly inhibited Staphylococcus aureus’s ability to produce a known toxin. Although treatment did not significantly decrease the severity of atopic dermatitis, additional clinical studies with a modified clinical trial design, augmented duration of treatment, and optimized formulation of the drug could lead to major advances in efforts to make bacteriotherapy for skin diseases a reality.

Osteoporosis Outcomes Differ by Race

Although osteoporosis is generally perceived as a disease affecting mostly older White women, women of other races and men suffer, too. Well-documented disparities exist in screening, diagnosis, and treatment of osteoporosis due to this misperception. For example, a 2020 paper by NIAMS-funded investigators using Medicare data demonstrated that, in the year following an osteoporosis-related fragility fracture, postmenopausal Black women were more likely to die than White women.¹⁰⁰ This important finding underscores the value of other NIAMS-funded work to understand attitudes and perceptions about osteoporosis and modifiable behaviors that influence risk among people from racial and ethnic minority groups.

Researchers Document Need for Broader Participation in Observational Studies of DMD

Observational studies provide valuable information for clinical trial design and decisions regarding patient care. When such studies lack diverse representation, investigators may draw erroneous conclusions regarding the natural history of disease progression and patient or caregiver values. A survey of 14 publications of data from U.S.-based observational cohort studies of people who have DMD revealed that more than 70 percent of participants were White. Less than 5 percent of people identified as Black/African American. Hispanic/Latino participant representation ranged from slightly more than 3 percent to nearly 27 percent. These findings document the need for additional efforts to recruit, enroll, and retain people from diverse backgrounds into observational research into DMD.¹⁰¹

American Indians Found to Be at Increased Risk of Statin-Associated Autoimmune Myopathy

Researchers working with American Indians in the Navajo region at the Gallup Indian Medical Center in Arizona discovered that statin treatment might be associated with an unexpectedly higher rate of myositis diseases, despite the treatment being used in many populations with minimal side effects.¹⁰² These findings provide a strong recommendation to stop statin treatment for American Indian patients who test positive for myositis to reduce and prevent permanent muscle damage.

Racial and Sex Disparities in Gout Prevalence Exist Among U.S. Adults

The historic notion that gout is a disease affecting mainly affluent White men who indulge in meaty food and alcohol may not be applicable to the current U.S. population. Researchers found Black men and women were at the highest risk of gout. Poverty, higher body mass index, and higher prevalence of chronic kidney disease were found as risk factors in these populations. These findings indicate that key social and lifestyle factors significantly impact the current racial and sex-specific disparities in gout.¹⁰³ This finding has implications for identifying people who should be considered at risk for gout because of a separate report that serum levels can predict a person’s risk of gout flares and hospitalization for recurrent gout.¹⁰⁴

Antiphospholipid Antibodies (aPL) Levels Vary by Race and Ethnicity in People Who Have SLE

APLs are highly pathogenic autoantibodies that can trigger serious pregnancy complications and influence the course of SLE by contributing to organ damage. Using data from seven cohorts of more than 2,500 people from racially, ethnically, and geographically diverse backgrounds who have SLE, investigators demonstrated that aPL levels varied significantly by race and ethnic groups, with the lowest levels in Black patients.¹⁰⁵ Because this group suffers disproportionately from SLE in terms of both incidence and severity, this finding raises considerable questions about factors influencing the disease and can inform the design of future studies relying on aPL levels as a way of measuring treatment response.

Growing Evidence Links Racial Discrimination to Worse SLE Outcomes

In the United States, the prevalence of SLE in Black women is nearly three times as high as in White women, and Black patients with SLE have significantly lower life expectancy compared with White patients. While the reasons for racial disparities in SLE outcomes are multifactorial, psychosocial factors such as the experience of racial discrimination are involved in disease progression. Now, the biological mechanisms responsible for these outcomes are becoming clear. NIAMS researchers discovered that new incidents of racial discrimination have an impact on inflammatory markers in women with SLE.¹⁰⁶ Researchers also found several risk factors associated with socioeconomic status leading to worse disease progression.¹⁰⁷ By illuminating the factors that contribute to the increased severity of SLE, this research emphasizes the need to address these systemic disparities and racism.

NIAMS Promotes Research on Understudied Skin Types

In 2023, NIAMS announced the institute’s special interest in accelerating skin research focused on uncovering the basis for suboptimal diagnosis, increased prevalence, elevated clinical severity, and altered treatment response in Black Americans and African Americans, Hispanics and Latinos, American Indians and Alaska Natives, Asians and Asian Americans, and Native Hawaiians and Pacific Islanders with skin diseases, as compared to European ancestry populations.¹⁰⁸ By addressing this fundamental research gap, the generated knowledge will yield basic, translational, and clinical insights to improve health pertinent to disorders of skin and specifically benefit populations with understudied skin types. It may also produce evidence to inform future innovative studies or new scientific directions to accelerate research that reduces or eliminates the health disparities these groups experience.

Workshop Explores Strategies to Tackle Health Disparities in Osteoarthritis

A two-day NIH workshop sponsored by NIAMS, NIA, and NIMHD aimed to better understand health disparities in caring for and treating people with OA and the role played by social determinants of health.¹⁰⁹ The meeting convened osteoarthritis investigators and health disparities researchers to discuss why disparities in OA treatment outcomes and access to care exist and how to address these challenges. The need to better integrate resources outside of the traditional health care arena into OA patient care was a common suggestion among participants. For example, community health workers, social workers, community centers, and libraries can all play an important role in bridging the gap between OA patients and health services. Given the role of excessive weight and physical inactivity in the development and progression of OA, participants also discussed the need to emphasize and integrate evidence-based interventions that can lead to improved health. To improve outcomes and address disparities, programs should be tailored to specific patient communities and cultures. Enhancing patient-provider communication and establishing easily accessible OA information resources were additional meeting themes. Resources need to target both patients and providers, while addressing language, cultural, and health literacy barriers. Additional research opportunities included the need for standardized OA measures and consistent reporting practices to enhance clinical assessment and outcome analysis. Another echoed theme was the need to leverage evidence-based resources and methods from other fields to address OA health disparities.

BMD Potentially Useful as Surrogate for Bone Fracture for Osteoporosis Clinical Trials

A partnership with the Foundation for the National Institutes of Health and the American Society for Bone and Mineral Research, with support from NIAMS, put forward as part of the Study to Advance BMD as a Regulatory Endpoint (SABRE) Bone Quality Project, a qualification plan to use BMD as a surrogate marker for fracture that was the first to be accepted by the FDA for a substitute endpoint under the 21st Century Cures Act. The project was born out of a request for applications that NIAMS released in 2002 for the development of tools that precisely assess bone strength and quality for fracture risk to target high-risk populations for preventive or therapeutic interventions. In 2022, the FDA approved BMD, as measured by dual-energy x-ray absorptiometry (DXA), to be used as a primary endpoint for osteoporosis instead of fracture in a phase 3 clinical trial. This is an exciting step towards BMD’s FDA qualification for use as an endpoint in future studies.

Videogame Cameras and Artificial Intelligence Are Useful for Phenotyping Low Back Pain Patients

Researchers have developed an approach for evaluating the biomechanics displayed by chronic low back pain patients that is now being used to phenotype participants in the BACPAC BEST Trial.¹¹⁰ In a study funded by the NIH HEAL Initiative, participants who had nonspecific lower back pain or adult spinal deformity, as well as healthy controls, performed sit-to-stand tests while being monitored by a video camera developed for use in gaming systems (the Microsoft Kinect motion capture camera). When investigators used unsupervised machine learning to identify differing movement strategies between the three groups, clear differences emerged, the most striking of which was a forward leaning strategy for standing up in the patients with back pain compared to the normal controls, despite such a motion resulting in increased spine loading. This movement pattern was strongly correlated with patient-reported outcomes of pain and disability.

Novel Technology Lays Groundwork for Home Testing of Lupus Patients

Building on a large volume of prior research, a team of lupus investigators developed a rapid and reproducible assay for detecting a promising biomarker in urine that allows the results to be read on a smartphone.¹¹¹ The marker, a protein named CD 166/ALCAM, exhibits one of the highest discriminatory powers for active lupus nephritis across multiple ethnicities, including African Americans, Whites, and Asian Americans. This new technology lays the groundwork for building a portable at-home testing device, like a pregnancy test, that can be readily used for regular monitoring of disease activity in lupus clinical trials and potentially serve as a diagnostic tool at point-of-care.

Human Skin Cell Atlas Provides a Foundation for Future Research

A consortium of skin researchers, many of whom are NIAMS-funded investigators, initiated the first steps to build a consensus Human Skin Cell Atlas and outlined a roadmap toward that goal by defining basic principles that should be followed to ensure proper representation and technical consistency in sample acquisition and processing.¹¹² The concerted effort promises a wealth of new information about common and rare skin cell lineages that will enable researchers to elucidate molecular pathways underlying skin diseases.

Skin Organ Model Holds Promise for Biomedical Research and Patient Care

Innervated hair-bearing skin organoids composed of self-assembled epidermal and dermal layers, adipocytes, and sebaceous glands were successfully generated entirely from human induced pluripotent stem cells.¹¹³ This organ model, protocol, and overall approach will serve as a roadmap for analysis of developmental skin cell interactions, help produce unlimited human hair follicles supply, advance skin transplantation, and provide tools for studying skin hereditary diseases and drug testing in skin diseases.

Myotonic Dystrophy Models Open Avenues for Preclinical Testing

The creation and characterization of models of myotonic dystrophy that include the long CTG repeats has allowed the identification and preclinical testing of many potential disease-specific interventions, including both gene-based therapies and small molecules. One group of investigators showed that the RNA toxicity in a mouse model of myotonic dystrophy leads to decreased muscle regeneration in the short term, and prolonged RNA-induced toxicity over a longer period leads to a muscular dystrophy phenotype.¹¹⁴ In the same paper, the group reported the identification of an antisense oligonucleotide compound that destroys the damaged RNA improves muscle regeneration and thereby reduces the dystrophic phenotype. Others studying a cell model described a proprietary compound that targets the gene expansion repeats and has the potential ability to alter the repeat instability at the DNA level instead of interfering once the gene is transcribed.¹¹⁵

Modified Data Analysis Approach Reveals Considerable Diversity in Human Neutrophils

A major component of the immune system, the neutrophil, is notoriously challenging to study and has been traditionally described as a homogenous cell type. NIAMS IRP investigators used conventional single-cell RNA sequencing to examine the cells along a continuum of transcriptional states but modified the data analysis approach to increase the amount and types of information they could obtain.¹¹⁶ They found that circulating human neutrophils are transcriptionally heterogeneous cells that can be classified into one of four transcriptional clusters. Not only does the finding nuance and enhance the understanding of an immune cell that is central in acute and chronic inflammatory conditions, but it also creates a framework for future studies of this key cell type.

Pathways to Prevention (P2P) Workshop Leads to NIH-Wide Efforts to Encourage Studies of Osteoporosis Drugs and Their Prescribing Practices

NIAMS, in collaboration with other NIH components, has taken important steps to close the knowledge gaps highlighted by NIH’s “P2P Workshop on the Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention.” The 2018 workshop was held to identify research questions that, if answered, could address the declining rates of osteoporosis treatment uptake stemming, in large part, from physician and patient concern about how to best treat long-term osteoporosis patients and the available treatments’ rare, adverse effects. Since then, NIAMS, NIA, the National Institute of Dental and Craniofacial Research, and ORWH issued a notice of special interest (NOSI) in understanding the development of two rare conditions associated with taking certain osteoporosis medications.¹¹⁷ NIAMS and NIA also issued a funding opportunity supporting research exploring strategies and the risks and benefits of long-term osteoporosis therapies, described in detail above.¹¹⁸

Wellstone Centers Program Promotes Interdisciplinary Team Science to Study Muscular Dystrophies

NIAMS, NICHD, NINDS, and NHLBI have a long history of supporting the Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Centers. These Centers promote collaborative basic, translational, and clinical research and provide important resources that can be used by the national muscular dystrophy research communities. The Centers also provide outstanding environments for the training of new researchers capable of addressing high-priority objectives in muscular dystrophy research. Center investigators are expected to participate in important community outreach efforts to increase awareness of their research activities among people with lived experience and the related advocacy communities and to incorporate community perspectives into the conduct of patient-centered research. As knowledge about the muscular dystrophies has expanded, NIH is now encouraging investigators to collaborate with others who have expertise in physiology, cardiology, pulmonology, neurology, bioinformatics, bioengineering, or other relevant fields as well as patient-oriented and synergistic preclinical research examining the mechanisms that underlie the effects of muscular dystrophies as well as research designed to improve the translation of existing knowledge of strategies for the prevention and treatment of muscular dystrophies.¹¹⁹

NIAMS-Led Public-Private Partnerships Advance Understanding of RA and SLE Cell Populations, Pathways, and Potential Drug Targets Using Single-Cell and Systems Biology Approaches

The AMP RA/SLE and AMP AIM programs were designed to deepen the fields’ understanding of autoimmune diseases and immune-mediated diseases. Through a team science approach, AMP RA/SLE established the value and feasibility of using high-dimensional single-cell analytic methods to study biopsy samples of diseased tissue, as well as urine and blood, from RA and SLE patients.¹²⁰ These biopsies, paired with urine and blood, enabled the discovery of novel biomarkers that more accurately reflect tissue damage—findings that hold promise for noninvasive diagnosis of disease, better monitoring of treatment response, and guidance of clinical decisions for early optimization of treatment.¹²¹ Building on the success of the AMP RA/SLE program, AMP AIM was launched in 2021 with the goal of deepening our understanding of the cellular and molecular interactions that lead to inflammation and autoimmune diseases. AMP AIM now extends to include other autoimmune diseases such as psoriasis, psoriatic arthritis, and Sjögren’s disease, in addition to RA and SLE. AMP AIM will also leverage novel, high-dimensional research tools to uncover cellular interactions in disease-relevant tissues that cause inflammation, injury, abnormal function, and clinical disease. The knowledge gained through these studies will lead to a better understanding of the biological processes that underlie autoimmune disorders and will facilitate development of more effective treatments.

The NIAMS Resource-Based Centers (P30) Program Provides Critical Research Infrastructure and Resources to NIAMS-Funded Investigators

With the goal of accelerating and enhancing the effectiveness of ongoing basic, translational, and clinical research and promoting new research within the NIAMS mission, the NIAMS Resource-Based Centers (P30) Program provides critical resources to groups of investigators studying musculoskeletal, rheumatologic, and skin diseases. With support from this program, investigators can utilize services, shared facilities, infrastructure, and other resources to conduct their research projects more efficiently and effectively. Some funded Administrative Cores, for example, have enabled NIAMS-supported researchers and their institutions to facilitate collaborations and implement mentorship programs. Some centers have used their Biospecimen and Cellular Analysis Cores to equip research communities with the resources to maintain repositories of data and extensive cell banks and use cutting-edge spatial transcriptomics to better understand pathologies at the cellular level. Other Cores have aided in the integration of research and clinical centers within electronic medical record systems, the launch of enrichment programs with seminars and symposiums, and recruitment efforts to attract the next generation of scientists.

Partnerships Across NIH Foster Emerging Opportunities to Advance the Health of Women

Since the development of the institute’s previous Strategic Plan, NIAMS has intensified its partnership with ORWH and the ORWH’s Office of Autoimmune Disease Research, an office established in 2023 to coordinate autoimmune disease research across NIH. NIAMS works closely with the NIH Division of Program Coordination Planning and Strategic Initiatives to design and implement activities related to the 2023 White House Initiative on Women’s Health Research, an effort led by First Lady Jill Biden and the White House Gender Policy Council. Other activities include working with both ORWH and the NIH Office of Data Science Strategy to promote team science and a robust workforce through the Team Science Leadership Scholar’s Program in Women’s Health, Autoimmune and Immune-Mediated Diseases, which also was established in 2023 to train the next generation of research scholars who are focused on understanding women’s health and health disparities in relation to autoimmune diseases. NIAMS also continues to partner with other institutes and centers on longstanding collaborative programs such as the Implementing a Maternal health and PRegnancy Outcomes Vision for Everyone (IMPROVE) initiative, led by NICHD, ORWH, and the National Institute of Nursing Research.

The D.C. Lupus Consortium (DCLC) Brings Together Researchers and Clinicians Across the District of Columbia and Surrounding Area

Almost a decade ago, the Lupus Clinical Research Program within the NIAMS IRP established the DCLC, a collaborative network of rheumatologists, nephrologists, physiatrists, and other health care providers interested in lupus clinical research in the metropolitan Washington, D.C., area. The DCLC’s purpose is to promote partnerships and referrals to the NIAMS Lupus Clinical Research Program and collaborations with local and regional clinicians caring for patients with lupus. In 2024, members of the consortium—including NIH scientists, researchers, patient advocacy groups, and physicians both within and outside of NIH—met to celebrate the 30th anniversary of NIH lupus clinical research. The event highlighted the outstanding progress in lupus clinical research made by NIH over the last three decades and featured testimonials from research participants, updates on current lupus research activities at NIAMS, and discussions on the future direction of lupus clinical research at NIH. Also in 2024, the local Montgomery County Council issued a proclamation during Lupus Awareness Month to acknowledge the NIAMS IRP’s contributions to lupus research.

Combining Gene Therapy and Mechanical Stimulation Creates a Controlled Drug Delivery System in Live Cartilage Tissue Constructs

A multidisciplinary research team guided by the current understanding of gene therapy, gene regulatory networks, mechanical physiology, and tissue engineering successfully generated live cartilage tissue constructs that can produce an anti-inflammatory molecule in response to mechanical stimulation.¹²² Not only could the novel class of drug-producing cartilage constructs generated in this study enhance the therapeutic potential of engineered tissues, promising a new treatment for cartilage defects and OA, the site-specific, mechanically controlled drug release could be applied to the treatment of a wide range of acute and chronic diseases. Furthermore, advanced research in this multidisciplinary collaborative direction could lead to the development and implementation of various types of similarly “smart” cells that could serve as sentinels for disease prevention, diagnosis, and monitoring.

Intramural Virtual Training and Research Opportunities (InVTRO) Provides Students With Research Experience

The NIAMS InVTRO was developed as a direct response to the ongoing challenges of providing meaningful research experiences to undergraduate trainees during the pandemic. Students from across the United States were selected among thousands of applicants to participate in this eight-week virtual program. InVTRO provided an online interactive platform of innovative and highly effective virtual professional career development and training in the biomedical sciences. Since its inception, the program has continued, morphing first into a hybrid format and now ongoing as an immersive in-person experience.