Johan Kälvesten

Adalimumab therapy reduces hand bone loss in early rheumatoid arthritis: Explorative analyses from the PREMIER study

Objective: The effect of adalimumab on hand osteoporosis was examined and related to radiographic joint damage in the three treatment arms of the PREMIER study: adalimumab plus methotrexate, adalimumab and methotrexate monotherapy. Predictors of hand bone loss were also searched for. Methods: 768 patients (537 fulfilled 2 years) with rheumatoid arthritis (RA) for less than 3 years, never treated with methotrexate, were included. Hand bone loss was assessed by digital x ray radiogrammetry (DXR) on the same hand radiographs scored with modified Sharp score at baseline, 26, 52 and 104 weeks. For DXR, metacarpal cortical index (MCI) was the primary bone measure. Results: At all time points the rate of percentage DXR–MCI loss was lowest in the combination group (−1.15; −2.16; −3.03) and greatest in the methotrexate monotherapy group (−1.42; −2.87; −4.62), with figures in between for the adalimumab monotherapy group (−1.33; −2.45; −4.03). Significant differences between the combination group and the methotrexate group were seen at 52 (p = 0.009) and 104 weeks (p<0.001). The order of hand bone loss across the three treatment arms was similar to the order of radiographic progression. Older age, elevated C-reactive protein and non-use of adalimumab were predictors of hand bone loss. Conclusion: This study supports a similar pathogenic mechanism for hand bone loss and erosions in RA. The combination of adalimumab and methotrexate seems to arrest hand bone loss less effectively than radiographic joint damage. Quantitative measures of osteoporosis may thus be a more sensitive tool for assessment of inflammatory bone involvement in RA.

Adalimumab reduces hand bone loss in rheumatoid arthritis independent of clinical response: subanalysis of the PREMIER study.

BackgroundAnti-TNF therapy has been shown to reduce radiographic joint damage in rheumatoid arthritis (RA) independent of clinical response. This has previously not been examined for periarticular bone loss, the other characteristic feature of bone involvement in RA.The objective of this study was to examine if treatment with the TNF-α inhibitor adalimumab also could reduce periarticular bone loss in RA patients independent of disease activity.MethodsRA patients were recruited from the PREMIER study and included 214 patients treated with methotrexate (MTX) plus adalimumab and 188 patients treated with MTX monotherapy. Periarticular bone loss was assessed by digital X-ray radiogrammetry metacarpal cortical index (DXR-MCI). Change in DXR-MCI was evaluated in patients with different levels of clinical response, as assessed by changes in DAS28 score at 52 weeks and in mean C-reactive protein (CRP) levels during follow-up.ResultsIn the MTX group, there was a greater median DXR-MCI loss among patients with moderate and high disease activity compared to those in remission or with low disease activity (-3.3% vs. -2.2%, p = 0.01). In contrast, periarticular bone loss was independent of disease activity (-1.9% vs. -2.4%, p = 0.99) in the combination group. In the MTX group patients with a mean CRP of ≥ 10 mg/l lost significantly more DXR-MCI than patients with low CRP (-3.1% vs. -1.9%, p <0.01) whereas in the combination group no significant differences between the two CRP groups was seen (-2.4% vs. -2.0%, p = 0.48).ConclusionAdalimumab in combination with MTX reduces periarticular bone loss independently of clinical response. These results support the hypothesis that TNF-α stimulates the osteoclast not only by the inflammatory pathway but do also have a direct effect on the osteoclast.Trial RegistrationClinicalTrials (NCT): NCT001195663

Short-Time In Vitro and In Vivo Precision of Direct Digital X-ray Radiogrammetry

Digital X-ray radiogrammetry (DXR) calculates peripheral bone mineral density (BMD) from hand radiographs. The aim of this study was to examine in vitro and in vivo precision for the new direct digital version of DXR, a development of the conventional DXR. The in vitro precision for direct DXR was tested on 4 different X-ray equipment, based on 31 radiographs of the same phantom. The in vivo precision was based on duplicate hand radiographs from both hands in 39 individuals. For the 4 X-ray equipment, in vitro precision ranged from 0.14% to 0.30%, expressed as coefficient of variations (CV%) and from 0.0012 to 0.0028 g/cm2, expressed as smallest detectable difference (SDD). The precision was correlated to the resolution of the radiographic equipment (r=0.95, p=0.05). The corresponding values for the in vivo precision for mean values of both hands were: CV%=0.46%; SDD=0.0046 g/cm2, and least significant change (LSC%)=1.28%. The DXR-BMD for 1 of the X-ray equipment differed 1.1% from the overall mean. The precision for direct DXR was highly satisfactory both in vitro and in vivo. DXR-BMD values may differ between the radiographic equipment, and follow-up measurements should be performed with the same X-ray equipment.

Four-month metacarpal bone mineral density loss predicts radiological joint damage progression after 1 year in patients with early rheumatoid arthritis: exploratory analyses from the IMPROVED study

Aim To assess whether in early (rheumatoid) arthritis (RA) patients, metacarpal bone mineral density (BMD) loss after 4 months predicts radiological progression after 1 year of antirheumatic treatment. Methods Metacarpal BMD was measured 4 monthly during the first year by digital X-ray radiogrammetry (DXR-BMD) in patients participating in the IMPROVED study, a clinical trial in 610 patients with recent onset RA (2010 criteria) or undifferentiated arthritis, treated according to a remission (disease activity score<1.6) steered strategy. With Sharp/van der Heijde progression ≥0.5 points after 1 year (yes/no) as dependent variable, univariate and multivariate logistic regression analyses were performed. Results Of 428 patients with DXR-BMD results and progression scores available, 28 (7%) had radiological progression after 1 year. Independent predictors for radiological progression were presence of baseline erosions (OR (95% CI) 6.5 (1.7 to 25)) and early DXR-BMD loss (OR (95% CI) 1.5 (1.1 to 2.0)). In 366 (86%) patients without baseline erosions, early DXR-BMD loss was the only independent predictor of progression (OR (95% CI) 2.0 (1.4 to 2.9)). Conclusions In early RA patients, metacarpal BMD loss after 4 months of treatment is an independent predictor of radiological progression after 1 year. In patients without baseline erosions, early metacarpal BMD loss is the main predictor of radiological progression.

Does digital X-ray radiogrammetry have a role in identifying patients at increased risk for joint destruction in early rheumatoid arthritis?

IntroductionThe aim of this study was to investigate the role of hand bone mineral density (BMD) loss analyzed with digital X-ray radiogrammetry (DXR) in early rheumatoid arthritis (RA) as a predictor for progression of joint damage.MethodsIn 379 patients with early RA, baseline and one-year hand BMD was measured with DXR and the hand bone loss (HBL) was analyzed using the smallest detectable change (HBLsdc) and tertiles (HBLtertiles). Joint damage in hands and feet were scored according to the Sharp van der Heijde (SHS) method at baseline and at one, two, five and eight years. At the same time-points Disease Activity Score (DAS28) was calculated and functional disability assessed. Rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (anti-CCP) were analyzed at baseline.ResultsSixty-six percent of the patients had hand BMD loss in the first year of RA determined by HBLsdc and 65% by HBLtertiles. Radiographic progression after two, five and eight years was associated with hand bone loss defined by HBLsdc. By HBLtertiles there were significant associations at all time-points except at eight years. The change in DXR at one year (ChDXR1yr) correlated significantly and inversely with the change in SHS (ChSHS) at two, five and eight years. Multivariate analysis showed that only change in SHS during the first year and the presence of anti-CCP were independent predictors of long-term progressive joint damage. If radiographic scores were not included, DXR-BMD loss was an independent predictor. Patients with great bone loss by HBLtertiles had significantly more often high disease activity after two years. However, neither bone loss by HBLsdc or HBLtertiles nor by ChDXR1yr was an independent predictor of remission after two, five and eight years.ConclusionsThis study confirms previous reports of an association of decrease in DXR-BMD during the first disease year with progression of radiographic joint damage over an extended period of time. This association was independent in a regression model only when radiological findings were excluded suggesting a possible predictive role of DXR-BMD in clinical practice when radiographic evaluation is not available. However, further studies are required before this can be established.

Digital X-ray radiogrammetry in the study of osteoporotic fractures: Comparison to dual energy X-ray absorptiometry and FRAX.

Osteoporosis is often underdiagnosed and undertreated. Screening of post-menopausal women for clinical risk factors and/or low bone mineral density (BMD) has been proposed to overcome this. Digital X-ray radiogrammetry (DXR) estimates hand BMD from standard hand X-ray images and have shown to predict fractures and osteoporosis. Recently, digital radiology and the internet have opened up the possibility of conducting automated opportunistic screening with DXR in post-fracture care or in combination with mammography. This study compared the performance of DXR with FRAX® and DXA in discriminating major osteoporotic fracture (MOF) (hip, clinical spine, forearm or shoulder), hip fracture and femoral neck osteoporosis. This prospective cohort study was conducted on 5278 women 65years and older in the Study of Osteoporotic Fractures (SOF) cohort. Baseline hand X-ray images were analyzed and fractures were ascertained during 10years of follow up. Age-adjusted area under receiver operating characteristic curve (AUC) for MOF and hip fracture and for femoral neck osteoporosis (DXA FN BMD T-score ≤-2.5) was used to compare the methods. Sensitivity to femoral neck osteoporosis at equal selection rates was tabulated for FRAX and DXR. DXR-BMD, FRAX (no BMD) and lumbar spine DXA BMD were all similar in fracture discriminative performance with an AUC around 0.65 for MOF and 0.70 for hip fractures for all three methods. As expected femoral neck DXA provided fracture discrimination superior both to other BMD measurements and to FRAX. AUC for selection of patients with femoral neck osteoporosis was higher with DXR-BMD, 0.76 (0.74-0.77), than with FRAX, 0.69 (0.67-0.71), (p<0.0001). In conclusion, DXR-BMD discriminates incident fractures to a similar degree as FRAX and predicts femoral neck osteoporosis to a larger degree than FRAX. DXR shows promise as a method to automatically flag individuals who might benefit from an osteoporosis assessment.

Potential sources of quantification error when retrospectively assessing metacarpal bone loss from historical radiographs by using digital X-ray radiogrammetry : an experimental study

During the past 15 yr, digital X-ray radiogrammetry (DXR) has been used to measure metacarpal bone mineral density (BMD). BMD is often measured in existing cohorts where X-ray images were not acquired in accordance with the DXR imaging protocol (DIP). The purpose of the present study was to analyze how deviations from DIP in historical radiographs may affect the reproducibility of DXR-BMD measurements. Cadaver hand phantoms were used to conduct repeat measurements of deviations from DIP with respect to voltage, exposure, lateral displacement, supination, combination of lateral displacement and supination or rotation, extension of the wrist, and edge enhancement. Direct digital radiography (Aristos; Siemens Healthcare, Erlangen, Germany) was used for image acquisition and dxr-online (Sectra, Linköping, Sweden) for DXR-BMD measurements. The influence of the tested deviations from DIP ranged from 0 to 32.5 mg/cm(2) (0-6.8%). On repetition with the same specimen, none of the deviations resulted in a within-specimen reproducibility error greater than 2 mg/cm(2) (0.4%, equivalent to a T-score of 0.042). Among the tested deviations, all except tube voltage had a magnitude greater than the normal measurement noise for the technique and must therefore be considered when planning a study based on historical images.

Bone mineral density loss in clinically suspect arthralgia is associated with subclinical inflammation and progression to clinical arthritis

Objective: Peripheral bone mineral density (BMD) may be decreased in early rheumatoid arthritis (RA) but it is unknown whether BMD loss emerges before arthritis is clinically apparent. We aimed to study whether BMD loss occurs in patients with clinically suspect arthralgia (CSA), and whether it is associated with progression to clinical arthritis and magnetic resonance imaging (MRI)-detected subclinical inflammation. Method: Patients with CSA had arthralgia for <1 year and were at risk of progressing to RA according to their rheumatologists. At baseline, a 1.5 T MRI was performed of unilateral metacarpophalangeal, wrist, and metatarsophalangeal joints, and scored on synovitis, bone marrow oedema, and tenosynovitis;. summing these features yielded the total MRI inflammation score. Digital X-ray radiogrammetry (DXR) was used to estimate BMD on two sequential conventional hand radiographs (mean interval between radiographs 4.4 months). The change in BMD was studied; BMD loss was defined as a decrease of ≥2.5 mg/cm2/month. Patients were followed for arthritis development for a median of 18.4 months. Results: In CSA patients (n = 108), change in BMD was negatively associated with age (β = −0.03, p = 0.007). BMD loss in CSA patients was associated with arthritis development [adjusted for age hazard ratio (HR) = 6.1, 95% confidence interval (CI) 1.7 to 21.4] and was most frequently estimated in the months before clinical arthritis development. The total MRI inflammation scores were associated with the change in BMD (adjusted for age β = −0.05, p = 0.047). The total MRI inflammation score and BMD loss were both independently associated with arthritis development (HR = 1.1, 95% CI 1.1 to 1.2, and HR = 4.6, 95% CI 1.2 to 17.2, respectively). Conclusion: In CSA patients, severe BMD loss is associated with MRI-detectable subclinical inflammation and with progression to clinical arthritis.

Mammography and Osteoporosis Screening-Clinical Risk Factors and Their Association With Digital X-Ray Radiogrammetry Bone Mineral Density.

The aim of this study was to study the association between digital X-ray radiogrammetry (DXR) T-score and clinical risk factors for osteoporosis. Women were recruited 2 d per wk at a single mammography screening center between year 2010 and 2012. Included women answered a questionnaire about risk factors for osteoporosis, and a radiograph of the nondominant hand was obtained for DXR analysis. Univariate associations between DXR T-score and risk factors were examined. A generalized linear regression model was fitted to independent variables with univariate associations at p<0.05. The multivariable model was reduced through manual backward elimination, with p>0.1 as the exclusion criterion. Seventy-six percent of the women chose to participate in the study (n=8810). The difference in number of daily mammograms performed on study vs nonstudy days was not significant. All univariate associations between DXR T-score and potential risk factors were highly significant. The multivariable model included height, weight, age, right-handedness, menopause before age 45, alcohol consumption, cortisone treatment, rheumatic disease, and age×smoking status. The coefficient of determination of the model was 0.37. The association between risk factors for osteoporosis and DXR T-score is similar to previously reported associations with dual-energy X-ray absorptiometry.

Fully automated joint space width measurement and digital X-ray radiogrammetry in early RA

Objectives To study fully automated digital joint space width (JSW) and bone mineral density (BMD) in relation to a conventional radiographic scoring method in early rheumatoid arthritis (eRA). Methods Radiographs scored by the modified Sharp van der Heijde score (SHS) in patients with eRA were acquired from the SWEdish FarmacOTherapy study. Fully automated JSW measurements of bilateral metacarpals 2, 3 and 4 were compared with the joint space narrowing (JSN) score in SHS. Multilevel mixed model statistics were applied to calculate the significance of the association between ΔJSW and ΔBMD over 1 year, and the JSW differences between damaged and undamaged joints as evaluated by the JSN. Results Based on 576 joints of 96 patients with eRA, a significant reduction from baseline to 1 year was observed in the JSW from 1.69 (±0.19) mm to 1.66 (±0.19) mm (p<0.01), and BMD from 0.583 (±0.068) g/cm2 to 0.566 (±0.074) g/cm2 (p<0.01). A significant positive association was observed between ΔJSW and ΔBMD over 1 year (p<0.0001). On an individual joint level, JSWs of undamaged (JSN=0) joints were wider than damaged (JSN>0) joints: 1.68 mm (95% CI 1.70 to 1.67) vs 1.54 mm (95% CI 1.63 to 1.46). Similarly the unadjusted multilevel model showed significant differences in JSW between undamaged (1.68 mm (95% CI 1.72 to 1.64)) and damaged joints (1.63 mm (95% CI 1.68 to 1.58)) (p=0.0048). This difference remained significant in the adjusted model: 1.66 mm (95% CI 1.70 to 1.61) vs 1.62 mm (95% CI 1.68 to 1.56) (p=0.042). Conclusions To measure the JSW with this fully automated digital tool may be useful as a quick and observer-independent application for evaluating cartilage damage in eRA. Trial registration number NCT00764725.