Hyaluronan drugs versus physical therapy in knee osteoarthritis
Osteoarthritis in 2007
Osteoarthritis (OA) is often a progressive and disabling disease resulting from a combination of risk factors, including age, genetics, trauma, and knee alignment, as well as an imbalance of physiologic processes resulting in inflammatory cascades on a molecular level. The synovium, bone, and cartilage are each involved in the pathophysiological mechanisms that lead to progressive joint degeneration, and, thus, also serve as targets for therapies. Efforts to identify disease-modifying osteoarthritis drugs (DMOADs) have been hampered by several factors, but the focus has now shifted toward the validation of chemical and imaging biomarkers that should aid in DMOAD development. In this review, we summarize current pathological mechanisms occurring in the individual but interconnected compartments of OA joints, as well as discuss related therapeutic interventions that are currently available or on the horizon
Bone marrow changes (edema and fatty infiltration) on MRI predict radiographic severity of knee OA
Pathogenesis of osteoarthritis
Approaching rheumatologic disease in older patients -- Conservative treatment and aggressive screening avoid excessive morbidity
Rheumatologic and other musculoskeletal symptoms are prevalent in older patients and often require close attention. Determining early whether an inflammatory or noninflammatory process is involved may help avoid unnecessary morbidity and prevent medication-related toxicities. Physicians should be especially aware of symptoms and signs that suggest giant cell arteritis and look for red flags in patients with low back pain that herald possible infection, visceral disease, or malignancy. Proactive screening and diagnostic testing for osteoporosis are essential to treat older patients and reduce fracture risk
The use of musculoskeletal ultrasound: Rheumatologists in the US
Synovial but not cartilage volumes on MRI predict radiographic severity of knee Osteoarthritis (OA)
Osteoarthritis: a tale of three tissues
While research in osteoarthritis has focused on the events that lead to the destruction of articular cartilage, recent evidence suggests that two other components of the joints-bone and synovium-also play key roles in pathogenesis. All three tissues undergo alterations in concert at the structural levels in response to mechanical stress and joint malalignment. Advanced imaging studies such as MRI support this interdependence, revealing the classical changes of joint space narrowing and cartilage degeneration as well as the more recently appreciated bone marrow lesions and synovitis that may correlate with clinical symptoms. Molecular evidence also points to a coordinated release of cytokines and other inflammatory mediators from each of the three tissues together in progression of disease, although we are still in search of biochemical signatures that will predict the subset of patients who progress more quickly-and who will provide key clues to successful molecular targets in future therapies. At this time we lack definitive evidence pointing to which, if any, of the three tissues should serve as the main target for disease modification or structure protection, although most efforts have focused on cartilage. Thus current therapies focus on controlling symptoms, while research efforts search for reliable imaging and molecular biomarkers to help guide future trials of potential disease-modifying agents
Erosive spinal tophus in a patient with gout and back pain
Musculoskeletal ultrasound in the diagnosis of rheumatic disease
The use of musculoskeletal ultrasound (MSKUS) in rheumatology practice and research has increased steadily over the last decade. An ever-growing body of literature shows parity and even superiority of MSKUS when compared to physical examination, plain radiography, and more expensive and static imaging modalities such as MRI. While many use the modality for procedure guidance, investigators continue to demonstrate its ability to impact diagnoses in a variety of rheumatic diseases. Initial efforts focused on establishing MSKUS as a helpful tool for rheumatoid arthritis (RA), especially in the detection of synovitis and joint erosions, but numerous studies are validating the use of MSKUS as a helpful diagnostic tool for the spondyloarthropathies, crystal diseases, osteoarthritis, and other rheumatic diseases. Advances in ultrasound technology are translating into more sensitive and accurate studies. Within the research community, current efforts aim at maximizing the direct clinical impact of MSKUS by developing global or patient level assessments and simplified joint scoring systems, with improvements in intra- and inter-reader reproducibility
The use of musculoskeletal ultrasound by rheumatologists in the United States
Fewer United States rheumatologists perform or utilize musculoskeletal ultrasound (MSUS) than those in Europe, though this disparity is narrowing. To document perceptions and use of MSUS in the U.S. rheumatology community, we sent an anonymous electronic survey to American College of Rheumatology (ACR) physicians and tailored versions to fellows and program directors. A separately-conducted survey was sent to a smaller group of rheumatologists already utilizing MSUS. Acknowledging survey bias, we found that 20% of rheumatologists and fellows who responded are utilizing MSUS, and those using it primarily do so for diagnosis and injection guidance. Many rheumatologists across the country think that ultrasound should become a standard tool in rheumatology training, practice, and research. Despite an inherent survey bias likely overstating interest in MSUS, this study is valuable as the first to document this trend among U.S. rheumatologists
ASSOCIATION OF INTERLEUKIN-1 RECEPTOR ANTAGONIST (IL-1RN) TTG HAPLOTYPE WITH RADIOGRAPHIC KNEE OA SEVERITY IN META-ANALYSIS
INTERLEUKIN-1 RECEPTOR ANTAGONIST GENE VARIATIONS PREDICT THE SEVERITY AND PROGRESSION OF KNEE OSTEOARTHRITIS
Association of genetic polymorphism in inflammatory cytokines with radiographic knee OA severity and generalized Osteoarthritis (GOA)
Purpose: Osteoarthritis is the most common form of arthritis, and the hereditable component of OA has been estimated to be 50-65%. The IL1 gene cluster region has been repeatedly associated with susceptibility to OA in various joints. This finding is consistent with the notion that inflammatory mediators, particularly IL-1, may be important in the pathogenesis and progression of OA. In these studies we examined the association of SNPs in inflammatory genes with the severity of knee OA and with the presence of generalized OA (GOA, here defined as knee plus hand OA). Method: One hundred forty-four OA patients (81 knee OA and 63 GOA) from two separate centers (NYUHJD, N=94 and Duke, N=50) met inclusion criteria: Caucasians of either sex, free of chronic disease other than osteoarthritis, and with a radiographic diagnosis of knee OA. Synovial fluid was available for the 50 Duke patients. Patients were genotyped for single nucleotide polymorphisms (SNPs). These subjects were divided into two groups: knee OA and GOA (knee and hand OA).We performed statistical analysis using Chi square and logistic regression, adjusting for age, gender and BMI to search for associations of radiographic knee OA severity and GOA with individual SNPs and with haplotypes. Results: After adjustment for age, gender, and BMI, individual TNF-a, IL1, IL1 receptor antagonist (IL1RN) SNPs were strongly associated with the presence of GOA (Table 1). In three of the four SNPs, alleles associated with increased incidence of GOA have been previously associated with increased cellular production of inflammatory mediators. These alleles are: IL1B (-3737) rs4848306 TT/CT, IL1B (-511) rs16944 CC/CT, and TNF-a (-308) rs1800629 AA/AG. In a separate analysis of knee OA severity based upon JSW, carriage of either one or two copies of a haplotype consisting of IL-1RN rs9005 (A), IL-1RN rs419598 (C), IL-1RN rs315952(T) was associated with lower odds of radiographic severity (OR 0.16; 95% CI 0.06-0.40), greater joint space width (JSW; p=0.0038) compared to those without these haplotypes. Patients with the protective haplotype had lower synovial fluid levels of IL-6 (p=0.018) and IL-10 (p=0.038). (Table Presented). Conclusion: Among the cytokines and receptor antagonist studied for genetic association, IL-1RN SNPs (rs9005, rs419598 & rs315952) predicted low risk for knee OA radiographic severity and haplotypes in IL-1B, TNFa ad IL-1RN (rs 315952) strongly associated with increased prevalence of GOA. These genetic markers provide insight into the possible role of inflammatory mediators in knee OA and could prove to be useful biomarkers in DMOAD drug development
Musculoskeletal ultrasound assessment of carpal tunnel syndrome in rheumatoid arthritis
Purpose: Wrist pain in rheumatoid arthritis (RA) is often complicated by carpal tunnel syndrome (CTS) secondary to active synovitis. In such cases it can be difficult to determine whether to inject the joint or the carpal tunnel - or treat systemically. Recent literature suggests that musculoskeletal ultrasound can diagnose CTS by identifying a median nerve cross sectional area of >10mm<sup>2</sup> at the inlet, or by using a wrist to forearm ratio of >1.4 (from inlet to 12 cm proximally) to correct for patients with confounding diagnoses that may cause larger nerves at baseline (Hobson-Webb 2008). In this pilot study, we aim to assess how well ultrasound can identify median nerve entrapment noninvasively specifically in RA patients with active wrist pain. Methods: We enrolled 19 consecutive patients with RA and active wrist pain in at least one wrist (total of 28 wrists) and assessed them for CTS by history and physical. Using gray scale ultrasound imaging at 12 MHz, we identified the median nerve at the level of the inlet (volar wrist between the scaphoid and pisiform) and 12 cm proximally to calculate the wrist-to-forearm ratio. More than a month after capture, we blindly evaluated median nerve cross-sectional area with a tracing function on the machine and calculated the ratio from wrist to forearm. We averaged the scores from two readings (one each by MMR and JS) for each patient. Results: In our pilot population of painful RA wrists, irrespective of CTS signs or symptoms, the overall average median nerve size at the inlet was 10.9 (range 5.5 to 26, SD of 3.9), while the overall average wrist-to-forearm ratio was 1.9 (range 1.32 to 2.80, SD of 0.47) Separating those with (n=12) and without (n=16) CTS signs and symptoms, the average median nerve areas at the inlet were 13 mm<sup>2</sup> and 9.42 mm<sup>2</sup> respectively (p=0.0097). The corresponding wrist to forearm ratios for patients with and without CTS signs and symptoms averaged 2.19 and 1.68 (p=.0032). Of the patients with CTS signs and symptoms, 92 % (11of 12) had an inlet nerve size >10 mm<sup>2</sup> and 100% (all 16) had a wrist-to-forearm ratio greater than the published 1.4 cutoff for CTS. Only 25% (4 of 16) of those without CTS signs and symptoms measured an inlet of >10 mm<sup>2</sup>, but 75 % (12 of 16) of these asymptomatic patients had a wrist-to-forearm ratio >1.4. (Figure presented) Conclusion: This pilot data suggests that ultrasound evaluation of the median nerve by assessing cross sectional area at the wrist inlet is a sensitive and specific test in RA patients with active wrist pain, as it is in the general population. Conversely, the wrist-to-forearm ratio, introduced to compensate for size variability in healthy median nerves, may reveal false positive results for carpal tunnel syndrome in patients with RA and wrist pain. Measurements of the median nerve at the inlet can help distinguish RA synovitis of the joint from median nerve compression-and thus spare patients from painful nerve conduction studies
Reproducibility of MR biomarkers of cartilage structure and composition in an osteoarthritis population at risk of progression
Purpose: Osteoarthritis (OA) is a slowly-progressing disease, and imaging biomarkers of cartilage structure have failed to detect short-term (< 6 months) change. An imaging biomarker of cartilage quality (i.e., tissue composition and function) such as magnetic resonance transverse relaxation time of hyaline cartilage water protons (T<sub>2</sub>), may be more a responsive biomarker of OA progression. T<sub>2</sub> is a proxy for disorder and hydration, and is easily measured without a contrast agent, but there are few data on variability of this marker over time in OA. The purpose of this study was to determine the short-term (1 week) reproducibility of cartilage T<sub>2</sub> and thickness obtained from an anatomically-corresponded regional analysis using statistical shape modelling. Method: We conducted a multi-centre, non-randomized study at 4 sites with a sample at risk of medial tibiofemoral progression including women, BMI>=25 kg/m<sup>2</sup>, symptomatic radiographic evidence of medial tibiofemoral OA (K&L grade 2-3, medial JSN>= lateral JSN), varus malalignment >=-2degree (anatomic axis), and pain. As part of a larger study, eligible participants had MRI scans of the same knee at baseline and 1 week. The OAI protocol for the index knee was deployed on 3T Siemens Trio systems. A trained operator, blind to time-point but not subject, manually segmented the cartilage from the DESSwe MR images using EndPoint (Imorphics). Anatomically corresponding regions of interest were identified on each image by fitting a bone model, and mean cartilage thickness (with areas denuded of cartilage included as having zero thickness - ThCtAB) within each region was calculated. Voxelwise transverse relaxation rates were calculated from a linear least-squares fit of the log of the signal values against echo time. Mean T<sub>2</sub> values were also recorded in each region from the 50% most exochondral and 50% most endochondral voxels. Coefficients of Variation (CoV) were calculated. Results:The 29 participants had a mean age of 62 years, mean BMI of 36 kg/m<sup>2</sup>, with 8 index knees graded as K&L =2 and 21 as K&L=3. Anatomical mal-alignment ranged from -1.9degree to 6.3degree, with mean 0.9degree, where varus mal-alignment is measured in the positive direction. 28 subjects provided data for reproducibility of ThCtAB and 20 for T<sub>2</sub>. (Table presented) Conclusion: T<sub>2</sub> can be measured reproducibly in an OA population in multicentre studies and with similar variability to a cartilage structural assessment. These results support further evaluation of T<sub>2</sub> as a candidate biomarker of cartilage composition for assessing interventions
Variable X-ray beam angulation improves quality of medial tibial plateau alignment in fixed-flexion knee radiographs of osteoarthritis (OA) patients
Purpose: To assess whether variability in caudal X-ray beam angulation (CBA) improves alignment of the medial tibial plateau (MTP) versus a fixed 10degree CBA, using non-fluoroscopic fixed-flexion knee radiographs. Methods: 133 subjects with knee OA underwent fixed-flexion AP X-ray examinations as part of a longitudinal study. We performed a cross sectional substudy in which 90 subjects were imaged with a 10degree CBA (Method 1) and 43 subjects were imaged using different CBAs (choosing from 5degree, 10degree, 15degree) determined by a trained radiology technician, depending on MTP alignment assessed in real time (Method 2). After reading a blinded training set of radiographs, an experienced radiologist, who was blinded to patients and method used, read the x-rays for MTP alignment quality using a 1-5 scale (1, 2=good, 3=acceptable, 4= poor, 5= unacceptable), and for Kellgren-Lawrence (KL) grade. Results: Method 1 subjects (10degree angulation): MTP alignment quality was scored as good or acceptable 62% and 69% of the time for the right and left knees, respectively. Method 2 subjects (variable angulation): Variable angulation resulted in good or acceptable MTP alignment quality on at least one x-ray 86% and 88% of the time for right and left knees, respectively. When CBA was changed, MTP alignment quality changed 84% of the time for the right knee and 77% of the time for the left knee in subjects who had at least 2 radiographs (n=43). The KL grade changed 28% and 46% of the time in the right and left knees, respectively, when MTP alignment quality changed in the same knee. The KL grade changed 38% and 36% of the time in the right and left knees, respectively, when there was no change in MTP alignment quality but there was a change in CBA. A change in CBA resulted in MTP alignment quality change in bilateral knees 66% of the time, of which this change was in the same direction (improved vs worsened) 86% of the time. Using a CBA of 10degree resulted in improved (over other angulations) MTP alignment quality 53% and 50% of the time for the right and left knees, respectively. Using a CBA of 10degree resulted in worsened MTP alignment 33% and 22% of the time for right and left knees, respectively. Conclusion: While fixed 10degree CBA in fixed-flexion radiographs results in acceptable or good MTP alignment quality the majority of the time, variable CBA improves this frequency in knee OA subjects. Changes in CBA often change the MTP alignment quality, usually in the same direction in both knees, and sometimes change the KL grade. More studies are needed to determine the optimal CBA for non-fluoroscopic fixed-flexion protocols and all radiographic knee OA studies should report the specific techniques used, including CBA
Concordance between ultrasound readers determining presence of monosodium urate crystal deposition in knee and toe joints
Background: Determination of monosodium urate (MSU) deposition in joints by musculoskeletal ultrasound (MSK-US) could have implications for uric acid (UA) management in patients with gout and possibly asymptomatic hyperuricemia (AH). Recently, criteria for sonographic diagnosis of MSU crystal deposition have been developed, but reproducibility of readings using these criteria has not been well established. Methods: We consecutively recruited male patients ages 55-85 during primary care visits to an urban VA hospital. We assessed all patients for gout by ACR criteria, and obtained serum UA levels. Patients were divided into 3 groups: gout, AH (no gout, UA >= 6.9 mg/dL), and controls (no gout, UA <= 6.8 mg/dL). 50 patients (14 with gout, 17 with AH, and 19 controls) returned for subsequent evaluation which included MSK-US of knees and 1st metatarsalphalangeal (MTP) joints to evaluate for the double contour sign (knees) and tophi (MTPs). All images were read blindly by two observers trained in rheumatology and MSK-US. Kappa statistics were used to estimate the amount of agreement between ultrasound measures scored by the two raters. We also calculated the total percent of observations in agreement. Results: Evidence of MSU crystal deposition was found in the same 10 patients by both observers (6 gout, 3 AH, 1 control), and in 3 additional patients by one of the observers (1 gout, 2 AH). These findings were further analyzed by site. MSU crystal deposition was identified in a total of 14 common joints by both observers, and in 4 additional joints by the first observer and 6 additional joints by the second observer. Percentage agreement and kappa statistics for our three primary ultrasound measures were as follows; total joints (n=200, 95% agreement, kappa 0.709), femoral articular cartilage (n=100, 95% agreement, kappa 0.679) and 1st MTPs (n=100, 95% agreement, kappa 0.734). Additional analyses by left and right side are shown in the table below. Ratings on only 10 out of 200 joints were in disagreement. (Table Presented) Conclusions: Both percentage agreement and agreement beyond chance between the raters (as estimated by kappa statistics) were very high for the three ultrasound measures. These findings support the use of MSK-US as a reliable modality for detecting MSU deposition. Since MSU deposition is an indication for urate lowering, this type of imaging could be performed noninvasively at the bedside or in the clinic to help direct therapy in gout patients, with possible implications for treatment in AH patients as well should these findings be reproducible in larger cohorts
Hand osteoarthritis (OA) a predictor of accelerated progression in knee OA?
Purpose: There is insufficient understanding regarding how generalized OA involving the hand and knee differs from isolated knee OA, which may result from other factors such as obesity or trauma. The purpose of these studies is to determine whether the presence of hand OA involving interphalangeal (IP) and first carpometacarpal (CMC) joints, alone or in combination, predicts progression of patients with symptomatic knee OA. Methods: Hand radiographs were obtained on 94 patients at NYUHJD who met ACR criteria for symptomatic knee OA, and who were enrolled in a two-year NIH-sponsored prospective study. The patients completed standardized fixed-flexion knee radiographs at baseline and 24 months, with progression the signal (more painful) knee OA determined by change in joint space width (JSW) and KL score. For these analyses, the patients were separated into two groups by results on their signal knee: 17 progressors, defined by at least 30% decreased JSW over 24 months, and 77 non-progressors. For each set of hand x-rays, 2 radiologists evaluated 18 IP joints and 2 CMC joints for joint space narrowing and/or osteophytes, and whether or not there was erosive change at the IP joints; we averaged the scores from the two readers. Results: Kappa scores between the two scoring radiologists for the IP and CMC joints, and for the presence of erosive IP disease, were 0.79, 0.87 and 0.96, respectively. The overall mean IP score was 5.6 and 1st CMC score was 0.9, while medians were 5 and 1.0, respectively. The 17 progressors had a higher average IP (but not CMC) score than the non-progressors, 7.2+/- 5.4 vs. 5.0+/-4.6, p=0.13. Since the IP scores were not normally distributed, we further analyzed data by dichotomizing the study populations into two groups using the median IP total (5) as the cutoff point. When so analyzed, the presence of hand OA increased the odds ratio of knee OA progression to 2.8 (p=0.096). Of interest, the severity of knee OA correlated with hand OA scores: the average total hand OA scores (out of 20 joints) increased with baseline KL score, with mean scores of 3.8+/-5.5, 6.1+/-6.1 and 7.2+/-5.6 for KL 1 to 3 (p=0.06). There is also an increasing trend of total hand OA joint scores by KL score (p=0.042) when dichotomized around the median (5 joints), and with IP scores alone (p=0.026). The 8 patients with radiographic evidence of erosive IP disease, as compared with the 31 non-erosive IP OA patients (>5 IP joints) and the 54 without IP OA, demonstrated faster knee OA progression over 2 years by average KL increases (1.00, 0.35, 0.30) and decreases in joint space width (0.65, 0.56, 0.36), although perhaps given small numbers, this was not statistically significant (p=0.839). Conclusions: In cross-sectional analysis, the quantitative burden of hand OA correlates with the radiographic severity of knee OA (KL). Moreover, radiographic hand OA at the IP joints, but not at the 1st CMC joint, predicts more rapid progression of knee OA. Erosive IP disease may be an even stronger predictor than non-erosive IP disease of accelerated progression of knee OA
Interleukin-1 receptor antagonist (IL-1RN) gene variations predict the severity and progression of knee osteoarthritis
Purpose: We have previously shown that carriage of an IL1RN haplotype (CTA) was associated with substantially lower odds of radiographic severity (KL score, joint space width [JSW]) (Ann Rheum Dis. 2010). In this 24 month prospective study we assessed whether IL1-RN haplotypes predicted disease progression in patients with symptomatic knee OA. Methods: Ninety-seven (N=97) patients from NYUHJD who met ACR criteria for symptomatic knee OA were genotyped for single nucleotide polymorphisms (SNPs) in the IL-1b and IL-1RN genes. Standardized fixed-flexion radiographs were taken on all patients at baseline and 24 months. Radiographic progression of signal (more painful) knee OA was determined by change in JSW over 24 months. To account for variations in baseline JSW, we defined progression as greater than 30% joint space narrowing (JSN) of the diseased compartment over 24 months, rather than in change in absolute JSW in millimeters. Results: Decreases in JSW ranged from zero to 3.7 mm over the 24 months; 19 of 97 patients exhibited < 30% JSN. (Figure presented) Patients with the IL-1RN (rs419598/rs315952/9005) TTG haplotype exhibited increased radiographic knee OA severity at baseline compared to those without TTG (p>0.08). These TTG patients exhibited increased risk for radiographic progression at 24 months that approached significance based on <=30% JSN [OR = 2.85; 95%CI=0.68-11.67; p>0.15]. In contrast, OA patients with IL-1RN CTA haplotype showed decreased risk for JSN over 24 months in the signal knee [OR= 0.33; 95%CI=0.170-1.014; p>0.05]. Differences in reported VAS pain between the CTA and TTG group were significant at 24 months (p> 0.01), indicating that while these patients were not distinguishable by radiograph or symptoms at onset, IL1RN haplotype predicted symptomatic differences at two years. Finally, the TTG haplotype group of patients expressed relatively increased IL-1b gene expression [15.683 +/- 9.407 (p>0.0001)] as assessed by TaqMan QPCR in peripheral blood leukocytes. The TTG patients also exhibited decreased sIL-1Ra [283.64 +/- 36.4 pg/ml (p>0.001) in plasma samples compared to IL-1RN CTA haplotype protective groups [IL-1b (fold change), 5.444 +/- 10.083; sIL-1Ra, 370.35 +/- 43.3pg/ml] of patients respectively. Conclusion: IL-1RN gene family polymorphisms, which appear to affect host production of IL-1Ra, merit evaluation as biomarkers that predict the risk of progression in patients with symptomatic knee OA
Radiographic severity of knee osteoarthritis predicts quantitative Bone Marrow Lesions on MRI
Objective: To evaluate the relationship of quantitative assessment of Bone Marrow Lesions (BML) with knee OA severity by radiographic findings. Methods: 58 OA patients (mean age 62+/-10, mean BMI 27+/-3, 59% female) underwent standardized nonfluoroscopic fixed-flexion knee radiographs. Two radiologists read the X-rays for KL grade, joint space width (JSW), and, using the OARSI atlas, joint space narrowing (JSN) and osteophytes; interreader agreement was assessed using Kappas and concordance correlation coefficients. Linear and logistic regression analysis was performed to assess associations while controlling the effects of age, sex and BMI. 3T-MRI included sagittal T2-weighted fat saturated spin-echo images (TR/TE=4000ms/75ms, FOV=15cm, matrix=256x128, slice thickness=3.0mm, receiver bandwidth 130Hz/pixel) and in/out of phase of FLASH images. Compartment-wise (medial tibial, lateral tibial, medial femur, lateral femur) BML volumes were quantified with T2-weighted fat saturated images and in/out of phase images respectively. BML volumes were dichotomized for statistical analysis. Results: KL score was a significant predictor of total BML volume (OR = 8.41, p = 0.0235). Medial tibial JSW, OARSI medial JSN, and medial tibial plateau osteophytes approached significance as predictors of BML volume at the medial tibia (OR = 0.71, p = 0.0551; OR = 2.16, p = 0.0597; and OR = 2.68, p = 0.0875, respectively). OARSI lateral JSN was a significant predictor of BML volume at the lateral tibia (OR = 3.62, p = 0.0169). Lateral tibial plateau osteophytes were predictors of total BML volume (OR = 4.58, p = 0.0299) and of BML volume at the lateral tibia (OR = 2.31, p = 0.0685). Lateral femoral condyle osteophytes approached significance as a predictor for BML at the lateral femur (OR = 2.25, p = 0.0651). Furthermore, quantitative BML volume strongly correlated with total quantitative synovial volume measured on MRI (beta= 0.22, p = 0.0003). Conclusions: Our data indicate that BML volume on MRI is a characteristic feature of progressive stages of OA, which not only correlates with JSN and osteophytes, but does so in a compartment-specific way. The data suggest that the altered mechanical forces that promote compartmental disease in OA lead to BML, JSN and osteophyte formation. Whether BML further contribute to cartilage loss, and are therefore targets of therapeutic intervention, remains to be determined
Musculoskeletal ultrasound as a diagnostic and prognostic tool in rheumatoid arthritis
The use of musculoskeletal ultrasound (MSKUS) has increased in a variety of rheumatic conditions, particularly rheumatoid arthritis (RA). MSKUS complements the physical examination by allowing for superior visualization of synovitis and erosive changes compared to conventional radiography and provides detail comparable or supplementary to magnetic resonance imaging (MRI). This modality is also less expensive than MRI and CT scans, without claustrophobia or other contraindications, while uniquely providing dynamic, rather than static imaging. A growing body of literature for MSKUS in RA is contributing significantly to the understanding of diagnostic and prognostic utility, longitudinal assessment, and disease remission. Furthermore, scoring systems focusing on the patient level rather than individual joints have been developed, allowing for simplification of exams while still retaining accuracy and utility. The combination of these advances has led to increased use of MSKUS in RA in the realm of research as well as at the bedside and in the clinic
INFLAMMATORY GENOMIC AND PLASMA BIOMARKERS PREDICT PROGRESSION OF SYMPTOMATIC KNEE OA (SKOA)
Heightened Aortic Wall Inflammation in Patients with Rheumatoid Arthritis Versus Patients with Established Coronary Artery Disease without Autoimmune Disease
Rilonacept (IL-1 TRAP) for treatment of colchicine resistant familial mediterranean fever (FMF): A randomized, multicenter double-blinded, alternating treatment trial
Background: There is no current treatment alternative for patients with FMF whose disease is resistant to, or do not tolerate colchicine. Since pyrin has an important role in IL-1beta regulation we hypothesize that IL-1 inhibition will decrease the number of FMF attacks in these patients. Aim: To determine if rilonacept, a fusion protein that binds and neutralizes IL-1, decreases the number of FMF attacks compared to placebo. Methods: Subjects were FMF patients >=4 years of age recruited at 6 U.S. sites, who had at least 1 FMF attack per month despite receiving adequate doses of, or who were intolerant of colchicine. Subjects received two 3-month courses of rilonacept (Arm A) at 2.2 mg/kg (max 160 mg) by weekly SC injection and two 3-month courses of placebo (Arm B). Patients were randomized to 1 of 4 treatment sequences (ABAB, BABA, ABBA, BAAB). Escape visits were allowed to permit switching arms (blinding was maintained) for patients with at least 2 attacks within a course. The primary outcome was the difference of FMF attacks between rilonacept and placebo courses with responders defined as subjects with a >40% difference. Results were analyzed by paired t-and signed rank tests. Results: Fourteen subjects were randomized, 8 males and 6 females, mean (+/-SD) age 24.4+/-11.8 years (range 4.5-47.3; 4 patients <18 years), disease duration 17.5+/-12.6 yrs, with a baseline of 3.1+/-2.0 attacks per month. Eleven completed the full study and 3 dropped out (1 due to lack of efficacy, 1 due to distance from study site and 1 lost to follow-up). Among 12 patients who completed at least 2 treatment courses the mean number of attacks per month on rilonacept was 1.0+/-1.2 vs. 1.8+/-0.9 on placebo (P=0.021 by paired t-test and 0.027 by signed rank test). There were 8 responders; all 4 non-responders were adults. There were 2 respiratory infection SAEs, 1 on rilonacept and 1 on placebo. Injections site reactions were significantly more frequent with rilonacept but no differences were seen in other adverse events, including infections. Conclusions: Rilonacept significantly reduced the number of FMF attacks and had an acceptable safety profile. IL-1 inhibition is a treatment option for most (especially children) colchicine resistant FMF patients
Underdiagnosis and Undertreatment Of Knee Osteoarthritis In The Obese Population: The Need For Physician Education and Advocacy
Interleukin-1 Receptor Antagonist (IL-1Ra) Plasma Levels Predict Radiographic Progression Of Symptomatic Knee Osteoarthritis Over 24 Months
Elevated Expression of Inflammatory Mediators Cyclooxygenase-2, Its Product Prostaglandin E2 and Interleukin-1 Beta by Peripheral Blood Leukocytes in Symptomatic Knee Osteoarthritis
Pain scores are the primary explanatory variable for higher global estimates by patients compared to doctors in patients with all rheumatic diseases
Background Estimates of global status by doctors (DOCGL) and patients (PATGL) are discordant in about 30-40% of patients with rheumatoid arthritis (RA).1,2 This discordance has been analyzed to date only in RA patients. Objectives To analyze levels of discordance between DOCGL and PATGL in all patients with any diagnosis seen in usual clinical care at a rheumatology setting. Methods Each patient seen at an academic rheumatology clinical setting since 2005 completes a self-report MDHAQ (multidimensional health assessment questionnaire) at each visit, with scales for physical function, pain, PATGL, fatigue, anxiety, depression and quality of sleep, and demographic data. DOCGL was completed by 2 rheumatologists. One random visit of patients seen between 2005 and 2011 was analyzed, patients were classified as PATGL=DOCGL (PATGL and DOCGL within 2 of 10 units), PATGL>DOCGL (PATGL >2 units than DOCGL), and DOCGL>PATGL (DOCGL >2 units than PATGL). Univariate odds ratios were computed to identify variables associated with discordance. Significant variables (p<0.05) were included in multivariate models, with selected variables when indicated. Results In a total of 980 patients studied, 509 (52%) had PATGL=DOCGL, 371 (38%) PATGL>DOCGL, and 100 (10%) DOCGL>PATGL. Patients with PATGL>DOCGL were more likely to be female, have less formal education and have higher MDHAQ scores (Table). In multivariate analysis, higher pain and fatigue scores were independent predictors of PATGL>DOCGL. If MDHAQ scores for pain and fatigue were not included in a second model, female gender, lower education and higher scores for depression and sleep problems were independent predictors of PATGL>DOCGL. In patients with DOCGL>PATGL, only lower fatigue was associated in multivariate analysis with lower odds of discordance (OR=0.88, 95% CI 0.79-0.98). Conclusions 38% of patients estimated their statusas worse than their physicians. These patients were more likely to score higher for pain and fatigue, be female and less educated tha!
ESTABLISHING A KNEE PRESERVATION REGISTRY TO FOLLOW PATIENTS WITH DEGENERATIVE JOINT DISEASE
COMPARISON OF KNEE OSTEOARTHRITIS TREATMENT IN THE NON-OBESE VS OBESE POPULATIONS ACROSS DIFFERENT MEDICAL SPECIALTIES
BMI, AGE, RADIOGRAPHIC SEVERITY AND ULTRASOUND GUIDANCE IMPACT THE RESPONSE TO HYALURONIC ACID INJECTIONS IN KNEE OSTEOARTHRITIS
Reduction of knee osteoarthritis symptoms in a cohort of bariatric surgery patients
Purpose: Obesity is a modifiable risk factor of knee osteoarthritis (KOA). While diet, exercise and other conservative treatments can have limited and often transient beneficial effects, an alternative strategy would target weight loss via surgery to delay or avoid joint replacement. Some retrospective data, including a study from our group, have in fact shown sustained improvement in KOA pain after bariatric surgery. We initiated a prospective study to evaluate painful KOA in the obese population, and track whether weight loss after bariatric surgery affects KOA-related pain and physical function. Methods: We screened consecutive patients prior to laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy, or gastric bypass (RYGB), at NYU Langone Medical Center and Bellevue Hospital Center. Patients age >21 with knee pain for >1 month and a visual analog scale pain score >30mm were enrolled, excluding those with lupus, rheumatoid arthritis, psoriatic arthritis, or psoriasis. Baseline pre-op assessments included x-rays for OA severity by Kellgren-Lawrence (KL) grade, the Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) with a Likert scale calculated from the KOOS. Patients were consented for optional tissue collection (blood, urine and intra-operative adipose samples) for future biomarker analysis. They are (still) completing the questionnaires and being measured for BMI and % excess weight loss (%EWL) at 1,3,6 and 12 month post-op intervals. Results: In total, we screened 537 patients planning to have bariatric surgery, found that 309 (58%) of them reported knee pain - and enrolled 176who met criteria and consented for the study. Our cohort is 89.7% female, with a mean BMI of 43.6 kg/m2+/-7 (31.6-60.6), a mean age of 42.4 +/-11 (18-73), and radiographic severity as follows: KL0=43 (25%), KL1=34 (19%), KL2=38 (22%), KL3=34 (19%), KL4=27 (15%). The mean pre-op KOOS scores were 45.4 for pain and 46.0 for ADL (0=worst, 100=best), the mean pre-op WOMAC pain score (Likert scale) was 11 (0=best, 20=worst), and the mean overall WOMAC index was 52 (0=best, 96=worst). Before surgery, a higher KL correlated with symptoms; mean KOOS pain was 53.2, 48.1 and 36.7 for KL0, KL1-2, and KL3-4 (p=0.00002 for KL0 vs KL3-4, and p=0.0005 for KL1-2 vs KL3-4), with similar trends across other KOOS and WOMAC scores. Higher BMI also trended with worse pre-op knee symptoms, as the tertiles with the lowest and highest BMIs (31-39 and 46-61) had mean KOOS pain scores of 46.8 and 43.7 (p=0.37). While 23 ultimately decided against weight loss surgery, we are collecting post-operative data on the 153 patients (40 RYGB=26%, 93 sleeve=61%, 20 LAGB=13%). Improvement in average KOOS and WOMAC scores over baseline has been observed at all intervals (67, 71, 65, and 42 responses at 1,3,6,12 month visits), with more improvement farther after surgery. At 6 months post-op, mean KOOS scores available thus far improved 29 points for pain, with mean WOMAC pain and index improving by 6 and 22 points. The %EWL correlated with knee symptoms at each interval and for all followups combined, as the smallest and largest %EWL quartiles (4-29%, 54-92%) showed mean improvements of 18 and 31 points (p=0.03) in KOOS pain - mirrored across KOOS and WOMAC scores. RYGB and sleeve yielded higher %EWL than LAGB (44%, 43% vs. 37%) across all intervals, and greater improvement in mean KOOS and WOMAC scores (e.g. mean KOOS pain increased by 28, 29 and 8). Neither presence nor severity of KOA severity affected knee pain improvement from weight loss. Conclusions: These data suggest that bariatric surgery improves patients' KOA pain proportional to percent excess weight loss, with durability over time. RYGB and sleeve gastrectomy have more impact on knee symptoms than LAGB. While patients with worse KL grades report more baseline pain and disability, as expected, x-ray severity did not impact the response to surgical weight loss
Elevated peripheral blood leukocyte inflammatory gene expression in radiographic progressors with symptomatic knee osteoarthritis: NYU and OAI cohorts
Purpose: We and others have demonstrated low grade inflammation exists in OA joint tissues, where it may contribute to disease pathogenesis. In the current studies we assessed whether inflammatory events occurring within joint tissues were reported in the peripheral blood leukocytes (PBLs) of patients with symptomatic knee OA (SKOA). Methods: PBL inflammatory gene expression (IL-1, TNFalpha, COX-2) was assessed in two independent cohorts of patients with SKOA, and a cohort of healthy control subjects: 1) 111 patients with tibiofemoral medial OA and 21 healthy volunteers from the NYUHJD Cohort, and 2) 200 patients from the OAI progression cohort who had "high quality radiographs", at both baseline and 24 months, and had KL2 or 3 in the signal knee at baseline. Radiographic progression was defined as narrowing of medial joint space width (JSW) in the signal knee between baseline and 24-months in each cohort. Radiographic progressors were defined as subjects who had JSN >0.0, 0.2 and 0.5mm over 24 months. For measuring predictive performance, we used the area under the curve (AUC) of a receiver operating characteristics (ROC). OAI SKOA subjects were dichotomized as radiographic non-progressors (JSN <0.0 mm) and progressors (JSN>0.0mm) for association studies. Results: Elevated PBL expression of IL-1, TNFalpha or COX-2 identified SKOA patients who were "fast progressors" (mean JSN 0= 0.71, 0.75 and 0.71 mm / 24 months, respectively) compared to patients with levels below the median. In a multivariable model, anthropometric traits alone (BMI, gender, age) did not predict progression, whereas addition of PBL gene expressions improved prediction of fast progressors (JSN>0.5mm). We next examined inflammatory gene expression in PBLs of radiographic progressors in the OAI cohort. Similar to the NYUHJD cohort, elevated expression of IL-1beta, TNFalpha and COX-2 mRNA distinguished radiographic progressors from non-progressors (Table 1). PBL IL-1beta expression found to be strongest predictor of all three radiographic progressors. In multivariate models that combine all three markers did not improve upon IL-1beta predictivity. We thus conclude that either the signal in TNFalpha and Cox-2 is already subsumed by IL-1beta and/or that it is not easy to capture the non-overlapping signals without increasing the sample size (i.e., fitting a stronger multivariate predictor will require more sample size). Conclusions: We identified, and confirmed in two cohorts, increased inflammatory gene expression (IL-1, TNFalpha or COX-2) by PBLs that predict radiographic progression in patients with SKOA. The data indicate that inflammatory events within joint tissues of patients with SKOA are reported in the peripheral blood. These PBL transcriptome signals of local joint inflammation merit further study as potential biomarkers for OA disease progression. (Table Presented)
Musculoskeletal Ultrasound Education Among Rheumatology Fellowship Programs in the United States
Reduction of Treatment Needed for Knee Osteoarthritis after Bariatric Surgery
Association Between Serum Urate and Osteoarthritis Progression in a Non-Obese Cohort
Comparison of Knee Osteoarthritis Treatment in the Non-Obese Versus Obese Populations Across Different Medical Specialties
Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population
Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. The FMF gene (MEFV) was cloned recently, and four missense mutations were identified. Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not originally found mutations and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) is located in exon 3. Consistent with another recent report, the E148Q mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicate reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helps account for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF. The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region
Enhanced COMP catabolism detected in serum of patients with arthritis and animal disease models through a novel capture ELISA
OBJECTIVE: The study aimed determining whether assessment of cartilage oligomeric matrix protein (COMP) degradation products could serve as a serological disease course and therapeutic response predictor in arthritis. METHODS: We generated a panel of monoclonal antibodies against COMP fragments and developed a novel capture enzyme-linked immunosorbent assay (ELISA) for detecting COMP fragments in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). This test was also used to monitor COMP fragments in surgically-induced OA, collagen-induced arthritis (CIA), and tumor necrosis factor (TNF) transgenic animal models. RESULTS: Compared with a commercial COMP ELISA kit that detected no significant difference in COMP levels between OA and control groups, a significant increase of the COMP fragments were noted in the serum of OA patients assayed by this newly established ELISA. In addition, serum COMP fragment levels were well correlated with severity in OA patients and the progression of surgically-induced OA in murine models. Furthermore, the serum levels of COMP fragments in RA patients, mice with CIA, and TNF transgenic mice were significantly higher when compared with their controls. Interestingly, treatment with TNFalpha inhibitors and methotrexate led to a significant decrease of serum COMP fragments in RA patients. Additionally, administration of Atsttrin [Tang, et al., Science 2011;332(6028):478] also resulted in a significant reduction in COMP fragments in arthritis mice models. CONCLUSION: A novel sandwich ELISA is capable of reproducibly measuring serum COMP fragments in both arthritic patients and rodent arthritis models. This test also provides a valuable means to utilize serum COMP fragments for monitoring the effects of interventions in arthritis.
Quantitative magnetic resonance imaging evidence of synovial proliferation is associated with radiographic severity of knee osteoarthritis
OBJECTIVE: To evaluate the relationships between both quantitative and semiquantitative assessments of the degree of knee synovitis on 3T magnetic resonance imaging (MRI) and the severity of knee osteoarthritis (OA) on radiography. METHODS: Fifty-eight patients with knee OA underwent nonfluoroscopic fixed-flexion knee radiography. In addition, dynamic contrast-enhanced 3T MRI of the knees was performed, before and after gadolinium administration, to quantify synovial membrane volume (SV) as a measure of synovial proliferation (expressed as the quantitative SV), and semiquantitative measures of synovitis were also applied using both contrast-enhanced and unenhanced images. Two radiologists scored the knee radiographs using the Osteoarthritis Research Society International atlas; interreader agreement was assessed using kappa statistics and concordance correlation coefficients. Multiple linear and logistic regression analyses were used to assess associations among variables, while controlling for the effects of age, body mass index, sex, and meniscal extrusion. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for measures of disease activity. RESULTS: The Kellgren/Lawrence (K/L) grade of radiographic knee OA severity (beta = 0.78), the diseased compartment joint space width (dcJSW) (beta = -0.22), and the diseased compartment joint space narrowing (dcJSN) score (beta = 0.53) were each significantly associated with the quantitative SV (P = 0.0001, P = 0.0003, and P = 0.0001, respectively). Furthermore, the quantitative SV strongly correlated with the total volume of subchondral bone marrow lesions (BMLs) (beta = 0.22, P = 0.0003). The K/L grade, dcJSW, and dcJSN score were each significantly associated with the semiquantitative Boston Leeds Osteoarthritis Knee Score (BLOKS) for the extent of infrapatellar synovitis (OR 9.05 [95% CI 1.94, 42.3] for K/L grade; OR 0.75 [95% CI 0.54, 1.03] for dcJSW; and OR 2.22 [95% CI 1.15, 4.31] for dcJSN score) and extent of joint effusion (OR 5.75 [95% CI 1.23, 26.8] for K/L grade; OR 0.70 [95% CI 0.50, 0.98] for dcJSW; and OR 1.96 [95% CI 1.02, 3.74] for dcJSN score). In addition, the semiquantitative synovitis grade on contrast-enhanced MRI was significantly associated with the K/L grade (beta = 0.036, P = 0.0040) and dcJSN score (beta = 0.015, P = 0.0266), and also significantly associated with the BLOKS synovitis score. CONCLUSION: Synovitis is a characteristic feature of advancing knee OA and is significantly associated with the K/L grade, JSW, JSN score, and total volume of BMLs on radiographs. Furthermore, BLOKS scoring of synovitis on unenhanced MRI is associated with measurements of synovitis on contrast-enhanced MRI
Newer therapeutic approaches to the vasculitides: biologic agents
Biologic therapies have emerged as important treatments in chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, and are now garnering more attention in the vasculitides. These agents, including tumor necrosis factor-alpha inhibitors, B-cell-depleting agents, interferon-alpha, and some antiviral treatments, target specific components of the immune system and may have lower side effect risk profiles than the conventional immunosuppressives and cytotoxic agents. This article addresses the encouraging data and the possible pitfalls of these new therapeutic options, thus far evaluated mostly by case reports, small series, and open-label trials. Confirming the efficacy of existing and newer therapies will require further clinical investigation through randomized placebo-controlled studies to identify the proper doses and treatment schedules and single out those drugs that may expose patients to dangers that outweigh the potential benefits.
Familial Mediterranean fever and the other autoinflammatory syndromes: evaluation of the patient with recurrent fever
PURPOSE OF REVIEW: The aim of this article is to summarize recent clinical, genetic and pathophysiologic findings of familial Mediterranean fever and several of the other systemic autoinflammatory diseases, a recently recognized group of disorders characterized by seemingly unprovoked inflammation but lacking high-titer autoantibodies. Genetic and clinical tools are improving the ability of the clinician to better approach patients with periodic fever and inflammation. RECENT FINDINGS: The spectrum of reported genetic mutations and susceptible ethnicities for the hereditary periodic fever subset of the autoinflammatory diseases has continued to expand. At the same time, the pathogeneses of many of these diseases are now understood to involve different aspects of a common pathway, largely affecting inflammatory cascades related to IL-1 or tumor necrosis factor-alpha. Three of these diseases which have been grouped as the cryopyrin-associated periodic syndromes result from defects in the same gene, and all three appear to respond well to anti-IL-1 therapy although controlled trials are still in progress. In addition, cytokine-based therapies are also now under investigation for hyperimmunoglobulinemia D with periodic fever syndrome and pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome. SUMMARY: The identification of the genes and proteins mutated in many of the autoinflammatory diseases has broadened our understanding of the regulation of inflammation and the immune system, and provided the basis for the use of targeted therapies in these syndromes. We propose an algorithm for the evaluation of a patient with periodic fever, taking into account the patient's age, ethnicity, symptoms and signs, and results from laboratory and genetic testing.
Human B cell tolerance and its failure in rheumatoid arthritis
Random V(D)J gene assembly generates many autoreactive B cell receptors (BCRs). In healthy donors, most autoreactive developing B cells are removed either in the bone marrow or in the periphery, revealing two B cell tolerance checkpoints. The regulation and the mechanisms that ensure this human B cell tolerance are poorly characterized, but they require proper BCR signaling. Indeed, patients with X-linked agammaglobulinemia who carry mutations in the BTK gene, which encodes an essential BCR signaling component, fail to establish proper central B cell tolerance, as demonstrated by the release of self-reactive B cells in the periphery. In autoimmune diseases such as rheumatoid arthritis (RA), B cell tolerance is broken and autoantibodies are secreted. Our recent results show that RA patients suffer from defective central and peripheral B cell tolerance checkpoints, which may favor the development of autoimmunity. Also, about half of our RA patients display unusual immunoglobulin light chain repertoires showing impaired secondary recombination regulation, which indicates that receptor editing, one of the mechanisms that normally ensures B cell tolerance, may often be defective in RA.
Impaired early B cell tolerance in patients with rheumatoid arthritis
Autoantibody production is a characteristic of most autoimmune diseases including rheumatoid arthritis (RA). The role of these autoantibodies in the pathogenesis of RA remains elusive, but they appear in the serum many years before the onset of clinical disease suggesting an early break in B cell tolerance. The stage of B cell development at which B cell tolerance is broken in RA remains unknown. We previously established in healthy donors that most polyreactive developing B cells are silenced in the bone marrow, and additional autoreactive B cells are removed in the periphery. B cell tolerance in untreated active RA patients was analyzed by testing the specificity of recombinant antibodies cloned from single B cells. We find that autoreactive B cells fail to be removed in all six RA patients and represent 35-52% of the mature naive B cell compartment compared with 20% in healthy donors. In some patients, RA B cells express an increased proportion of polyreactive antibodies that can recognize immunoglobulins and cyclic citrullinated peptides, suggesting early defects in central B cell tolerance. Thus, RA patients exhibit defective B cell tolerance checkpoints that may favor the development of autoimmunity.
Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 25-1999. A 16-year-old boy with recurrent abdominal pain
Current concepts in the pathogenesis of osteoarthritis
Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health
Regarded as the most common and best understood of the hereditary periodic fever syndromes, familial Mediterranean fever (FMF) is a recessively inherited disease of episodic fever with some combination of severe abdominal pain, pleurisy, arthritis, and a characteristic ankle rash. The flares typically last for up to 3 days at a time, and most patients are completely asymptomatic between attacks; if untreated with prophylactic colchicine, some patients later develop amyloidosis and renal failure. The recent cloning of the FMF gene on the short arm of chromosome 16p, and the subsequent finding that its tissue expression is limited to granulocytes, has helped to explain the dramatic accumulation of neutrophils at the symptomatic serosal sites; the wild-type gene likely acts as an upregulator of an anti-inflammatory molecule or as a downregulator of a pro-inflammatory molecule. For nearly half a century, FMF was thought to cluster primarily in non-Ashkenazi Jews, Arabs, Armenians, and Turks, although the screening of the 8 known mutations in an American cohort has identified substantial numbers of people from the Ashkenazi Jewish and Italian populations in the United States who also have this disease. Nevertheless, the symptoms often go unrecognized and patients remain undiagnosed for years, not receiving the highly efficacious colchicine therapy; their histories often include multiple laparotomies, laparoscopies, and psychiatric evaluations. The combinations of clinical manifestations among FMF patients are quite heterogeneous, but our American cohort did not establish any connections between individual mutations and specific clinical pictures--as is seen in other diseases like cystic fibrosis, in which distinct genotypes target certain organ systems. Specifically, the data from our American series are insufficient to evaluate the hypothesis that the M694V/M694V genotype confers a more severe phenotype, or increases the risk of amyloidosis; but both our data and the recent literature (160) indicate that amyloidosis can occur in FMF patients with only 1 copy, or no copies, of the M694V mutation. It appears that specific MEFV mutations are probably not the sole determinants of phenotype, and that unknown environmental factors or modifying genes act as accomplices in this disease. Although we hope the discovery of the FMF gene will allow the diagnosis of FMF to become genetically accurate, the reality is that both clinical and genetic tools must still be used together unless mutations are identified on both of a patient's chromosomes. Physicians should be careful not to rule out the diagnosis in patients of high-risk ethnic backgrounds just because of atypical clinical features, as our data indicate that MEFV mutations are sometimes demonstrable in such patients. At the same time, physicians cannot yet rely solely on a genetic diagnosis because we have not yet identified a sufficient spectrum of mutations, and it is not currently feasible to examine every patient's full DNA sequence for the entire gene; screening an ethnically consistent and clinically positive patient for the 8 known mutations frequently identifies a mutation on only 1 chromosome, and genetic analysis of other classic cases will often reveal none of the 8 mutations. Still, our data suggest that ethnic background is an important predictor of finding 1 of the presently known mutations, and the knowledge of ancestries atypical for FMF can suggest the diagnosis of other hereditary periodic fever syndromes. As the list of FMF-associated MEFV mutations is expanded, and/or new sequencing technologies permit more rapid screening, the value and interpretation of genetic testing for FMF will become more straightforward. Moreover, as the pathophysiology of this disorder becomes less of a hypothesis and more of an understood entity, it is likely that treatment options will broaden beyond the use of daily prophylactic colchicine. (ABSTRACT TRUNCATED)
Increased interleukin-1beta gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis
OBJECTIVE: To evaluate whether gene expression profiles could serve as biomarkers of symptomatic knee osteoarthritis (OA) by examining gene expression profiles in peripheral blood leukocytes (PBLs) from patients with OA compared with those from non-OA controls, and to determine whether candidate genomic biomarkers (PBL expression of inflammatory genes) predict an increased risk of disease progression in patients with symptomatic radiographic knee OA. METHODS: Three independent cohorts of patients with knee OA and non-OA control subjects were studied. Two cohorts (a learning cohort and a validation cohort) were recruited at New York University Hospital for Joint Diseases (NYUHJD), and 1 cohort (a validation cohort) was recruited at Duke University Medical Center. PBL gene expression was assessed using Affymetrix microarray and was confirmed by quantitative polymerase chain reaction (qPCR). Radiographic progression at 2 years was assessed in 86 patients. RESULTS: We identified 173 genes that were significantly up-regulated or down-regulated (>/=1.5-fold change) in OA PBLs, at a false discovery rate of 5%. Cluster analysis revealed 2 distinct subgroups among the patients with OA: those in whom the expression of interleukin-1beta (IL-1beta) was increased >/=2-fold compared with controls, and those in whom the expression of IL-1beta was comparable with that in controls. Overexpression of IL-1beta in these OA subclasses was validated using qPCR in all 3 cohorts. Patients with the inflammatory 'IL-1beta signature' had higher pain scores and decreased function and were at higher risk of radiographic progression of OA. CONCLUSION: PBLs from patients with symptomatic knee OA display a characteristic transcriptome profile. Moreover, increased expression of IL-1beta identifies a subset of patients with OA who have increased pain and are at higher risk of radiographic progression of OA
Targeting the synovial tissue for treating osteoarthritis (OA): where is the evidence?
Osteoarthritis (OA) is often a progressive and disabling disease, which occurs in the setting of a variety of risk factors--such as advancing age, obesity and trauma--that collude to incite a cascade of pathophysiological events within joint tissues. An important emerging theme in OA is a broadening of focus from a disease of cartilage to one of the 'whole joint.' The synovium, bone and cartilage are each involved in pathological processes that lead to progressive joint degeneration. Additional themes that have emerged over the past decade are novel mechanisms of cartilage degradation and repair, the relationship between biomechanics and biochemical pathways, the importance of inflammation and the role of genetics. In this article, we review the molecular, clinical and imaging evidence that synovitis is not an 'incidental finding of OA', but plays a significant role in disease pathogenesis, and could therefore represent a target for future treatments
Radiographic severity of knee osteoarthritis is conditional on interleukin 1 receptor antagonist gene variations
BACKGROUND: A lack of biomarkers that identify patients at risk for severe osteoarthritis (OA) complicates development of disease-modifying OA drugs. OBJECTIVE: To determine whether inflammatory genetic markers could stratify patients with knee OA into high and low risk for destructive disease. METHODS: Genotype associations with knee OA severity were assessed in two Caucasian populations. Fifteen single nucleotide polymorphisms (SNPs) in six inflammatory genes were evaluated for association with radiographic severity and with synovial fluid mediators in a subset of the patients. RESULTS: Interleukin 1 receptor antagonist (IL1RN) SNPs (rs419598, rs315952 and rs9005) predicted Kellgren-Lawrence scores independently in each population. One IL1RN haplotype was associated with lower odds of radiographic severity (OR=0.15; 95% CI 0.065 to 0.349; p<0.0001), greater joint space width and lower synovial fluid cytokine levels. Carriage of the IL1RN haplotype influenced the age relationship with severity. CONCLUSION: IL1RN polymorphisms reproducibly contribute to disease severity in knee OA and may be useful biomarkers for patient selection in disease-modifying OA drug trials
Large-scale meta-analysis of interleukin-1 beta and interleukin-1 receptor antagonist polymorphisms on risk of radiographic hip and knee osteoarthritis and severity of knee osteoarthritis
OBJECTIVE: To clarify the role of common genetic variation in the Interleukin-1beta (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. METHODS: We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. RESULTS: The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P>0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR)=0.71 95%CI 0.56-0.91; P=0.006, I(2)=74%), and achieved borderline statistical significance in a random-effects model (OR=0.61 95%CI 0.35-1.06 P=0.08). CONCLUSION: Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA
Polyarticular gout attacks following cerebrovascular accidents: is hemiparesis in fact protective? 2 cases and a review of the literature
Cerebrovascular disease appears to have implications on rheumatic diseases, including gout. Accumulating evidence suggests that hemiparesis exerts a protective effect against gout via the down-regulation of mechanical and neural modulators of inflammation in neurologically impaired extremities. We present 2 divergent cases of unilateral gout following cerebrovascular events. One patient with a hemorrhagic stroke developed polyarticular gout only on the ipsilateral side to his hemiparesis, while another patient with basilar artery thrombosis and locked-in syndrome suffered a polyarticular gout flare only on the side that had regained limited function. As suggested by these cases, the effect of hemiparesis on gout is complex. Further insight into the interplay between gouty flares and hemiparesis may lead to novel therapeutic strategies for gout
End-stage hemophilic arthropathy in a patient from a developing nation
Inflammation-independent defective early B cell tolerance checkpoints in rheumatoid arthritis
OBJECTIVE: Rheumatoid arthritis (RA) patients who have never received treatment for RA have been found to have defective early B cell tolerance checkpoints, resulting in impaired removal of developing autoreactive B cells. However, it is unclear whether these defects in B cell tolerance checkpoints are a primary aspect of the disease or are the result of ongoing inflammatory processes in these patients. The aim of this study was to assess the impact of standard immunosuppressive treatments, methotrexate and anti-tumor necrosis factor alpha (anti-TNFalpha) agents, on early B cell tolerance checkpoints in RA patients. METHODS: Blood samples were obtained from RA patients before and after treatment with methotrexate and/or anti-TNFalpha agents. B cells were tested pre- and posttherapy for reactivity of recombinant antibodies cloned from single B cells, which allowed us to determine the evolution of the frequency of autoreactive clones in the mature naive B cell compartment in RA patients before and after treatment. B cells from healthy donors were used as controls. RESULTS: Posttreatment frequencies of autoreactive mature naive B cells were elevated in the blood of RA patients. Nevertheless, the frequencies after treatment remained similar to those observed in the same patients before treatment. CONCLUSION: Despite the achievement of clinical improvement in RA patients following treatment with methotrexate and/or anti-TNFalpha agents, these therapies did not correct the accumulation of peripheral autoreactive mature naive B cells in these patients, suggesting that inflammation is not responsible for the defective early B cell tolerance checkpoints in RA
Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: Concordance between readers
OBJECTIVE: Criteria for sonographic diagnosis of monosodium urate (MSU) crystal deposition have been developed, but the interreader reproducibility of this modality is not well established. We therefore assessed agreement using a systematic approach. METHODS: Fifty male subjects ages 55-85 years were recruited during primary care visits to an urban Veterans Affairs hospital, and were assessed by musculoskeletal ultrasound (US) of the knees and first metatarsophalangeal (MTP) joints to evaluate for the double contour sign and tophi as evidence of MSU crystal deposition. Images were read by 2 blinded rheumatologists trained in musculoskeletal US, and the degree of concordance was determined for individual subjects, total joints, femoral articular cartilage (FAC), and first MTP joints. Subjects were further categorized into 3 diagnostic groups: gout, asymptomatic hyperuricemia (no gout, serum uric acid [UA] >/=6.9 mg/dl), and controls (no gout, serum UA </=6.8 mg/dl), and reader concordance within these 3 groups was assessed. RESULTS: We observed almost perfect agreement between readers for 1) individual subjects (yes/no; n = 50, 100% agreement, kappa = 1.000), 2) total joints (n = 200, 99% agreement, kappa = 0.942), 3) FAC (n = 100, 99% agreement, kappa = 0.942), and 4) first MTP joints (n = 100, 99% agreement, kappa = 0.942). Furthermore, findings by side (right/left) and diagnostic group (gout, asymptomatic hyperuricemia, control) showed substantial to almost perfect concordance for all measures. MSU deposition was seen most commonly in gout patients, and deposition was also seen in some subjects with asymptomatic hyperuricemia, but in only 1 control. CONCLUSION: Musculoskeletal US is reliable for detecting MSU deposition in FAC and first MTP joints in gout and asymptomatic hyperuricemia
Can cartilage loss be detected in knee osteoarthritis (OA) patients with 3-6 months' observation using advanced image analysis of 3T MRI?
PURPOSE: Prior investigations of magnetic resonance imaging (MRI) biomarkers of cartilage loss in knee osteoarthritis (OA) suggest that trials of interventions which affect this biomarker with adequate statistical power would require large clinical studies of 1-2 years duration. We hypothesized that smaller, shorter duration, 'Proof of Concept' (PoC) studies might be achievable by: (1) selecting a population at high risk of rapid medial tibio-femoral (TF) progression, in conjunction with; (2) high-field MRI (3T), and; (3) using advanced image analysis. The primary outcome was the cartilage thickness in the central medial femur. METHODS: Multi-centre, non-randomized, observational cohort study at four sites in the US. Eligible participants were females with knee pain, a body mass index (BMI)> or =25 kg/m(2), symptomatic radiographic evidence of medial TF OA, and varus mal-alignment. The 29 participants had a mean age of 62 years, mean BMI of 36 kg/m(2), with eight index knees graded as Kellgren-Lawrence (K&L)=2 and 21 as K&L=3. Eligible participants had four MRI scans of one knee: two MRIs (1 week apart) were acquired as a baseline with follow-up MRI at 3 and 6 months. A trained operator, blind to time-point but not subject, manually segmented the cartilage from the Dual Echo Steady State water excitation MR images. Anatomically corresponding regions of interest were identified on each image by using a three-dimensional statistical shape model of the endosteal bone surface, and the cartilage thickness (with areas denuded of cartilage included as having zero thickness - ThCtAB) within each region was calculated. The percentage change from baseline at 3 and 6 months was assessed using a log-scale analysis of variance (ANOVA) model including baseline as a covariate. The primary outcome was the change in cartilage thickness within the aspect of central medial femoral condyle exposed within the meniscal window (w) during articulation, neglecting cartilage edges [nuclear (n)] (nwcMF x ThCtAB), with changes in other regions considered as secondary endpoints. RESULTS: Anatomical mal-alignment ranged from -1.9 degrees to 6.3 degrees , with mean 0.9 degrees . With one exception, no changes in ThCtAB were detected at the 5% level for any of the regions of interest on the TF joint at 3 or 6 months of follow-up. The change in the primary variable (nwcMF x ThCtAB) from (mean) baseline at 3 months from the log-scale ANOVA model was -2.1% [95% confidence interval (CI) (-4.4%, +0.2%)]. The change over 6 months was 0.0% [95% CI (-2.7%, +2.8%)]. The 95% CI for the change from baseline did not include zero for the cartilage thickness within the meniscal window of the lateral tibia (wLT x ThCtAB) at 6 month follow-up (-1.5%, 95% CI [-2.9, -0.2]), but was not significant at the 5% level after correction for multiple comparisons. CONCLUSIONS: The small inconsistent compartment changes, and the relatively high variabilities in cartilage thickness changes seen over time in this study, provide no additional confidence for a 3- or 6-month PoC study using a patient population selected on the basis of risk for rapid progression with the MRI acquisition and analyses employed
Musculoskeletal ultrasound prompts a rare diagnosis of Mycobacterium marinum infection
Rilonacept for colchicine-resistant or -intolerant familial mediterranean Fever: a randomized trial
Chinese translation BACKGROUND: Currently, there is no proven alternative therapy for patients with familial Mediterranean fever (FMF) that is resistant to or intolerant of colchicine. Interleukin-1 is a key proinflammatory cytokine in FMF. OBJECTIVE: To assess the efficacy and safety of rilonacept, an interleukin-1 decoy receptor, in treating patients with colchicine-resistant or -intolerant FMF. DESIGN: Randomized, double-blind, single-participant alternating treatment study. (ClinicalTrials.gov number: NCT00582907). SETTING: 6 U.S. sites. PATIENTS: Patients with FMF aged 4 years or older with 1 or more attacks per month. INTERVENTION: One of 4 treatment sequences that each included two 3-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two 3-month courses of placebo. MEASUREMENTS: Differences in the frequency of FMF attacks and adverse events between rilonacept and placebo. RESULTS: 8 males and 6 females with a mean age of 24.4 years (SD, 11.8) were randomly assigned. Among 12 participants who completed 2 or more treatment courses, the rilonacept-placebo attack risk ratio was 0.59 (SD, 0.12) (equal-tail 95% credible interval, 0.39 to 0.85). The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, -1.74 [95% CI, -3.4 to -0.1]; P = 0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; P = 0.004) and with a decrease in attacks of greater than 50% compared with the baseline rate during screening (75% vs. 35%; P = 0.006) than with placebo. However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days [-0.5 and 2.4 days in the first and third quartiles, respectively]; P = 0.32). Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month [medians of -4 and 0 in the first and third quartiles, respectively]; P = 0.047), but no differences were seen in other adverse events. LIMITATION: Small sample size, heterogeneity of FMF mutations, age, and participant indication (colchicine resistance or intolerance) were study limitations. CONCLUSION: Rilonacept reduces the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration, Office of Orphan Products Development.
Relation between cartilage volume and meniscal contact in medial osteoarthritis of the knee
BACKGROUND: The purpose was to determine the relationship between the cartilage volumes in different regions of the femur and tibia, and the lengths of contacts between the meniscus and cartilage. The rationale was that less meniscal contact would make the cartilage more susceptible to loss of volume due to degeneration and wear. METHODS: Fifty MRI scans of osteoarthritic knees at varying degrees of severity were obtained. Computer models of the cartilage layers of the distal femur and proximal tibia were generated, from which cartilage volumes and thicknesses were calculated for different regions. The lengths of meniscal contact and heights were measured in frontal and sagittal views. RESULTS: Cartilage loss progressed initially on the central and inner regions of the distal femur, and on the tibia in the region uncovered by the meniscus. As the cartilage volume decreased further, the wear spread medially, and to a lesser extent anteriorly and posteriorly. There were inverse relations between the loss of volume on both the femur and tibia, and the meniscal contacts and heights. CONCLUSIONS: Cartilage loss initially occurred where there was direct contact between the cartilage of the femur and tibia. The meniscus did not prevent this, nor prevent the spread of the wear medially. This may have been due to the progressive reduction of cartilage-meniscal contact as the meniscus subluxed or lost substance, as the cartilage loss and deformity progressed. This suggested that the meniscus was not able to ameliorate the forces and pressures on the cartilage surfaces to prevent degeneration.
Prognostic biomarkers in osteoarthritis
PURPOSE OF REVIEW: Identification of patients at risk for incident disease or disease progression in osteoarthritis remains challenging, as radiography is an insensitive reflection of molecular changes that presage cartilage and bone abnormalities. Thus there is a widely appreciated need for biochemical and imaging biomarkers. We describe recent developments with such biomarkers to identify osteoarthritis patients who are at risk for disease progression. RECENT FINDINGS: The biochemical markers currently under evaluation include anabolic, catabolic, and inflammatory molecules representing diverse biological pathways. A few promising cartilage and bone degradation and synthesis biomarkers are in various stages of development, awaiting further validation in larger populations. A number of studies have shown elevated expression levels of inflammatory biomarkers, both locally (synovial fluid) and systemically (serum and plasma). These chemical biomarkers are under evaluation in combination with imaging biomarkers to predict early onset and the burden of disease. SUMMARY: Prognostic biomarkers may be used in clinical knee osteoarthritis to identify subgroups in whom the disease progresses at different rates. This could facilitate our understanding of the pathogenesis and allow us to differentiate phenotypes within a heterogeneous knee osteoarthritis population. Ultimately, such findings may help facilitate the development of disease-modifying osteoarthritis drugs (DMOADs).
Comment on "the effects of bariatric surgery weight loss on knee pain in patients with osteoarthritis of the knee"
Ultrasound and Treatment Algorithms of RA and JIA
Musculoskeletal ultrasound has emerged as a key tool for the diagnosis, prognosis, and management of patients with RA (rheumatoid arthritis) and other rheumatic diseases. The most important sonographic findings in RA include erosions, effusions, synovitis, and tenosynovitis. Investigators have suggested various "optimal" numbers of joints to scan in RA to assess disease activity, gauge treatment response, provide prognostic information, and guide management decisions. The complexity of pediatric sonoanatomy has delayed its validation in juvenile idiopathic arthritis, yet ultrasound reliably measures the extent of synovitis/tenosynovitis and guides precise injections.
Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones
Complement receptor 2-negative (CR2/CD21(-)) B cells have been found enriched in patients with autoimmune diseases and in common variable immunodeficiency (CVID) patients who are prone to autoimmunity. However, the physiology of CD21(-/lo) B cells remains poorly characterized. We found that some rheumatoid arthritis (RA) patients also display an increased frequency of CD21(-/lo) B cells in their blood. A majority of CD21(-/lo) B cells from RA and CVID patients expressed germline autoreactive antibodies, which recognized nuclear and cytoplasmic structures. In addition, these B cells were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. Moreover, gene array analyses of CD21(-/lo) B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage. Thus, CD21(-/lo) B cells contain mostly autoreactive unresponsive clones, which express a specific set of molecules that may represent new biomarkers to identify anergic B cells in humans.
Low-Grade inflammation in symptomatic knee osteoarthritis: Prognostic value of inflammatory plasma lipids and peripheral blood leukocyte biomarkers
OBJECTIVE: Inflammatory mediators, such as PGE2 and IL-1beta, are produced by osteoarthritic joint tissues, where they may contribute to disease pathogenesis. We examined whether inflammation, reflected in plasma and peripheral blood leukocytes (PBLs) reflected presence of osteoarthritis (OA), progression or symptoms in patients with symptomatic knee osteoarthritis (SKOA). METHODS: SKOA patients were enrolled in a 24-month prospective study of radiographic progression. Standardized knee radiographs were obtained at baseline and 24 months. Biomarkers assessed at baseline included plasma lipids PGE2 and 15-HETE, and transcriptome analysis of PBLs by microarray and qPCR. RESULTS: Baseline PGE synthases (PGES) by PBL microarray gene expression, and plasma PGE2 distinguished SKOA patients from non-OA controls (AUCs 0.87 and 0.89 respectively, p<0.0001). Baseline plasma 15-HETE was significantly elevated in SKOA versus non-OA controls (p<0.019). In the 146 patients who completed the 24-month study, elevated baseline expression of IL-1beta, TNFalpha and COX-2 mRNA in PBLs predicted higher risk for radiographic progression by joint space narrowing (JSN). In a multivariate model, AUC point estimates of models containing COX-2 in combination with demographic traits overlap the confidence interval of the base model in two out of the three JSN outcome measures (JSN >0.0mm, >0.2mm and >0.5mm, AUC=0.62-0.67). CONCLUSION: Inflammatory plasma lipid biomarkers PGE2 and 15-HETE identify patients with SKOA. PBL inflammatory transcriptome identifies a subset of SKOA patients at higher risk for radiographic progression. These findings may reflect low-grade inflammation in OA and may be useful as diagnostic and prognostic biomarkers in clinical development of disease-modifying OA drugs. This article is protected by copyright. All rights reserved.
Age-dependent ferritin elevations and HFE C282Y mutation as risk factors for symptomatic knee osteoarthritis in males: a longitudinal cohort study
BACKGROUND: Age, gender and genetic predisposition are major intrinsic risk factors for osteoarthritis (OA). Iron increases are associated with age and gene mutation. In the present study, we examined whether serum ferritin, an indicator of total body iron stores, correlates with clinical features in patients with OA, and whether the hemochromatosis Fe (HFE) gene mutation plays a role. METHODS: In a 2-year longitudinal observational study, 127 patients with knee OA and 20 healthy individuals (controls) were enrolled. All patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiographs. Peripheral blood samples were analyzed for serum ferritin, and genotyped for HFE using allelic discrimination methods. RESULTS: Higher levels of serum ferritin were found in patients older than 56 years (P =0.0186) and males (P =0.0006), with a trend toward higher ferritin in patients with OA. HFE gene mutation carriers were more prevalent among patients with OA than among healthy controls. When stratified further by gender, we found that male patients with OA had higher levels of serum ferritin than male control subjects [odds ratio = 4.18 (limits of 95% confidence interval: 0.86-27.69, P = 0.048)]. Analyses of radiographic data indicated that higher ferritin was associated with narrower joint space width at baseline (P = 0.032) in male patients. Additionally, among men, risk prediction of radiographic severity [Kellgren-Lawrence (KL) grade >2)] in the higher ferritin group was almost five times that of the lower ferritin group (odds ratio = 4.74, P = 0.023). CONCLUSION: Our data suggest that increased ferritin levels are associated with symptomatic knee OA in males. This finding needs to be validated in a larger cohort of patients.
Discordance of global estimates by patients and their physicians in usual care of many rheumatic diseases is associated with 5 MDHAQ scores not found on the HAQ
Objective: To analyze discordance between global estimates by patients (PATGL) and their physicians (DOCGL) according to demographic and self-report variables on a multidimensional health assessment questionnaire (MDHAQ), in patients with many rheumatic diseases seen in usual care. Methods: Each patient completes an MDHAQ at each visit, which includes scores for physical function, pain and PATGL, each found on the HAQ, and scores for sleep quality, anxiety, depression, self-report joint count and fatigue, which are not found on the HAQ. A random visit of 980 patients with any rheumatic diagnosis was analyzed in 3 categories: PATGL=DOCGL (within 2/10 units); PATGL>DOCGL (by >/=2/10 units); DOCGL>PATGL (by >/=2/10 units), using descriptive statistics and multinomial logistic regression models. Results: Patients included 145 with rheumatoid arthritis, 57 systemic lupus erythematosus, 173 osteoarthritis, 348 other inflammatory, and 257 other non-inflammatory diseases. Overall, PATGL=DOCGL in 509 (52%), PATGL>DOCGL in 371 (38%) and DOCGL>PATGL in 100 (10%). PATGL>DOCGL was associated significantly with older age, female gender, low formal education, Hispanic ethnicity, not working, high MDHAQ physical function and pain, and high scores for fatigue, poor sleep, anxiety, depression, and self-report joint count, not available on the HAQ. Pain and fatigue were significant in a final multinomial logistic regression; the other variables may raise awareness of discordance to clinicians. Conclusions: Global estimates of patients indicated significantly poorer status than estimates of their physicians in 38% of 980 patients with rheumatic conditions, and were associated with demographic and MDHAQ scores, 5 of which are not available on the HAQ. (c) 2013 American College of Rheumatology.
The Effect of Rilonacept versus Placebo on Health-Related Quality of Life in Patients with Poorly Controlled Familial Mediterranean Fever
Objective. To examine the effect of rilonacept on the health-related quality of life (HRQoL) in patients with poorly controlled familial Mediterranean fever (FMF). Methods. As part of a randomized, double-blinded trial comparing rilonacept and placebo for the treatment of FMF, patients/parents completed the modified Child Health Questionnaire (CHQ) at baseline, and at the start and end of each of 4 treatment courses, 2 each with rilonacept and placebo. Results. Fourteen subjects were randomized; mean age was 24.4 +/- 11.8 years. At baseline the physical HRQoL score was significantly less (24.2 +/- 49.5) but the psychosocial score was similar to the population norm (49.5 +/- 10.0). There were significant improvements in most HRQoL concepts after rilonacept but not placebo. Significant differences between rilonacept and placebo were found in the physical (33.7 +/- 16.4 versus 23.7 +/- 14.5, P = 0.021) but not psychosocial scores (51.4 +/- 10.3 versus 49.8 +/- 12.4, P = 0.42). The physical HRQoL was significantly impacted by the treatment effect and patient global assessment. Conclusion. Treatment with rilonacept had a beneficial effect on the physical HRQoL in patients with poorly controlled FMF and was also significantly related to the patient global assessment. This trial is registered with ClinicalTrials.gov Identifier NCT00582907.
Presence of gout is associated with increased prevalence and severity of knee osteoarthritis among older men: results of a pilot study
BACKGROUND: Gout and osteoarthritis (OA) are the most prevalent arthritides, but their relationship is neither well established nor well understood. OBJECTIVES: We assessed whether a diagnosis of gout or asymptomatic hyperuricemia (AH) is associated with increased prevalence/severity of knee OA. METHODS: One hundred nineteen male patients aged 55 to 85 years were sequentially enrolled from the primary care clinics of an urban Veterans Affairs hospital, assessed and categorized into 3 groups: gout (American College of Rheumatology Classification Criteria), AH (serum urate >/=6.8 mg/dL, no gout), and control (serum urate <6.8 mg/dL, no gout). Twenty-five patients from each group subsequently underwent formal assessment of knee OA presence and severity (American College of Rheumatology Clinical/Radiographic Criteria, Kellgren-Lawrence grade). Musculoskeletal ultrasound was used to detect monosodium urate deposition at the knees and first metatarsophalangeal joints. RESULTS: The study showed 68.0% of gout, 52.0% of AH, and 28.0% of age-matched control subjects had knee OA (gout vs control, P = 0.017). Odds ratio for knee OA in gout versus control subjects was 5.46 prior to and 3.80 after adjusting for body mass index. Gout subjects also had higher Kellgren-Lawrence grades than did the control subjects (P = 0.001). Subjects with sonographically detected monosodium urate crystal deposition on cartilage were more likely to have OA than those without (60.0 vs 27.5%, P = 0.037), with crystal deposition at the first metatarsophalangeal joints correlating most closely with OA knee involvement. CONCLUSIONS: Knee OA was more prevalent in gout patients versus control subjects and intermediate in AH. Knee OA was more severe in gout patients versus control subjects.
Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis
OBJECTIVE: Pro- and anti-inflammatory mediators, such as IL-1beta and IL1Ra, are produced by joint tissues in osteoarthritis (OA), where they may contribute to pathogenesis. We examined whether inflammatory events occurring within joints are reflected in plasma of patients with symptomatic knee osteoarthritis (SKOA). DESIGN: 111 SKOA subjects with medial disease completed a 24-month prospective study of clinical and radiographic progression, with clinical assessment and specimen collection at 6-month intervals. The plasma biochemical marker IL1Ra was assessed at baseline and 18 months; other plasma biochemical markers were assessed only at 18 months, including IL-1beta, TNFalpha, VEGF, IL-6, IL-6Ralpha, IL-17A, IL-17A/F, IL-17F, CRP, sTNF-RII, and MMP-2. RESULTS: In cross-sectional studies, WOMAC (total, pain, function) and plasma IL1Ra were modestly associated with radiographic severity after adjustment for age, gender and body mass index (BMI). In addition, elevation of plasma IL1Ra predicted joint space narrowing (JSN) at 24 months. BMI did associate with progression in some but not all analyses. Causal graph analysis indicated a positive association of IL1Ra with JSN; an interaction between IL1Ra and BMI suggested either that BMI influences IL1Ra or that a hidden confounder influences both BMI and IL1Ra. Other protein biomarkers examined in this study did not associate with radiographic progression or severity. CONCLUSIONS: Plasma levels of IL1Ra were modestly associated with the severity and progression of SKOA in a causal fashion, independent of other risk factors. The findings may be useful in the search for prognostic biomarkers and development of disease-modifying OA drugs.