Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis.

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of these 815 genes were most robustly expressed by lining layer synovial fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human lining layer fibroblasts and human dorsal root ganglion neurons expressing calcitonin gene-related peptide (CGRP+). Both RA synovial fibroblast culture supernatant and netrin-4, which is abundantly expressed by lining fibroblasts and was within the GbGMI-identified pain-associated gene module, increased the branching of pain-sensitive murine CGRP+ dorsal root ganglion neurons in vitro. Imaging of solvent-cleared synovial tissue with little inflammation from humans with RA revealed CGRP+ pain-sensing neurons encasing blood vessels growing into synovial hypertrophic papilla. Together, these findings support a model whereby synovial lining fibroblasts express genes associated with pain that enhance the growth of pain-sensing neurons into regions of synovial hypertrophy in RA.

Machine Learning Reveals Synovial Fibroblast Genes Associated with Pain Affect Sensory Nerve Growth in Rheumatoid Arthritis.

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We identified a module of 815 genes associated with pain, using a novel machine learning approach, Graph-based Gene expression Module Identification (GbGMI), in samples from patients with longstanding RA, but limited synovial inflammation at arthroplasty, and validated this finding in an independent cohort of synovial biopsy samples from early, untreated RA patients. Single-cell RNA-seq analyses indicated these genes were most robustly expressed by lining layer fibroblasts and receptor-ligand interaction analysis predicted robust lining layer fibroblast crosstalk with pain sensitive CGRP+ dorsal root ganglion sensory neurons. Netrin-4, which is abundantly expressed by lining fibroblasts and associated with pain, significantly increased the branching of pain-sensitive CGRP+ neurons in vitro . We conclude GbGMI is a useful method for identifying a module of genes that associate with a clinical feature of interest. Using this approach, we find that Netrin-4 is produced by synovial fibroblasts in the absence of inflammation and can enhance the outgrowth of CGRP+ pain sensitive nerve fibers. One Sentence Summary: Machine Learning reveals synovial fibroblast genes related to pain affect sensory nerve growth in Rheumatoid Arthritis addresses unmet clinical need.

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.

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.

Prevalence of Occult Infections in Posterior Instrumented Spinal Fusion.

STUDY DESIGN: This is a prospective observational study. OBJECTIVE: The aim of this study is to determine the rate of occult infection after instrumented spine surgery in presumed aseptic patients. SUMMARY OF BACKGROUND DATA: The reported incidence rate of delayed/occult infection determined by positive culture swabs after instrumented spine surgery in prospective studies is 0.2%-6.9%. However, this rate may be higher as delayed infections are challenging to diagnose. Fever can be absent and inflammatory markers are often normal. If indolent organisms exist in low concentrations surrounding the instrumentation, these organisms can possibly avoid detection and disrupt bone formation leading to instrumentation loosening, pain generation, and/or failure of a solid fusion. MATERIALS AND METHODS: This study included 50 consecutive presumed aseptic patients undergoing a posterior revision requiring removal of instrumentation at least 6 months following their index procedure. Common markers of infection were examined preoperatively. Multiple culture swabs were taken directly from the removed instrumentation and cultured for 14 days. RESULTS: Of the 50 patients, 19 (38%) were culture-positive (CP) for bacteria upon removal of their instrumentation, with 14 patients (28%) having ≥2 positive specimens of the same organism. The average length of time between the index procedure and the revision surgery was 4.55 years (range: 0.53-21 y). Polymicrobial infections were found in 26% (5/19) of CP patients. The most prevalent microorganism found was Propionibacterium acnes, in 63% (12/19) of CP patients. There was no significant difference between CP and culture-negative patients regarding preoperative markers for infection, age, or length between index and revision procedures. CONCLUSIONS: The results of this study indicate a positive culture rate of 38% in presumed aseptic patients who had previously undergone instrumented spine surgery. These results are consistent with other retrospective studies and are >6 times greater than any previous prospective study utilizing culture swabs. LEVEL OF EVIDENCE: Level-III.

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 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.

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.

Flares in Patients with Rheumatoid Arthritis after Total Hip and Total Knee Arthroplasty: Rates, Characteristics, and Risk Factors.

OBJECTIVE: Rates of total knee arthroplasty (TKA) and total hip arthroplasty (THA) remain high for patients with rheumatoid arthritis (RA), who are at risk of flaring after surgery. We aimed to describe rates, characteristics, and risk factors of RA flare within 6 weeks of THA and TKA. METHODS: Patients with RA were recruited prior to elective THA and TKA surgery and prospectively followed. Clinicians evaluated RA clinical characteristics 0-2 weeks before and 6 weeks after surgery. Patients answered questions regarding disease activity including self-reported joint counts and flare status weekly for 6 weeks. Per standard of care, biologics were stopped before surgery, while glucocorticoids and methotrexate (MTX) were typically continued. Multivariable logistic regression was used to identify baseline characteristics associated with postsurgical RA flares. RESULTS: Of 120 patients, the mean age was 62 years and the median RA duration 14.8 years. Ninety-eight (82%) met 2010/1987 American College of Rheumatology/European League Against Rheumatism criteria, 53 (44%) underwent THA (and the rest TKA), and 61 (51%) were taking biologics. By 6 weeks, 75 (63%) had flared. At baseline, flarers had significantly higher disease activity (as measured by the 28-joint Disease Activity Score), erythrocyte sedimentation rate, C-reactive protein, and pain. Numerically more flarers used biologics, but stopping biologics did not predict flares, and continuing MTX was not protective. A higher baseline disease activity predicted flaring by 6 weeks (OR 2.12, p = 0.02). CONCLUSION: Flares are frequent in patients with RA undergoing arthroplasty. Higher baseline disease activity significantly increases the risk. Although more patients stopping biologics flared, this did not independently predict flaring. The effect of early postsurgery flares requires further study.

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.

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.

Diagnostic biopsy of the pronator teres and a motor branch of the median nerve: indications and technique.

PURPOSE: Biopsy of muscle tissue and motor nerve is helpful in the neurological evaluation of patients who present with upper limb and/or diffuse motor weakness. The procedure is indicated to supplement clinical, serological, and imaging diagnostic work-up of myopathic and neuropathic disorders. We describe a surgical technique and clinical series of biopsy of the pronator teres muscle and a motor branch of the median nerve. METHODS: We performed a retrospective review of 20 patients who underwent biopsy of the pronator teres and a motor branch of the median nerve as part of a clinical, serological, and radiographic evaluation for weakness of the upper extremity. All of the biopsies were performed by a single surgeon. The surgical technique is described. Follow-up visits with both the surgeon and the neurologist were reviewed to evaluate preoperative and postoperative neurological function to identify any changes in nerve or muscle function and any postoperative complications. RESULTS: Biopsied tissue was sufficient for pathological diagnosis in all 20 patients. Diagnoses included multifocal motor neuropathy in 14 patients, amyotrophic lateral sclerosis in 3 patients (2 sporadic; 1 familial), inclusion body myositis (1 patient), inflammatory myopathy (1 patient), and chronic inflammatory demyelinating polyneuropathy (1 patient). At a mean follow-up of 11 weeks (range, 5-31 wk), there were 6 minor surgical complications, all of which were superficial hematomas that resolved with use of a compressive wrap. CONCLUSIONS: Biopsy of the pronator teres and a motor branch of the median nerve was safe and effective. The technique is particularly useful when considering the diagnosis of multifocal motor neuropathy affecting the upper extremity.

High- and low-dose OPG-Fc cause osteopetrosis-like changes in infant mice.

BACKGROUND: Receptor activator of nuclear factor-κB ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, osteoprotegerin-immunoglobulin Fc segment complex (OPG-Fc), in a growing animal model of OI, the col1α2-deficient mouse (oim/oim) and its wild-type controls (+/+). METHODS: Treated mice showed runting and radiographic evidence of osteopetrosis with either high- (20 mg/kg twice weekly) or low-dose (1 mg/kg/week) OPG-Fc. Because of this adverse event, OPG-Fc treatment was halted, and the mice were killed or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (tartrate-resistant acid phosphatase 5b, TRACP-5b) until 25 wk of age. RESULTS: Twelve weeks of OPG-Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative tartrate-resistant acid phosphatase staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared 4-8 wk post-treatment. CONCLUSION: Both high- and low-dose OPG-Fc treatment resulted in osteopetrotic changes in infant mice, an outcome that was not seen in studies with the RANKL inhibitor RANK-immunoglobulin Fc segment complex (RANK-Fc) or in studies with older animals. Further investigations of RANKL inhibitors are necessary before their consideration for use in children.

Fibrodysplasia ossificans progressiva: middle-age onset of heterotopic ossification from a unique missense mutation (c.974G>C, p.G325A) in ACVR1.

Fibrodysplasia ossificans progressiva (FOP) is the rare mendelian disease characterized by congenital malformation of the great toes preceding heterotopic ossification (HO) and caused by heterozygous activating mutation of the ACVR1 gene, which encodes the ALK2 receptor for bone morphogenetic proteins. Early adult life is the latest reported presentation for the HO of FOP. The patient of our report first developed HO from FOP at 47 years of age. She had congenital hallux valgus deformity but despite various traumas was previously well. HO began several months after a brief, seemingly viral, illness. Sudden and progressive pain, redness, warmth, and swelling appeared over a scapula. Computed tomography was remarkable for asymmetrical thickening of muscles and fascial planes. At first, the significance of the great toe abnormalities went unrecognized elsewhere, and biopsy for suspected inflammatory fasciitis revealed proliferating fibroblasts with scattered inflammatory cells. Prednisone improved her symptoms but, when tapered, swellings developed on her chest, posterior thorax, and flank, and FOP was diagnosed. Methylprednisolone, methotrexate, and alendronate seemed to help her symptoms, but the lesions worsened and HO appeared and rapidly progressed. Mutation analysis of the ACVR1 gene revealed heterozygosity for a unique missense defect (c.974G>C, p.G325A) that predicted a conservative (mild) amino acid change within the kinase domain of ALK2. Hence, HO in FOP can be delayed until middle-age, and perhaps provoked by a viral illness. Nevertheless, progression of HO can then be rapid despite bisphosphonate and high-dose immunosuppressive therapy. Possibly, our patient's late-onset HO reflects her mild alteration of ALK2 or some protective and therapeutically useful genetic, epigenetic, or nongenetic factor. Recognition of presymptomatic individuals or late-onset HO in FOP should have these patients avoid traumas, treatments, and maybe viral illnesses that can initiate or exacerbate the HO. If the diagnosis of FOP is unclear, ACVR1 mutation analysis is available at certified laboratories.