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Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown pathogenesis that may be diagnostically difficult in extranodal sites. It is commonly an unsuspected diagnosis when arising in bone and soft tissue, especially when it presents without associated lymphadenopathy. Its variable clinical presentation and nonspecific imaging findings make the diagnosis quite challenging, particularly in small biopsies. The problem is compounded by its less-characteristic histomorphologic features in comparison with nodal disease. Awareness of the potential diagnostic pitfalls in Rosai-Dorfman disease of bone and soft tissue should raise the degree of diagnostic accuracy. To review the clinical manifestations, imaging characteristics, and histomorphologic features of Rosai-Dorfman disease of bone and soft tissue along with a brief discussion of its differential diagnosis, pathogenesis, and current management. Thorough review of the literature with focus on clinical manifestations, imaging findings, key histomorphologic features, pathogenesis, and treatment. The diagnosis of Rosai-Dorfman disease of bone and soft tissue may be quite challenging because of its variable clinical presentation and nonspecific imaging findings. It may be asymptomatic without systemic manifestations or associated lymphadenopathy. The definitive diagnosis relies on histopathologic identification of the characteristic S-100-positive histiocytes demonstrating emperipolesis. Bone and soft tissue lesions tend to have lower numbers of characteristic histiocytes and less conspicuous emperipolesis and often demonstrate areas of fibrosis or storiform spindle cell areas resembling fibrohistiocytic lesions. Awareness of these unusual features is necessary in order to consider Rosai-Dorfman disease in the differential diagnosis when confronting these rare and often misleading lesions.

Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, multiplexed imaging and spatial transcriptomics along with in vitro modeling of cell-extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell-derived cytokines, TNF, IFN-γ, IL-1β or lack thereof, drive four distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium. Smith et al. present a resource detailing drivers of transcriptional heterogeneity of synovial fibroblasts cell states in the inflamed joints of human patients with rheumatoid arthritis.

Background We sought to identify features that distinguish osteoarthritis (OA) and rheumatoid arthritis (RA) hematoxylin and eosin (H&E)-stained synovial tissue samples. Methods We compared fourteen pathologist-scored histology features and computer vision-quantified cell density (147 OA and 60 RA patients) in H&E-stained synovial tissue samples from total knee replacement (TKR) explants. A random forest model was trained using disease state (OA vs RA) as a classifier and histology features and/or computer vision-quantified cell density as inputs. Results Synovium from OA patients had increased mast cells and fibrosis ( p < 0.001), while synovium from RA patients exhibited increased lymphocytic inflammation, lining hyperplasia, neutrophils, detritus, plasma cells, binucleate plasma cells, sub-lining giant cells, fibrin (all p < 0.001), Russell bodies ( p = 0.019), and synovial lining giant cells ( p = 0.003). Fourteen pathologist-scored features allowed for discrimination between OA and RA, producing a micro-averaged area under the receiver operating curve (micro-AUC) of 0.85±0.06. This discriminatory ability was comparable to that of computer vision cell density alone (micro-AUC = 0.87±0.04). Combining the pathologist scores with the cell density metric improved the discriminatory power of the model (micro-AUC = 0.92±0.06). The optimal cell density threshold to distinguish OA from RA synovium was 3400 cells/mm 2 , which yielded a sensitivity of 0.82 and specificity of 0.82. Conclusions H&E-stained images of TKR explant synovium can be correctly classified as OA or RA in 82% of samples. Cell density greater than 3400 cells/mm 2 and the presence of mast cells and fibrosis are the most important features for making this distinction.

Background Bone quantity, quality, and turnover contribute to whole bone strength. Although bone mineral density, or bone quantity, is associated with increased fracture risk, less is known about bone quality. Various conditions, including disorders of mineral homeostasis, disorders in bone remodeling, collagen disorders, and drugs, affect bone quality. Questions/purposes The objectives of this review are to (1) identify the conditions and diseases that could adversely affect bone quality besides osteoporosis, and (2) evaluate how these conditions influence bone quality. Methods We searched PubMed using the keywords “causes” combined with “secondary osteoporosis” or “fragility fracture.” After identifying 20 disorders/conditions, we subsequently searched each condition to evaluate its effect on bone quality. Results Many disorders or conditions have an effect on bone metabolism, leading to fragility fractures. These disorders include abnormalities that disrupt mineral homeostasis, lead to an alteration of the mineralization process, and ultimately reduce bone strength. The balance between bone formation and resorption is also essential to prevent microdamage accumulation and maintain proper material and structural integrity of the bone. As a result, diseases that alter the bone turnover process lead to a reduction of bone strength. Because Type I collagen is the most abundant protein found in bone, defects in Type I collagen can result in alterations of material property, ultimately leading to fragility fractures. Additionally, some medications can adversely affect bone. Conclusions Recognizing these conditions and diseases and understanding their etiology and pathogenesis is crucial for patient care and maintaining overall bone health.

To confirm how often histologic diagnoses correspond to reported clinical diagnoses in patients undergoing total joint arthroplasties. We compared the submitting operative diagnosis with the pathologic diagnosis in 16,587 total joint arthroplasties for the seven most common diagnoses. The discrepancy rates between the submitted operative and histologic diagnosis were 18.8% for 7,968 total hip replacements and 9.4% for 8,619 total knee replacements. In addition, 5.4% of hip joints and 1.4% of knee joints demonstrated discordant histologic findings that had not been suspected clinically and should have affected clinical management and patient outcomes. Our findings demonstrated significantly more diagnostic discrepancies and discordance than has been suggested by the previously published literature. A large part of the difference may be due to more careful diagnostic analyses of orthopedic specimens than in other institutions. These analyses include some diagnoses that are not often made elsewhere but may have important future implications for patients.

* Context.--Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown pathogenesis that may be diagnostically difficult in extranodal sites. It is commonly an unsuspected diagnosis when arising in bone and soft tissue, especially when it presents without associated lymphadenopathy. Its variable clinical presentation and nonspecific imaging findings make the diagnosis quite challenging, particularly in small biopsies. The problem is compounded by its less-characteristic histomorphologic features in comparison with nodal disease. Awareness of the potential diagnostic pitfalls in Rosai-Dorfman disease of bone and soft tissue should raise the degree of diagnostic accuracy.

In the rheumatoid arthritis (RA) synovium, resident fibroblast-like synoviocytes (FLS) express MHC class II molecules (HLA-D) but lack the costimulatory signals typically required for T cell activation. Here, we demonstrate that antigen presentation by FLS induces a distinct T cell activation state characterized by high CD69 yet reduced CD25 and HLA-DR expression, suppressed proliferation, and decreased effector cytokine production compared with professional antigen-presenting cells (APCs), such as macrophages. FLS were also capable of suppressing macrophage-induced T cell activation, underscoring their dominant immunomodulatory role in the synovial microenvironment. Mechanistically, we identify indoleamine 2,3-dioxygenase-mediated (IDO1-mediated) tryptophan depletion as the primary driver of FLS-induced T cell hyporesponsiveness. Spatial transcriptomics revealed colocalization of IDO1 and CD69 within ectopic lymphoid structures in RA synovium, further supporting the in vivo relevance of this pathway. These findings provide the groundwork for positioning FLS as critical T cell regulators in RA and highlight the importance of preserving their immunosuppressive properties when therapeutically targeting pathogenic FLS functions.

Objective Fatigue is important for patients with rheumatoid arthritis (RA) but is poorly understood. We sought to study associations of fatigue with clinical features, disease activity, and synovial histology. Methods Patients meeting the American College of Rheumatology/EULAR 1987 and/or 2010 RA criteria were recruited before elective total joint replacement. Demographics, RA characteristics, tender and swollen joints, erythrocyte sedimentation rate (ESR) and C‐reactive protein, and patient‐reported fatigue, categorized as mild, moderate, or severe, were collected. Hematoxylin and eosin stains of sectioned synovium were systematically scored by a pathologist. Relationships between fatigue and studied variables were evaluated with Kendall's tau. A directed acyclic graph (DAG) was used to illustrate associations of exposures, outcome variables, mediators, and confounders. Multivariable ordered logistic regression was used to further study associations. Results Of 160 included patients, 85.6% were women, with a median age of 63.5 (55.25–71.40) and mean disease activity scores in 28 joints using ESR (DAS28‐ESR) of 3.91 (SD 1.3). There were no differences in comorbidities across fatigue categories. Fatigue correlated with DAS28‐ESR, synovial lining hyperplasia (SLH), anxiety, depression, and pain. In the DAG, DAS28‐ESR was associated with fatigue, full mediation by pain, partial mediation by depression and anxiety, and confounding by female sex. SLH was independently associated with fatigue but did not confound the relationship between DAS28‐ESR and fatigue. SLH was affected by synovial lymphocytic inflammation. In multivariable models, female sex, DAS28‐ESR, and SLH were all associated with higher fatigue. Conclusion Although fatigue is associated with DAS28‐ESR, it is also associated with SLH independently of disease activity.

Objective We quantified inflammatory burden in rheumatoid arthritis (RA) synovial tissue by using computer vision to automate the process of counting individual nuclei in hematoxylin and eosin images. Methods We adapted and applied computer vision algorithms to quantify nuclei density (count of nuclei per unit area of tissue) on synovial tissue from arthroplasty samples. A pathologist validated algorithm results by labeling nuclei in synovial images that were mislabeled or missed by the algorithm. Nuclei density was compared with other measures of RA inflammation such as semiquantitative histology scores, gene‐expression data, and clinical measures of disease activity. Results The algorithm detected a median of 112,657 (range 8,160‐821,717) nuclei per synovial sample. Based on pathologist‐validated results, the sensitivity and specificity of the algorithm was 97% and 100%, respectively. The mean nuclei density calculated by the algorithm was significantly higher (P < 0.05) in synovium with increased histology scores for lymphocytic inflammation, plasma cells, and lining hyperplasia. Analysis of RNA sequencing identified 915 significantly differentially expressed genes in correlation with nuclei density (false discovery rate is less than 0.05). Mean nuclei density was significantly higher (P < 0.05) in patients with elevated levels of C‐reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and cyclized citrullinated protein antibody. Conclusion Nuclei density is a robust measurement of inflammatory burden in RA and correlates with multiple orthogonal measurements of inflammation.

Symptomatic intraneural hemorrhage occurs rarely. It presents with pain and/or weakness in the distribution following the anatomic innervation pattern of the involved nerve. When a purely sensory nerve is affected, the symptoms can be subtle. We present a previously healthy 36-year-old female who developed an atraumatic, spontaneous intraneural hematoma of her sural nerve. Sural dysfunction was elicited from the patient’s history and physical examination. The diagnosis was confirmed with magnetic resonance imaging, and surgical decompression provided successful resolution of her preoperative symptoms. To our knowledge, this entity has not been reported previously. Our case highlights the importance of having a high index of suspicion for nerve injury or compression in patients whose complaints follow a typical peripheral nerve distribution. Prior studies have shown that the formation of intraneural hematoma and associated compression of nerve fibers result in axonal degeneration, and surgical decompression decreases axonal degeneration and aids functional recovery.