Clonally expanded CD38hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.

Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38hiCD127- CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38hiCD127- T cells, which were frequently bound by the therapeutic anti-PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.

Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis.

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-1ß 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.

Rosai-Dorfman Disease of Bone and Soft Tissue.

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. OBJECTIVE.­: 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. DATA SOURCES.­: Thorough review of the literature with focus on clinical manifestations, imaging findings, key histomorphologic features, pathogenesis, and treatment. CONCLUSIONS.­: 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.

Subarticular Inflammatory Pseudoabscesses: A Pathologic Study With Clinical Correlation.

Abnormal accumulation of neutrophils in a subarticular bone usually raises the concern for osteomyelitis or septic arthritis, a disabling and potentially life-threatening medical condition. At the pathology department of a specialized orthopedic institute, we observed a distinct pattern of subarticular inflammation mimicking infection characterized by collections of neutrophils, macrophages, and fibrin in pseudocystic spaces of variable size and extent in the superficial subarticular bone not accompanied by granulation tissue or necrosis. We coined the term "inflammatory pseudoabscess" to describe these accumulations. From 1997-2015, we reported inflammatory pseudoabscesses in 157 primary arthroplasty/osteotomy specimens from 143 patients without penetrating trauma or hardware in the affected joint. The predominant gross and histologic features were those of destructive/inflammatory joint disease, including lymphoplasmacytic synovitis (95.3%), subchondral osseous chronic inflammation (80.3%), exudative synovitis (58.0%), synovial pannus (52.0%), and marginal erosions of articular cartilage and/or subarticular bone (43.3%). Clinical information was available in 137 (95.8%) patients, 107 (overall: 74.8%) of whom had preoperatively or postoperatively diagnosed inflammatory arthropathy, most commonly rheumatoid arthritis. The remaining 30 (overall: 21.0%) patients had no documented inflammatory disorders, but some had bilateral or multijoint arthropathy, hands/feet involvement, lymphoplasmacytic synovitis, ulcerative colitis, or family history of inflammatory arthropathy. There was no documented infection-associated implant failure. We believe that inflammatory pseudoabscess represents an intraosseous manifestation of noninfectious inflammatory disorders of joints. This feature should be recognized by pathologists and used to suggest further clinical evaluation for undiagnosed inflammatory joint diseases.

Rheumatoid Arthritis Morning Stiffness Is Associated With Synovial Fibrin and Neutrophils.

OBJECTIVE: Morning stiffness is a hallmark symptom of rheumatoid arthritis (RA), but its etiology is poorly understood. This study was undertaken to determine whether any histologic features of synovium are associated with this symptom. METHODS: Data on patient-reported morning stiffness duration and severity, and Disease Activity Score in 28 joints (DAS28) were collected from 176 patients with RA undergoing arthroplasty. Synovium was scored for 10 histopathologic features: synovial lining hyperplasia, lymphocytes, plasma cells, Russell bodies, binucleate plasma cells, fibrin, synovial giant cells, detritus, neutrophils, and mucin. Fibrinolysis of clots seeded with various cell types was measured in turbidimetric lysis assays. RESULTS: Stiffness severity and morning stiffness duration were both significantly associated with DAS28 (P = 0.0001 and P = 0.001, respectively). None of the synovial features examined were associated with patient-reported stiffness severity. The presence of neutrophils and fibrin in RA synovial tissue were significantly associated (P < 0.0001) with patient-reported morning stiffness of ≥1 hour, such that 73% of patients with both synovial fibrin and neutrophils reported morning stiffness of ≥1 hour. Further, neutrophils and fibrin deposits colocalized along the synovial lining. In in vitro analyses, fibrin clots seeded with necrotic neutrophils were more resistant to fibrinolysis than those seeded with living neutrophils or no cells (P = 0.008). DNase I treatment of necrotic neutrophils abrogated the delay in fibrinolysis. CONCLUSION: In RA, prolonged morning stiffness may be related to impaired fibrinolysis of neutrophil-enmeshed fibrin deposits along the synovial membrane. Our findings also suggest that morning stiffness severity and duration may reflect distinct pathophysiologic phenomena.

Rheumatoid Arthritis Flares After Total Hip and Total Knee Arthroplasty: Outcomes at One Year.

OBJECTIVE: Most patients with rheumatoid arthritis (RA) undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) have active RA and report postoperative flares; whether RA disease activity or flares increase the risk of worse pain and function scores 1 year later is unknown. METHODS: Patients with RA were enrolled before THA/TKA. Patient-reported outcomes, including the Hip disability and Osteoarthritis Outcome Score (HOOS)/Knee Injury and Osteoarthritis Outcome Score (KOOS) and physician assessments of disease characteristics and activity (Disease Activity Score in 28 joints [DAS28] and Clinical Disease Activity Index), were collected before surgery. Patient-reported outcomes were repeated at 1 year. Postoperative flares were identified using the RA Flare Questionnaire weekly for 6 weeks and were defined by concordance between patient report plus physician assessment. We compared baseline characteristics and HOOS/KOOS scores using 2-sample t-test/Wilcoxon's rank sum test as well as chi-square/Fisher's exact tests. We used multivariate linear and logistic regression to determine the association of baseline characteristics, disease activity, and flares with 1-year outcomes. RESULTS: One-year HOOS/KOOS scores were available for 122 patients (56 with THA and 66 with TKA). Although HOOS/KOOS pain was worse for patients who experienced a flare within 6 weeks of surgery, absolute improvement was not different. In multivariable models, baseline DAS28 predicted 1-year HOOS/KOOS pain and function; each 1-unit increase in DAS28 worsened 1-year pain by 2.41 (SE 1.05; P = 0.02) and 1-year function by 4.96 (SE 1.17; P = 0.0001). Postoperative flares were not independent risk factors for pain or function scores. CONCLUSION: Higher disease activity increased the risk of worse pain and function 1 year after arthroplasty, but postoperative flares did not.

Lytic Lesion in the Proximal Humerus After a Flu Shot: A Case Report.

CASE: There has been a recent campaign to vaccinate patients in an effort to prevent widespread flu pandemic. Although the complication rate after vaccine is low, there have been reports of Guillain-Barré syndrome and shoulder injury related to vaccine administration (SIRVA). In this case presentation, we discuss a patient who developed a large lytic lesion in the proximal humerus after a deeply administered flu shot. CONCLUSIONS: SIRVA is a rare cause of shoulder pain after injections, but one that progresses and often necessitates operative management. Clinicians should be wary of persistent shoulder pain after a flu shot.

HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness.

Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor-dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, medication redirected them into a state that is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions.

Histologic and Transcriptional Evidence of Subclinical Synovial Inflammation in Patients With Rheumatoid Arthritis in Clinical Remission.

OBJECTIVE: Patients with rheumatoid arthritis (RA) in clinical remission may have subclinical synovial inflammation. This study was undertaken to determine the proportion of patients with RA in remission or with low disease activity at the time of arthroplasty who had histologic or transcriptional evidence of synovitis, and to identify clinical features that distinguished patients as having subclinical synovitis. METHODS: We compared Disease Activity Score in 28 joints (DAS28) to synovial histologic features in 135 patients with RA undergoing arthroplasty. We also compared DAS28 scores to RNA-Seq data in a subset of 35 patients. RESULTS: Fourteen percent of patients met DAS28 criteria for clinical remission (DAS28 <2.6), and another 15% met criteria for low disease activity (DAS28 <3.2). Histologic analysis of synovium revealed synovitis in 27% and 31% of samples from patients in remission and patients with low disease activity, respectively. Patients with low disease activity and synovitis also exhibited increased C-reactive protein (CRP) (P = 0.0006) and increased anti-cyclic citrullinated peptide (anti-CCP) antibody levels (P = 0.03) compared to patients without synovitis. Compared to patients with a "low inflammatory synovium" subtype, 183 genes were differentially expressed in the synovium of patients with subclinical synovitis. The majority of these genes (86%) were also differentially expressed in the synovium of patients with clinically active disease (DAS28 ≥3.2). CONCLUSION: Thirty-one percent of patients with low clinical disease activity exhibited histologic evidence of subclinical synovitis, which was associated with increased CRP and anti-CCP levels. Our findings suggest that synovial gene expression signatures of clinical synovitis are present in patients with subclinical synovitis.

Identification of Three Rheumatoid Arthritis Disease Subtypes by Machine Learning Integration of Synovial Histologic Features and RNA Sequencing Data.

OBJECTIVE: In this study, we sought to refine histologic scoring of rheumatoid arthritis (RA) synovial tissue by training with gene expression data and machine learning. METHODS: Twenty histologic features were assessed in 129 synovial tissue samples (n = 123 RA patients and n = 6 osteoarthritis [OA] patients). Consensus clustering was performed on gene expression data from a subset of 45 synovial samples. Support vector machine learning was used to predict gene expression subtypes, using histologic data as the input. Corresponding clinical data were compared across subtypes. RESULTS: Consensus clustering of gene expression data revealed 3 distinct synovial subtypes, including a high inflammatory subtype characterized by extensive infiltration of leukocytes, a low inflammatory subtype characterized by enrichment in pathways including transforming growth factor ß, glycoproteins, and neuronal genes, and a mixed subtype. Machine learning applied to histologic features, with gene expression subtypes serving as labels, generated an algorithm for the scoring of histologic features. Patients with the high inflammatory synovial subtype exhibited higher levels of markers of systemic inflammation and autoantibodies. C-reactive protein (CRP) levels were significantly correlated with the severity of pain in the high inflammatory subgroup but not in the others. CONCLUSION: Gene expression analysis of RA and OA synovial tissue revealed 3 distinct synovial subtypes. These labels were used to generate a histologic scoring algorithm in which the histologic scores were found to be associated with parameters of systemic inflammation, including the erythrocyte sedimentation rate, CRP level, and autoantibody levels. Comparison of gene expression patterns to clinical features revealed a potentially clinically important distinction: mechanisms of pain may differ in patients with different synovial subtypes.

Success of scaphoid nonunion surgery is independent of proximal pole vascularity.

We followed 35 consecutive patients with scaphoid nonunions in a prospective longitudinal registry. All nonunions were treated with curettage, non-vascularized autogenous grafting and headless screw fixation. Preoperative magnetic resonance imaging, intraoperative bleeding points and histopathological analysis of cancellous bone in the proximal pole were recorded as measures of viability. Healing was categorized as ≥50% bony bridging on computed tomographic images in the plane of the scaphoid. Nine of 23 proximal poles demonstrated ischaemia on magnetic resonance imaging but none were interpreted as infarcted. Twenty-eight of 33 were found to have impaired vascularity as assessed by intraoperative bleeding. Fourteen of 32 demonstrated ≥50% trabecular necrosis and four of 33 demonstrated ≥50% tissue necrosis on histopathological analysis. Thirty of 33 demonstrated focal or robust remodelling activity. Despite pathological evidence of impaired vascularity in over half of the patients, 33 of the 35 scaphoids had healed by 12 weeks. We conclude that proximal pole infarction is decidedly rare and that vascularized bone grafting is seldom required. LEVEL OF EVIDENCE: IV.

Sonography of Morton Neuromas: What Are We Really Looking At?

OBJECTIVES: To determine what accounts for the sonographic appearance of a Morton neuroma by correlating preoperative sonograms with the sonographic appearance of the resected surgical specimen, the surgical findings, and the pathologic examination. METHODS: Ten Morton neuromas that had preoperative sonograms underwent postoperative specimen sonography and histologic evaluation. The appearance and size of the neuromas were compared between the preoperative and postoperative specimen images and were compared to the surgical and pathologic appearances. RESULTS: Preoperative images showed a fibrillar echogenic nerve coursing into a heterogeneous hypoechoic mass measuring 14.3 mm in average length (range, 9.0-24.0 mm) that contained a round, mildly echogenic mass within it measuring 7.6 mm in average length (range, 4.5-12.0 mm). Surgically, the specimens showed scarred intermetatarsal bursas and tangled vessels surrounding the nerve. Specimen sonography showed echogenic focal enlargement of the nerve at the site of the neuroma, measuring 6.8 mm in average length (range, 3.5-11.0 mm). The size of the resected neuroma was smaller than the hypoechoic mass on the presurgical images (P < .001). Within the hypoechoic mass, the small echogenic focus showed no difference in size compared to the specimen (P = .40), but the shape of the echogenic specimen was fusiform, whereas the preoperative appearance was round. Histologically, the resected specimens showed sclerosis and mucoid degeneration of the nerve fascicles and fibrotic thickening of the perineurium. CONCLUSIONS: The hypoechoic heterogeneous mass that is referred to as a Morton neuroma sonographically is really a "neuroma-bursal complex" that is much larger than the actual neuroma itself.

The effect of myofibroblasts and corticosteroid injections in adhesive capsulitis.

HYPOTHESIS: Adhesive capsulitis is a condition that results in restricted glenohumeral motion. Fibroblasts have been implicated in the disease process; however, their role as a contractile element in the development of fibrosis and capsular contracture is not well understood. We hypothesized (1) that myofibroblast prevalence in capsular biopsy specimens from patients with adhesive capsulitis would be increased compared with controls and (2) that patients treated with an intra-articular injection of corticosteroid would have fewer myofibroblasts. METHODS: The study prospectively enrolled 20 consecutive patients with adhesive capsulitis scheduled for capsular release and matched controls. Tissue samples were collected from the posterior and anterior capsule for histomorphologic and immunohistologic analyses. Identical sectioning and preparation was performed in 14 additional adhesive capsulitis specimens from patients who had not received corticosteroid injections. RESULTS: Patients with adhesive capsulitis not treated with preoperative corticosteroid demonstrated more histologic evidence of fibromatosis, synovial hyperplasia, and an increase in positive staining for α-smooth muscle actin than patients who had received intra-articular injections of steroid. No specimens obtained from control patients demonstrated positive staining for α-smooth muscle actin. DISCUSSION: There was a higher prevalence of myofibroblast staining in patients with adhesive capsulitis, implicating activation of the myofibroblast in the pathophysiology of capsular contracture. Intra-articular steroid injection decreases the presence and amount of fibromatosis, vascular hyperplasia, fibrosis, and the presence of fibroblasts staining for α-smooth muscle actin. This supports the use of steroid injections to alter the disease process by decreasing the pathologic changes found in the capsular tissue.

Characteristics of glomus tumors in the hand not diagnosed on magnetic resonance imaging.

PURPOSE: To determine whether the diagnosis of hand glomus tumors by magnetic resonance imaging (MRI) is associated with tumor size, tumor pathology, tumor location, and/or clinical suspicion. METHODS: We reviewed our pathology database for patients with hand glomus tumors diagnosed between 2006 and 2013 and included those patients who had preoperative MRI at our institution. We excluded patients with recurrent and persistent tumors. Magnetic resonance imaging reports were reviewed for clinical history, tumor location, and associated bone erosion. Pathology reports were reviewed for diagnosis and tumor size. We classified MRI studies as positive (glomus tumor diagnosis), negative (no mention of glomus tumor as possible diagnosis), or indeterminate (glomus tumor mentioned as possible differential diagnosis). Fisher exact test was used to compare positive studies and those that were nondiagnostic (ie, either negative or indeterminate). RESULTS: Of the 46 patients who had pathologically confirmed hand glomus tumors, 38 had preoperative MRI studies. A total of 24 MRI studies were positive, 5 were indeterminate, and 7 were negative. Five patients had atypical pathology, 1 had a multifocal tumor, and 2 had extra-digital hand glomus tumors. Failure to diagnose glomus tumors on MRI was associated with atypical pathology, atypical location (ie, not located in the subungual region), absence of bone erosion, and lack of clinical suspicion. Tumor size was not associated with MRI diagnosis. CONCLUSIONS: In this series of 36 hand glomus tumors, one-third of MRI studies were nondiagnostic. Occurrence of nondiagnostic MRIs was more likely when glomus tumors were pathologically and/or anatomically atypical, without bone erosion, and with no or unrelated clinical history provided. These findings highlight the continued importance of clinical suspicion in glomus tumor diagnosis. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV.

Recurrent pigmented villonodular synovitis and multifocal giant cell tumor of the tendon sheath: case report.

Intra- and extra-articular giant cell tumor of tendon sheath (GCTTS) and pigmented villonodular synovitis (PVNS) are histologically similar, usually benign tumors that can be characterized by synovial involvement (GCTTS) or overgrowth (PVNS). These tumors are most often found in the knee and digits of the hand. Although recurrence is a common feature of both conditions, multifocal lesions are rare. We present an unusual case of multifocal, recurrent, bilateral GCTTS/PVNS involving both upper and lower extremities. Recurrent right ankle and right index finger masses, in addition to masses on the right small finger and left thumb, were excised over a 14-year period.

The anatomy and histology of the bicipital tunnel of the shoulder.

BACKGROUND: The bicipital tunnel is the extra-articular, fibro-osseous structure that encloses the long head of the biceps tendon. METHODS: Twelve cadaveric shoulder specimens underwent in situ casting of the bicipital tunnel with methyl methacrylate cement to demonstrate structural competence (n = 6) and en bloc harvest with gross and histologic evaluation (n = 6). The percentage of empty tunnel was calculated histologically by subtracting the proportion of cross-sectional area of the long head of the biceps tendon from that of the bicipital tunnel for each zone. RESULTS: Cement casting demonstrated that the bicipital tunnel was a closed space. Zone 1 extended from the articular margin to the distal margin of the subscapularis tendon. Zone 2 extended from the distal margin of the subscapularis tendon to the proximal margin of the pectoralis major tendon. Zone 3 was the subpectoral region. Zones 1 and 2 were both enclosed by a dense connective tissue sheath and demonstrated the presence of synovium. Zone 3 had significantly greater percentage of empty tunnel than zones 1 and 2 did (P < .01). CONCLUSION: The bicipital tunnel is a closed space with 3 distinct zones. Zones 1 and 2 have similar features, including the presence of synovium, but differ from zone 3. A significant bottleneck occurs between zone 2 and zone 3, most likely at the proximal margin of the pectoralis major tendon. The bicipital tunnel is a closed space where space-occupying lesions may produce a bicipital tunnel syndrome. Careful consideration should be given to surgical techniques that decompress both zones 1 and 2 of the bicipital tunnel.

Spontaneous intraneural hematoma of the sural nerve.

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.

An atraumatic case of extensive Achilles tendon ossification.

BACKGROUND: Ossification of the Achilles tendon is rare with most cases of ossification or calcification consisting of small, focal lesions. This pathology is usually predisposed by surgery, trauma, or other factors. CASE DESCRIPTION: A case of extensive Achilles ossification and calcification, without prior surgery or trauma, is reported. Following removal of one of the largest ossific masses reported in the literature, measuring 11.0cm×2.5cm×2.0cm with additional 6.5cm calcifications, surgical reconstruction was required. PURPOSE AND CLINICAL RELEVANCE: The objective of this report was to describe an unusual case of Achilles tendon ossification and calcification that occurred without the presence of predisposing factors. When a large gap is present after removal of the ossification, direct repair may be impossible and V-Y lengthening plus flexor hallucis longus (FHL) transfer is a viable option for pain relief and return to function.