Generation and characterization of human induced pluripotent stem cells (iPSCs) from hand osteoarthritis patient-derived fibroblasts.

Knowledge and research results about hand osteoarthritis (hOA) are limited due to the lack of samples and animal models of the disease. Here, we report the generation of two induced pluripotent stem cell (iPSC)-lines from patients with radiographic hOA. Furthermore, we wondered whether these iPSC-lines carried single nucleotide polymorphisms (SNPs) within genes that have been associated with hOA. Finally, we performed chondrogenic differentiation of the iPSCs in order to prove their usefulness as cellular models of the disease. We performed a non-integrative reprogramming of dermal fibroblasts obtained from two patients with radiographic rhizarthrosis and non-erosive hOA by introducing the transcriptional factors Oct4, Sox2, Klf4 and c-Myc using Sendai virus. After reprogramming, embryonic stem cell-like colonies emerged in culture, which fulfilled all the criteria to be considered iPSCs. Both iPSC-lines carried variants associated with hOA in the four studied genes and showed differences in their chondrogenic capacity when compared with a healthy control iPSC-line. To our knowledge this is the first time that the generation of iPSC-lines from patients with rhizarthrosis and non-erosive hOA is reported. The obtained iPSC-lines might enable us to model the disease in vitro, and to deeper study both the molecular and cellular mechanisms underlying hOA.

Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?

BACKGROUND: Familial digital arthropathy-brachydactyly (FDAB) and Thiemann disease are non-inflammatory digital arthropathies with many phenotypic similarities. Thirty-three cases of Thiemann disease have been described so far (Mangat et al, Ann Rheum Dis 64:11-2, 2005; Ha et al, Thiemann's disease: a case Report, 2017) but no gene variants have been identified as causative to date. FDAB is reported in only a few patients and has been associated with three heterozygous missense variants in the Transient receptor potential vanilloid 4 (TRPV4) gene. We report a TRPV4 variant in a father and son referred with a diagnosis of Thiemann disease and compare the clinical and radiological features of Thiemann disease with Familial digital arthropathy-brachydactyly (FDAB). We hypothesize that these two entities may be one and the same. METHODS: We describe a father and son referred with a diagnosis of Thiemann disease who were subsequently identified with a heterozygous variant (c.809G > T) in TRPV4. The identical genetic variant was previously reported to cause FDAB. A PUBMED® database search was conducted to retrieve articles related to Thiemann disease and FDAB. We were able to review the clinical and radiological findings of nineteen individuals affected by Thiemann disease and compare them with three families affected by FDAB. RESULTS: Thiemann disease initially affects the proximal interphalangeal joints and primarily the middle phalangeal bases. In FDAB, the distal phalangeal joints are first affected with the middle phalangeal heads being the primary site of changes. Radial deviation has only been described in FDAB. Our analysis determined that 5 of 20 individuals affected by Thiemann disease have clinical and radiological findings that also fit well with FDAB. CONCLUSION: FDAB and Thiemann disease are non-inflammatory digital arthropathies with phenotypic overlap. Although more extensive joint involvement, a distal hand joint preponderance and brachydactyly are expected in FDAB, there are striking clinical and radiological similarities between the two entities. Our analysis suggests that these two phenotypes may represent phenotypic variability of the same entity. Despite many attempts to identify other reported patients affected by Thiemann disease, we were not able to procure DNA from any of the cases to verify our findings. Genetic testing of an affected individual will be crucial in order to provide accurate reproductive genetic counselling about the autosomal dominant nature of this condition.

A preliminary analysis of microRNA profiles in the subchondral bone between Kashin-Beck disease and primary knee osteoarthritis.

INTRODUCTION: Kashin-Beck disease (KBD) is a chronic osteochondral disorder primarily associated with cartilage degeneration. The bone texture structure in KBD was also changed but it was not identical to primary knee osteoarthritis (OA). This study investigates the differences in microRNA (miRNA) profiles of subchondral bone collected from patients suffering from KBD in comparison with those with primary knee osteoarthritis (OA). METHODS: Subchondral bone tissues were taken from four patients with KBD and four patients with primary knee OA undergoing total knee replacement. The miRNA array profiling was performed using an Affymetrix miRNA 4.0 Array, and then the target gene predictions and function annotations of the predicted targets were performed. RESULTS: Our results showed that 124 miRNAs had lower expression levels in the subchondral bone sampled from KBD patients in comparison with OA patients. Gene ontology (GO) and KEGG pathway analyses of the predicted targets demonstrated numerous significantly enriched GO terms and signal pathways essential for bone development and integrity, such as metabolic processes, PI3K-Akt, and MAPK signaling pathways. CONCLUSIONS: Our study confirms that a large set of miRNAs are differentially expressed in the subchondral bone of patients with KBD and OA and contributes new insights into potential pathological changes in the subchondral bone of KBD patients.

Lower serum clusterin levels in patients with erosive hand osteoarthritis are associated with more pain.

BACKGROUND: The aims of this study were to analyse the serum concentrations of clusterin (CLU) in patients with hand osteoarthritis (OA) and in healthy controls, to compare CLU levels between patients with erosive and non-erosive disease, and to examine the association of CLU levels with clinical and laboratory parameters. METHODS: A total of 135 patients with hand OA (81 with erosive and 54 with non-erosive disease) and 53 healthy individuals were included in this study. All patients underwent clinical and hand joint ultrasound examination. The Australian/Canadian (AUSCAN) hand osteoarthritis index, algofunctional index and a visual analogue scale (VAS) for the measurement of pain were assessed. Serum levels of CLU were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum levels of CLU were significantly lower in patients with hand OA than in control subjects (p < 0.0001). In addition, patients with erosive hand OA had significantly lower CLU levels than those with non-erosive disease (p = 0.044). Negative correlations between CLU levels and pain as assessed by the AUSCAN score and the VAS were found in patients with erosive hand OA (r = - 0.275; p = 0.013 and r = - 0.220; p = 0.049, respectively). CONCLUSION: The present study demonstrates that lower concentrations of CLU are found in hand OA patients than in healthy individuals, especially in those with erosive disease, and that CLU concentrations have a negative association with hand pain.

Biomarkers of hand osteoarthritis.

Hand osteoarthritis (OA) is a common degenerative joint disorder leading to substantial pain and disability. The most severe subtype is erosive hand OA characterized by an abrupt onset, local inflammation, subchondral erosions and worse outcomes than non-erosive disease. Biomarkers of hand OA could help to diagnose the disease earlier, to distinguish patients with erosive and non-erosive forms, to assess disease severity or to predict its future progression. The objective of this review was to summarize the role of potential biomarkers of hand OA. A PubMed search for soluble biomarkers associated with hand OA was performed from inception to June 2017. In total, 21 relevant publications were found and reviewed. These publications identified 20 potential biomarkers of hand OA. C-terminal cross-linking telopeptide of type II collagen, cartilage oligomeric matrix protein, osteocalcin, hyaluronan, urinary pentosidine, vascular cell adhesion molecule 1, monocyte chemotactic protein 1, osteoprotegerin and interleukin 1 have been shown as potential biomarkers for assessing disease severity. C-terminal cross-linking telopeptide of type I collagen, hyaluronan, urinary pentosidine and myeloperoxidase were shown to differentiate between erosive and non-erosive hand OA patients. A number of biomarkers reflecting joint tissue metabolism and inflammation have been studied in hand OA. Some were identified as potential biomarkers of disease severity and progression, others were shown to differentiate between erosive and non-erosive disease. However, further research is necessary to assess the value of biomarkers for use in clinical practice.

Scintigraphy for detecting tumour necrosis factor-α on the skin of patients with psoriatic arthritis.

OBJECTIVE: This study assessed the use of scintigraphy and magnetic resonance imaging (MRI) in identifying the presence and amount of tumour necrosis factor-α (TNF-α) in the joint or skin of patients with psoriatic arthritis, to guide the course of treatment more efficiently. METHOD: We compared the results of scintigraphy and MRI in two patients with psoriatic arthritis who underwent technetium-99m (99mTc)-anti-TNF-α scintigraphy, and MRI 5 days later. RESULTS: Greater uptake of 99mTc-anti-TNF-α was observed in the left wrist and right second metacarpal in patient 1, and in the left ulnocarpal joint and distal interphalangeal joint of the left first metacarpal in patient 2. These results correlated with the MRI findings. CONCLUSIONS: 99mTc-anti-TNF-α scintigraphy may recognize the molecule involved in the inflammatory process. This may provide crucial information to help physicians make decisions about which drugs to use based on biological evidence, and which are cost-effective and appropriate for the treatment of choice. To the best of our knowledge, this is the first time that TNF-α has been shown in the skin of a patient using diagnostic imaging methods.

Association between serum levels of the proinflammatory protein S100A8/A9 and clinical and structural characteristics of patients with established knee, hip, and hand osteoarthritis.

OBJECTIVES: To explore the association between S100A8/A9 serum levels with clinical and structural characteristics of patients with established knee, hip, or hand osteoarthritis (OA). METHOD: A cross-sectional exploratory study was conducted with 162 OA patients. Measures for pain, stiffness, and function included the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire or the Australian Canadian Osteoarthritis Hand (AUSCAN) Index and for structural abnormalities, osteophytes and joint space narrowing grades. The association between S100A8/A9 and clinical or structural characteristics was analysed using linear regression or logistic regression where appropriate. RESULTS: The mean age of the OA patients was 56 years, 71% were female, and 61% had a Kellgren and Lawrence (K&L) score ≥ 2. The serum S100A8/A9 level did not differ between knee, hip, and hand OA patients and no association was found between serum S100A8/A9 and clinical characteristics. The serum S100A8/A9 level was negatively associated with the sum score of osteophytes after adjusting for sex and body mass index (BMI) [adjusted ß -0.015, 95% confidence interval (CI) -0.030 to 0.001, p = 0.062] and positively associated with erythrocyte sedimentation rate (ESR) > 12 mm/h (adjusted OR 1.002, 95% CI 1.000-1.004 p = 0.049) for each increase in S100A8/A9 of 1 ng/mL. For hand OA patients, a negative association of S100A8/A9 with sum score of joint space narrowing was found (adjusted ß -0.007, 95% CI -0.016 to 0.001, p = 0.099). CONCLUSIONS: The results from this cross-sectional exploratory study do not support an important role for serum S100A8/A9 levels as a biomarker for clinical and structural characteristics in established knee, hip, and hand OA patients. The inverse association with structural abnormalities and the positive association with ESR may reflect inflammatory synovial processes in patients with OA before structural abnormalities occur.

Associations between biomarkers of joint metabolism, hand osteoarthritis, and hand pain and function: the Johnston County Osteoarthritis Project.

OBJECTIVE: To determine the associations between joint metabolism biomarkers and hand radiographic osteoarthritis [(rOA), based on Kellgren Lawrence (KL) grade ≥ 2], symptoms, and function. METHODS: Cross-sectional data were available for 663 participants (mean age 63 yrs, 63% white, 49% women). Three definitions of hand rOA were considered: (1) a composite measure involving at least 3 hand joints distributed bilaterally with 2 of 3 in the same joint group, including ≥ 1 distal interphalangeal joint, without metacarpophalangeal (MCP) swelling; (2) rOA in at least 1 joint of a group; and (3) number of joints with KL ≥ 2. We assessed hand symptoms and the 15-item Australian Canadian Hand Osteoarthritis Index (AUSCAN; Likert format). We measured serum cartilage oligomeric matrix protein (sCOMP), hyaluronic acid (sHA), carboxy-terminal propeptide of type II collagen, type II collagen degradation product, urinary C-terminal crosslinked telopeptide of type II collagen, and urinary N-terminal crosslinked telopeptide. Linear regression models were performed to assess associations between each biomarker with hand rOA, AUSCAN, and symptoms, adjusting for age, sex, race, current smoking/drinking status, body mass index, and hip and knee rOA. RESULTS: In adjusted analyses, MCP (p < 0.0001) and carpometacarpal rOA (p = 0.003), and a higher number of hand joints with rOA (p = 0.009), were associated with higher levels of sHA. Positive associations were seen between AUSCAN and hand symptoms and levels of sCOMP (p ≤ 0.003) and sHA (p ≤ 0.048). CONCLUSION: Hand symptoms and higher AUSCAN scores were independently associated with higher levels of both sCOMP and sHA; hand rOA was associated only with sHA levels.

Treatment of erosive osteoarthritis with peroxisome proliferator-activated receptor alpha agonist fenofibrate: a pilot study.

Hand osteoarthritis (HOA) is a common condition associated with high disease burden and frequently accompanied by comorbidities including dyslipidemia, atherosclerosis and obesity. The most debilitating HOA phenotype is erosive HOA (EHOA), characterized by synovial inflammation, formation of erosions, and substantial decline in hand function. Currently, there is no proven symptomatic treatment for the EHOA. Due to their broad spectrum effects directed on lipid metabolism, inflammation and pain, the agonists of peroxisome proliferator-activated receptor alpha or fibrates are a candidate class of drugs for the treatment of EHOA. In this study, we assessed the influence of fenofibrate treatment on clinical efficacy parameters, in vivo cytokine and adipokine production and concentrations of endothelial progenitor cells (EPC) in patients with EHOA. Fourteen patients received treatment with 145 mg of fenofibrate/day for 12 weeks. Fenofibrate treatment was associated with significant decreases in pain score, tender joint count, duration of morning stiffness, disease activity score, Cochin index, and ESR. Eight (57.14 %) patients developed Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society response at the end of treatment. Paracetamol consumption did not change during the treatment course. There was a significant reduction in triglyceride levels. No changes were detected in serum pro-inflammatory cytokine and adipokine concentrations while circulating IL-10 levels significantly decreased. There were no differences in circulating EPC numbers before and after the treatment. Fenofibrate was well tolerated, no patient experienced disease flare during the treatment. In conclusion, in EHOA patients, fenofibrate is associated with pleiotropic effects on pain, inflammation, and lipid profile. Larger, controlled studies are needed to confirm these results.

Dual energy computed tomography for quantification of tissue urate deposits in tophaceous gout: help from modern physics in the management of an ancient disease.

Gout has been recognized for centuries but is also a modern day scourge. It is the most common type of inflammatory arthritis in men and appears to be increasing in both incidence and prevalence (Arromdee et al. in J Rheumatol 29(11):2403-2406, 2002). Despite these facts, few advances have been made in the diagnosis and treatment of gout for over 50 years. Difficult cases of gout challenge available therapeutic options. It is only recently that the Food and Drug Administration has approved febuxostat as a treatment option for patients intolerant of allopurinol. We describe a difficult case of tophaceous gout notable for several reasons: utilization of rasburicase as uricolytic treatment to dramatically reduce tissue urate burden; treatment of gout flares with interleukin-1ß inhibition; and quantification of tissue urate with novel dual energy computed tomography technology before and after uricolytic therapy.

Hybrid 18F-FDG PET-MRI of the hand in rheumatoid arthritis: initial results.

18F-fluorodeoxyglucose PET (18F-FDG PET) is highly sensitive to inflammatory changes within the synovial tissue in rheumatoid arthritis (RA). However, the highest spatial resolution for soft tissue can be achieved with MRI. Here, we report on the first true hybrid PET-MRI examination of the hand in early RA exploiting the advantages of both modalities. PET-MRI was performed with a prototype of an APD-based magneto-insensitive BrainPET detector (Siemens Healthcare, Erlangen, Germany) operated within a standard 3T MR scanner (MAGNETOM Trio, Siemens). PET images were normalized, random, attenuation and scatter-corrected, iteratively reconstructed and calibrated to yield standardized uptake values (SUV) of 18F-FDG uptake. T1-weighted TSE in coronal as well as sagittal orientation prior to and following Gadolinium administration were acquired. Increased 18F-FDG uptake was present in synovitis and tenovaginitis as identified on contrast-enhanced MRI. The tracer distribution was surrounding the metacarpophalangeal joints II and III. Maximum SUV of 3.1 was noted. In RA, true hybrid 18F-FDG PET-MRI of the hand is technically feasible and bears the potential to directly visualize inflammation.

Serum hyaluronic acid as a potential marker with a predictive value for further radiographic progression of hand osteoarthritis.

OBJECTIVE: To compare serum levels of hyaluronic acid (HA) between patients with erosive and non-erosive hand osteoarthritis (HOA), and investigate its association with morphological changes and radiographic progression over 2 years. METHODS: Fifty-five women with erosive and 33 women with non-erosive HOA were included in this study. All underwent clinical examination, which included assessment of pain, swelling, deformity and deviation of small hand joints and completed health assessment questionnaires. Serum levels of HA were measured by ELISA. Three-phase bone scintigraphy was performed at baseline. Radiographs of both hands were performed at baseline and after 2 years and scored according Kallman grading scale. RESULTS: Serum levels of HA were significantly higher in patients with erosive than with non-erosive HOA (P<0.01). It correlated significantly with the number of hand joints with deviations and deformities. HA adjusted for age and disease duration significantly correlated with radiographs at baseline and after 2 years in all patients with HOA (r=0.560 and r=0.542, P<0.01 for both correlations). Although there was an association between HA and radiographic score in erosive disease, after adjustment for confounders it remained no longer significant. HA adjusted for confounders correlated significantly with the late phase in all patients with HOA (r=0.412, P<0.01) and in patients with erosive disease (r=0.320, P<0.05). CONCLUSION: HA is increased in patients with erosive HOA and could be proposed as a surrogate marker with a predictive value for further radiographic progression of HOA in general. Further investigation is necessary to confirm these results.

Mechanisms of bone erosion in gout: a quantitative analysis using plain radiography and computed tomography.

OBJECTIVE: The underlying basis of bone erosion in gout remains speculative. The aim of this study was to understand the mechanisms of bone erosion in gout using non-invasive imaging techniques. METHODS: Paired plain radiographs and computed tomography (CT) scans of 798 individual hand and wrist joints from 20 patients with gout were analysed. Radiographs were scored for erosion (0-5) using the Sharp/van der Heijde method. CT scans were scored for the presence and diameter of bone erosions and tophi. The presence of intraosseous tophus (tophus visualised within bone) was recorded. The relationships between radiographic erosion, CT erosion and tophus scores were analysed. RESULTS: With increasing radiographic erosion scores, the percentage of joints with intraosseous tophus increased (p<0.001). For those joints with a radiographic erosion score of 4 or 5, 96/98 (98%) had CT evidence of intraosseous tophus. There was a significant relationship between the radiographic erosion scores and intraosseous tophus size (p<0.001). For those joints with CT erosion, 194/237 (81.8%) had visible intraosseous tophus. Of the joints with CT erosions greater than 5 mm, 106/112 (94.6%) had visible intraosseous tophus and all (56/56) erosions greater than 7.5 mm had intraosseous tophus. There was a strong correlation between CT erosion diameter and intraosseous tophus diameter (r = 0.93, p<0.001). Intraosseous tophi were larger than non-intraosseous tophi, but had similar density and calcification. CONCLUSION: There is a strong relationship between bone erosion and the presence of intraosseous tophus. These results strongly implicate tophus infiltration into bone as the dominant mechanism for the development of bone erosion and joint damage in gout.

Do metabolic factors add to the effect of overweight on hand osteoarthritis? The Rotterdam Study.

BACKGROUND: As hand joints are non-weight bearing, the association between overweight and hand osteoarthritis (HOA) is critical to understanding how overweight may associate with osteoarthritis (OA) apart from axial load. Overweight might be associated with the occurrence of OA through other metabolic factors. AIM: To evaluate the role of overweight in HOA, cross-sectional data of a population-based study were used (> or =55 years, n = 3585). The role of diabetes, hypertension and total cholesterol:high-density lipoprotein (HDL)-cholesterol ratio on HOA, and whether they play an intermediate role in the association of overweight/HOA was investigated. Furthermore, the prevalence of HOA in the concurrent presence of overweight and other metabolic factors was evaluated. RESULTS: Independently of other metabolic factors, overweight (body mass index (BMI) >27.4 kg/m(2)) showed a significant association with HOA (OR 1.4, 95% CI 1.2 to 1.7). The association between diabetes and HOA was only present in people aged 55-62 years (OR 1.9, 95% CI 1.0 to 3.8), but was absent in the total population or in other age groups. The association of hypertension with HOA was weak, and disappeared after adjustment for BMI. The total/HDL cholesterol ratio showed no significant association with HOA. The concurrent presence of overweight, diabetes and hypertension resulted in an even higher prevalence of HOA (OR 2.3, 95% CI 1.3 to 3.9) compared with subjects with none of these characteristics; this prevalence increased further in the younger age group (OR 3.2, 95% CI 1.1 to 8.8). CONCLUSION: No intermediate effect of metabolic factors on the association of overweight with HOA was found. An increase in the prevalence of HOA, however, seems to be present when overweight occurs together with hypertension and diabetes especially at a relatively young age.