Tripterine ameliorates monosodium urate crystal-induced gouty arthritis by altering macrophage polarization via the miR-449a/NLRP3 axis.

OBJECTIVE: Tripterine (Trip) is frequently applied to alleviate inflammation in various diseases such as rheumatoid arthritis. Macrophages have both anti-inflammatory and pro-inflammatory functions. However, whether Trip can inhibit cell inflammation in gouty arthritis (GA) remains undiscovered and whether the mechanism involved in macrophage polarization is also undetermined. This paper aims to study the effects of Trip on inflammation and macrophage polarization in GA. METHODS: Monosodium urate (MSU) crystals were used to establish GA mouse models, and bone marrow-derived macrophages (BMDMs) were induced to construct GA cell models. Pretreatments of Trip and injection of Antagomir-449a/Agomir-449a were performed on mice for 6 days. The effects of Trip and miR-449 on toe swelling, joint damage of GA mouse were examined. The alternations on cell morphology, cell proliferation marker Ki67, inflammatory cytokines, NLRP3 inflammasome, and NF-κB signaling-related proteins were also determined both in vivo and in vitro. Dual-luciferase reporter gene assay and RIP assay were adopted to estimate the targeting relationship between miR-449a and NLRP3. RESULTS: GA mouse model had increased M1 macrophage, intensified inflammation response, along with suppressed miR-449a expression. Following administration of Trip attenuated cell inflammation, promoted macrophage polarize to M2 phenotype, elevated miR-449a expression, repressed the phosphorylation levels of NF-κB signaling-related proteins, and diminished IκBα expression in vivo and in vitro. However, inhibition of miR-449a hindered the favorable effect of Trip on GA and increased NLRP3 inflammasome expression. MiR-449a directly targeted NLRP3. Overexpression of NLRP3 partially eliminated the biological effects of miR-449a agonist. CONCLUSION: Trip regulates macrophage polarization through miR-449a/NLRP3 axis and the STAT3/NF-κB pathway to mitigate GA. The elucidation on the molecular mechanism of Trip in GA may provide theoretical guidance for clinical therapy of GA.

Treatment of Dactylitis and Enthesitis in Psoriatic Arthritis with Biologic Agents: A Systematic Review and Metaanalysis.

OBJECTIVE: Biologic agents with different mechanisms of action [inhibitors of tumor necrosis factor-α (TNF-α), interleukin (IL)-12/23, and IL-17] showed efficacy in randomized controlled trials (RCT) in the treatment of psoriatic arthritis. We conducted a pooled metaanalysis of these agents for treatment of dactylitis and enthesitis and compared results with the American College of Rheumatology 20 (ACR20) response and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. METHODS: A systematic literature search was performed and a pooled metaanalysis of RCT with anti-TNF-α (infliximab, golimumab, adalimumab), anti-IL-12/23 (ustekinumab), and anti-IL-17 (secu kinumab, ixekizumab) was conducted using the random-effects model. Bias was assessed using the Cochrane risk-of-bias tool. RESULTS: Eighteen RCT were included in the pooled analysis (n = 6981). Both TNF-α inhibitors and novel biologics (ustekinumab, secukinumab, ixekizumab) demonstrated significant resolution of dactylitis at Week 24 with pooled risk ratios (RR) versus placebo of 2.57 (95% CI 1.36-4.84) and 1.88 (95% CI 1.33-2.65), respectively. For resolution of enthesitis at Week 24, RR for TNF-α inhibitors was 1.93 (95% CI 1.33-2.79) versus 1.95 (95% CI 1.60-2.38) for novel biologics. Both biologic categories showed overlapping ranges of ACR20 responses (TNF-α inhibitors: RR = 2.23, 95% CI 1.60-3.11; pooled IL-12/23 and -17: RR = 2.30, 95% CI 1.94-2.72) and similar quality of life improvement scores with mean HAQ-DI score changes of -0.29 (95% CI -0.39 to -0.19) and -0.26 (95% CI -0.31 to -0.22), respectively. CONCLUSION: The pooled analysis demonstrated that anti-TNF-α agents have the same efficacy as novel agents (ustekinumab, secukinumab, and ixekizumab) in dactylitis and enthesitis.

Psoriatic Nail Dystrophy Is Associated with Erosive Disease in the Distal Interphalangeal Joints in Psoriatic Arthritis: A Retrospective Cohort Study.

OBJECTIVE: To assess whether the association between psoriatic nail dystrophy and radiographic damage in the hands of patients with psoriatic arthritis (PsA) is specific to the distal interphalangeal (DIP) joints. METHODS: A convenience sample of patients was collated from the Bath longitudinal PsA cohort. All patients had PsA according to the ClASsification for Psoriatic ARthritis criteria (CASPAR) criteria, scored radiographs of their hands, and documented nail scores as measured by the Psoriatic Nail Severity Score. Chi-square tests were performed to examine for association between features of nail dystrophy and radiographic damage in the DIP joints, and proximal interphalangeal or metacarpophalangeal (non-DIP) joints of the corresponding digits. RESULTS: There were 134 patients included, with a median age of 53 years (interquartile range; IQR 44-61) and disease duration of 7 years (IQR 3-17). The presence of any form of psoriatic nail dystrophy was associated with erosion at the DIP joints of the corresponding digit (OR 1.9, 95% CI 1.23-2.83; p < 0.004) and this association was primarily driven by the presence of nail onycholysis (OR 1.72; 95% CI 1.12-2.62; p = 0.02). Nail subungual hyperkeratosis was more strongly associated with joint space narrowing, erosions, and osteoproliferation at the corresponding DIP joint compared to non-DIP joints (p < 0.001). Nail pitting was not associated with erosions or osteoproliferation. CONCLUSION: The presence of psoriatic nail dystrophy, particularly onycholysis, is associated with erosive disease at the DIP joints. Subungual hyperkeratosis is more strongly associated with erosive damage at the DIP than non-DIP joints. These findings support the anatomical and pathological link between nail and DIP joint disease.

Bone change after surgical treatment of mucous cyst at the interphalangeal joint of the great toe in a patient with rheumatoid arthritis.

Digital mucous cysts are a type of benign cysts of the digits, typically located at the distal interphalangeal joints or in the proximal nail fold, which usually occur on the hands. The diagnosis of digital mucous cysts is relatively easy because of its light-transmitting property, but the treatment is often difficult because of complications including recurrence, infection, diminished range of motion, and nail deformity. We report a case of rheumatoid arthritis (RA) showing good course after surgical treatment of mucous cyst at the interphalangeal joint of the great toe. In a case of RA, combination of synovectomy with surgical treatment of mucous cyst might be effective.

Enthesitis and Dactylitis in Psoriatic Disease: A Guide for Dermatologists.

Psoriatic arthritis (PsA) is an inflammatory arthritis that is estimated to affect approximately 30% of patients with psoriasis. Enthesitis and dactylitis, two hallmarks of PsA, are associated with radiographic peripheral/axial joint damage and severe disease. Clinical symptoms of enthesitis include tenderness, soreness, and pain at entheses on palpation, whereas dactylitis is recognized by swelling of an entire digit that is different from adjacent digits. Both ultrasound and magnetic resonance imaging can be used to diagnose enthesitis and dactylitis, especially in patients in whom symptoms may be difficult to discern. Delayed treatment of PsA can result in irreversible joint damage and reduced quality of life. Thus, it is recommended that dermatologists monitor patients with psoriasis for these two early and important manifestations of PsA.

The impact of transferred vascularized toe joint length on motion arc of reconstructed finger proximal interphalangeal joints: a cadaveric study.

Vascularized toe joint transfer for finger proximal interphalangeal joint reconstruction can result in sub-optimal arc of motion and extension lag due to inappropriate intercalated bony segment length. We investigated the impact of intercalated segment length on passive arc of motion and extension lag of the reconstructed proximal interphalangeal joint. Cadaveric intercalated joint grafts were harvested from lesser toes and transferred to cadaveric fingers. The pre-determined finger proximal interphalangeal joint defect size was 2 cm. Three different intercalated segment lengths were inserted and resulting proximal interphalangeal joint arc of motion and extension lag were measured. The average arc of motion of finger proximal interphalangeal joints was 81° and 54° for toe proximal interphalangeal joints. Long intercalated segments had an average arc of motion of 30° with 32° extension lag. Equal-length intercalated segments had an average 49° arc of motion with 15° extension lag. Short intercalated segments had an average arc of motion of 71° with 8° extension lag. Shorter intercalated segments provide the greatest reduction in extension lag.

Underlying Adenocarcinoma of the Lung Metastasizing to the Proximal Phalanx of the Foot Causing Complex Regional Pain SyndromeA Case Report.

We report an unusual case of adenocarcinoma of the lung metastasizing to the proximal phalanx of the third digit in a 56-year-old woman with overlying complex regional pain syndrome. The patient was initially treated for neuroma, fracture, and neuropathic pain with no improvement over a 4-month period before presenting to the emergency department for left third digit pain. Radiographic imaging showed substantial osteopenia and mottling; magnetic resonance imaging demonstrated an aggressive lesion to the proximal phalanx. The patient underwent excision of the lesion, revealing metastatic moderately differentiated adenocarcinoma.

Dactylitis in enteropathic spondyloarthritis.

OBJECTIVES: Dactylitis has long been recognised as one of the significant features of spondyloarthropathies. In the literature, the prevalence of dactylitis in enteropathic spondyloarthritis (EASpA) ranges between 2% and 4%. The aim of this study was to identify the prevalence of dactylitis in EASpA patients and to investigate its association with clinical subset and with articular and bowel disease activity. METHODS: 78 EASpA patients and 78 controls were enrolled for this study. All patients and controls underwent a rheumatological and a gastroenterological clinical examination. Demographic and clinical features were recorded. Diagnosis of dactylitis was made by physical examination and was evaluated using the Leeds Dactylitis Instrument (LDI). RESULTS: In our study the prevalence of dactylitis in EASpA was 15.38%, mainly in patients with Crohn's disease (CD) and peripheral arthritis. A significantly higher articular and bowel disease activity was found in patients with dactylitis compared to those without it. The family history of psoriasis represented a predictor of occurrence of dactylitis. Finally, a significant correlation between disease activity and LDI score was found in EASpA. CONCLUSIONS: The results of our study showed a high prevalence of dactylitis in EASpA. It was more frequent in patients with CD and peripheral involvement with a higher articular disease activity, confirming that dactylitis may be a severity marker and a prognostic factor for EASpA. The significant correlation between disease activity and LDI score could address LDI as a potential tool of assessment of dactylitis.

Vascularized transfer of two coherent toe joints in simultaneously reconstructing MCP and PIP of a mutilated finger.

BACKGROUND: The reconstruction of metacarpal- and interphalangeal joints after severe hand injuries has been proven to be challenging. Commonly used procedures like arthrodesis, amputation or ray resection of the finger compromise the functionality of the injured finger. Especially for young patients, the restoration of all functions of the fingers is a priority. Local tissue transfers for finger joint reconstructions is not an option due to inacceptable donor site morbidity; microsurgical tissue transfers in terms of free toe joint transfers have proven to be a valuable method. METHODS: We present the case of a patient who suffered an excessive injury from a circular saw to his dominant hand. The MCP Joints of D2-D4 were fully destroyed, along with the PIP joint of a subtotally amputated D4. Arteries, nerves and tendons could be coapted directly, while primarily reconstructing of the finger joints was impossible. To ensure a possible regain of full functionality, two coherent joints, the MTP and the PIP of one toe, were transferred to the ring finger as a single transplant, reconstructing the MCP and the PIP joints of the injured finger in a one step procedure. Additionally the MCP joint of the D2 was reconstructed by the use of a free PIP-joint transfer, further the MCP joint of the D3 was replaced by an MCP endoprosthesis. RESULTS: After a follow up of 3 years the patient displayed full function of his dominant hand including sensitivity, and has gone back to manual work without limitations. The result was cosmetically acceptable and the donor site defect was easily being tolerated by the patient who is playing soccer in the regional soccer league. CONCLUSION: Free double toe joint transfer has been proven feasible in this patient. While transferring a single toe joint to reconstruct a finger joint is a well-established method, our review of the latest literature showed no case of a free transfer of two coherent joints and three transplanted joints in one hand. The applied microsurgical technique should be considered by microsurgically trained hand surgeons for the treatment of comparable severe hand injuries. In comparison to the most common procedures described for the repair and reconstruction of severely injured finger joints this method showed superior results.

Enthesitis as a component of dactylitis in psoriatic juvenile idiopathic arthritis: histology of an established clinical entity.

CONTEXT: Imaging of dactylitis in adult psoriatic arthritis suggests a pathophysiological role for enthesitis. However, histological definition of the dactylitic digit is unavailable. OBJECTIVE: We evaluated the role of enthesitis in dactylitis associated with psoriatic juvenile idiopathic arthritis (psJIA) in a child who underwent detailed imaging and histologic evaluation. DESIGN: Radiographs, ultrasound and high-resolution magnetic resonance imaging were employed to define the locus of disease in two dactylitic digits from a 14-year-old girl with psJIA. Biopsies were stained with hematoxylin and eosin, CD3, CD20, CD4, CD8 and CD117 and examined via light microscopy. RESULTS: Radiologic features of dactylitis included enhanced signal at digital entheses without accompanying synovitis or tenosynovitis. Histologically, finger and toe tissue exhibited hypervascular tenosynovium with a fibromyxoid expansion of fibrous tissue. This was accompanied by sparse to moderate perivascular lymphocytic inflammation consisting predominantly of T cells, with occasional admixed B cells and mast cells. Neutrophils and plasma cells were absent. Fibrocartilage exhibited reactive features including increased extracellular myxoid matrix, binucleation, and focal necrosis, without cellular inflammation. Fibrinous synovitis and mild reactive synoviocyte hyperplasia were seen. CONCLUSIONS: Dactylitis in psJIA bears a radiographic resemblance to the condition in adult psoriatic arthritis. Histologic hallmarks include an expanded mast cell-populated extracellular myxoid matrix, cartilage degeneration, and a T cell-rich perivascular inflammatory infiltrate. These findings help to define enthesitis as a clinicopathologic entity.

High-resolution MRI assessment of dactylitis in psoriatic arthritis shows flexor tendon pulley and sheath-related enthesitis.

OBJECTIVE: Dactylitis is a hallmark of psoriatic arthritis (PsA) where flexor tenosynovitis is common. This study explored the microanatomical basis of dactylitis using high-resolution MRI (hrMRI) to visualise the small entheses around the digits. METHODS: Twelve patients with psoriatic dactylitis (4 fingers, 8 toes), and 10 healthy volunteers (6 fingers, 4 toes) had hrMRI of the digits using a 'microscopy' coil and contrast enhancement. All structures were evaluated including the tendons and ligaments, related enthesis organs, pulleys, volar/plantar plates and tendon sheaths. RESULTS: In dactylitis, collateral ligament enthesitis was seen in nine digits (75%), extensor tendon enthesitis in six digits (50%), functional enthesitis (5 digits, 42%), abnormal enhancement at the volar plates (2/5 joints, 40%) and the plantar plate (1/5 joints, 20%). Nine cases (75%) demonstrated flexor tenosynovitis, with flexor tendon pulley/flexor sheath microenthesopathy observed in 50% of all cases. Less abnormalities which were milder was observed in the normal controls, none of whom had any signal changes in the tendon pulleys or fibrous sheaths. CONCLUSIONS: This study provides proof of concept for a link between dactylitis and 'digital polyenthesitis' including disease of the miniature enthesis pulleys of the flexor tendons, further affirming the concept of enthesitis in PsA.

MRI of hand and foot joints of patients with anticitrullinated peptide antibody positive arthralgia without clinical arthritis.

BACKGROUND: Anticitrullinated peptide antibodies (ACPA) and acute phase reactants may be increased before arthritis becomes clinically detectable, suggesting that the processes underlying rheumatoid arthritis (RA) start preclinically. Whether local inflammation occurs in the preclinical phase is unknown. Therefore, we studied the small joints of ACPA positive arthralgia patients for local subclinical inflammation. METHODS: Imaging was performed using 1.5 T extremity MRI. Painful hand or foot joints of 21 ACPA positive arthralgia patients without clinical arthritis were imaged. For comparison, hand and foot joints of 22 ACPA positive RA patients and 19 symptom free controls were studied. Within ACPA positive arthralgia patients, painful and symptom free joint regions were imaged. Scoring was performed according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) method. Analyses were performed on joint region level and focused on inflammation (synovitis plus bone marrow oedema). RESULTS: The mean combined inflammation scores of the metacarpophalangeal/proximal interphalangeal joints of controls, painful joints of ACPA positive arthralgia patients and ACPA positive RA patients were 0.1, 0.7 and 3.7, respectively (p<0.001). Likewise, the mean combined inflammation scores of the wrist were 0.9, 2.3 and 10.3, respectively (p<0.001) and that of the metatarsophalangeal joints 0.5, 0.9 and 3.8, respectively (p=0.10). At the MCP joints, the combined inflammation score was significantly correlated with C reactive protein and erythrocyte sedimentation rate levels (rs=0.83 and rs=0.78, respectively) CONCLUSIONS: The present data suggest that local subclinical inflammation occurs in ACPA positive arthralgia patients.

Interphalangeal joint involvement of the big toe in gout: a rare presentation.

Atypical presentation of gout can cause diagnostic dilemmas. We report a case of gout that presented with an expansile lytic lesion involving the interphalangeal joint of the hallux, lack of a history of gout, and an associated solitary lung nodule. Magnetic resonance imaging showed an expansile destructive bony lesion with soft-tissue involvement suggestive of a possible bony metastasis. A needle biopsy was performed, and histopathologic features were diagnostic of chronic tophaceous gout.

Variations in chondrocyte apoptosis may explain the increased prevalence of osteoarthritis in some joints.

OBJECTIVES: To investigate whether there are any variations in chondrocyte susceptibility to an apoptotic stimulus between cells of articular cartilage (AC) from equine joints that differ in prevalence of osteoarthritis (OA). METHODS: Cartilage from macroscopically normal equine metacarpophalangeal (MCP), proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints was used. Prior to culture, chondrocyte viability was assessed using the fluorescein diacetate (FDA) and propidium iodide paravital staining method. AC explants were subsequently treated with tumour necrosis factor-α (TNF-α) in combination with Actinomycin D to induce apoptosis. Apoptosis of chondrocytes in cartilage sections was assessed by expression of active caspase-3 using indirect immunohistochemistry and sections also histologically graded using a 'modified' Mankin scoring system. RESULTS: Prior to culture (mean ± standard deviation) chondrocyte viability was 80.7% (3.5). The extent of chondrocyte apoptosis induced by TNF-α/Actinomycin D varied markedly according to the joint type that the cartilage was sampled from. For MCP joints, the extent of overall chondrocyte apoptosis was significantly higher (P < 0.001) in stimulated explants (26.7%, 10.3) than that observed in unstimulated control samples (9.6%, 7.5). Conversely, chondrocytes from PIP and DIP joint cartilage did not respond significantly to apoptotic stimulation (P > 0.05). Significant variations in cellularity and thickness were also evident between cartilages of different joint types. CONCLUSIONS: Data in this study demonstrate that chondrocytes from three equine joint types with varying prevalences of OA differ significantly in terms of susceptibility to apoptosis induction. This may provide a possible explanation for the joint-specific nature of the disease.

A report of a rare phalangeal periosteal chondroma of the foot.

Periosteal chondroma is a benign, slow-growing cartilaginous tumor that typically occurs at the metaphysis of long tubular bones beneath the periosteal membrane. A case is presented of a 42-year-old male who developed a firm, tender, uneven mass encircling the lateral, dorsal, and medial aspects of the right second proximal phalanx following a traumatic event. The mass was excised en toto and histopathologic findings are presented.

Do children who in-toe need to be referred to an orthopaedic clinic?

The objective of this study was to investigate the outcome of in-toeing referrals to a paediatric orthopaedic department. Two hundred and two patients referred to the Royal Hospital for Sick Children, Edinburgh between July 2005 and March 2008 were retrospectively reviewed. Increased femoral anteversion and internal tibial torsion formed the majority of diagnoses. The median age of referral was 4 years. No patient in the audit period required surgery. Eighty-six percent of children were discharged after their first visit. No significant pathology was identified in the 14% reviewed. Management and outcome for these children were not affected by referral to the orthopaedic clinic.