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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Objective

To evaluate digital x-ray radiogrammetry (DXR) and the Radiogrammetry Kit program as new diagnostic tools for quantifying disease-related periarticular osteoporosis and for measuring joint space narrowing according to the severity and duration of rheumatoid arthritis (RA).

Methods

Using DXR, we performed computerized calculations of bone mineral density (BMD) and the metacarpal index (MCI) in 258 patients with active RA. Using the Radiogrammetry Kit program, we also performed semiautomated measurements of joint space width (JSW) at the second through the fifth metacarpophalangeal (MCP) joints in these patients.

Results

All correlations between the different parameters of both techniques (BMD and the MCI as measured by DXR and MCP JSW as measured by the Radiogrammetry Kit) were significant (0.36 ≤ R ≤ 0.63; P < 0.01). As expected, a significant negative association was shown between the different MCP JSW results and the results of all scoring methods (−0.67 ≤ R ≤ −0.29). The BMD and the MCI measured by DXR both decreased significantly between Steinbrocker stage I and stage IV (by 32.7% and 36.6%, respectively; both P < 0.01). Reductions in the overall (mean) MCP JSW varied from 35.3% (Larsen score) to 52.9% (Steinbrocker stage). Over a period of 6 years, we observed relative decreases in BMD and the MCI as measured by DXR (32.1% and 33.3%, respectively), as well as in the overall (mean) MCP JSW (23.5%), and these were pronounced in early RA (duration <1 year). In addition, excellent reproducibility of DXR and Radiogrammetry Kit parameters was verified (coefficients of variation <1%).

Conclusion

DXR with the integrated Radiogrammetry Kit program could be a promising, widely available diagnostic tool for supplementing the different RA scoring methods with quantitative data, thus allowing an earlier and improved diagnosis of RA and more precision in determining disease progression.

Rheumatoid arthritis (RA) is a systemic and chronic disease characterized by inflammation in and around the soft tissues, cartilage, and bone in the joints, frequently and preferentially affecting the small joints of the hand (1). The characteristic pattern of juxtaarticular inflammatory involvement includes both cartilage destruction and bone erosion (2), which are distinctive characteristics of RA that distinguish it from most other inflammatory joint diseases. Aside from bone erosion, the process of joint destruction is further advanced by the degradation and dissolution of the cartilage tissue caused by the direct effects of enzymes and other synovial cell products that accumulate in the synovial fluid (3), resulting in a narrowing of the joint space (JSN). Specifically, chondrocytes, when stimulated by tumor necrosis factor α or interleukin-1β, can release proteolytic enzymes that cause cartilage matrix degeneration (4), particularly by the production of matrix metalloproteinase 1 and complement C1s at the sites of cartilage destruction as well as by invasiveness of transformed synovial fibroblasts (5). In addition, high levels of nitric oxide may also influence joint alterations through various mechanisms, including decreased proteoglycan synthesis, metalloproteinase release, induction of chondrocyte apoptosis, accelerated bone resorption, and impairment of osteoblast function (3, 6).

In addition to inflammation-related joint alterations (i.e., bone erosion and cartilage destruction), osteoporosis is a significant clinical complication in RA and occurs in 2 forms: periarticular osteoporosis occurring in close proximity to the inflamed joints, which is a typical phenomenon in early RA; and generalized osteoporosis affecting the axial and appendicular bones, which occurs during the course of RA (7, 8). Generalized bone loss may also be enhanced by immobility, the inflammatory process itself, and therapeutic treatments such as steroids, while periarticular demineralization is probably due to the local release of inflammatory agents (2, 3, 6). Recently, RANKL and osteoprotegerin (OPG), a decoy receptor for RANKL, have been identified as central regulators of osteoclast recruitment and activation. OPG and RANKL production are modulated by various cytokines, growth factors, and hormones. In affected synovium, fibroblasts and activated T cells both express RANKL and maintain osteoclast recruitment and activation. Thus, OPG and RANKL are important molecular agents that have a lasting effect on bone resorption in the juxtaarticular bone (9).

Osteoporosis occurs more frequently in patients with RA, which results in low bone mineral density (BMD) and in microarchitectural deterioration of bone tissue. These conditions lead to diminished biomechanical competence of the skeleton, which in turn, commonly leads to low-trauma or atraumatic fractures, particularly at the spine, hip, and wrist (7, 8, 10). The high risk of fractures in RA patients contributes substantially to morbidity, mortality, and health care costs (10, 11).

Because the hand shows the earliest manifestations of RA and the destruction of small joints correlates well with alterations seen on images of large joints (1, 12, 13), periodic radiography of the hands is advisable in order to verify the progression of the disease during the course of RA, as well as to monitor the effects of antirheumatic therapy (12, 14, 15). The extent of joint destruction visualized on radiographs of the hands and feet varies widely in patients with RA, but it is significantly associated with cumulative joint inflammation (16).

Conventional radiography, a widely available and cost-effective method, remains the standard of reference for the detection and quantification of joint destruction in the course of RA (14, 17). The disadvantage of conventional imaging is its limited sensitivity in detecting early JSN and periarticular osteoporosis, the latter of which is highly prevalent in the metacarpal bones (18), and generally, demineralization is only very imprecisely verified using radiographs at a reduction of >35% (19).

For earlier identification of inflammatory changes, which would enable a better prognosis and improved success of treatment strategies in patients with RA, the use of digital techniques for the acquisition and processing of radiographs has increased substantially and has continually gained wider acceptance in recent years. The availability of digital approaches provides the opportunity for quantitative measurements of radiographic features (20, 21).

Recently, the clinical application of radiogrammetry, which was introduced first as a technique for evaluation of bone status by Barnett and Nordin (22), has shown significant improvement as a result of further refinement, computerization, and the use of algorithms for automatic image analysis (23–25). Our study was performed with the Pronosco X-Posure System (version 2.0; Sectra Pronosco, Vedbaek, Denmark), which uses a computerized radiogrammetric analysis of the 3 middle metacarpal bones for the measurement of BMD and the metacarpal index (MCI; defined as 2 times the cortical thickness [in mm] divided by the outer diameter of the metacarpal bone [in mm]). The potential of digital x-ray radiogrammetry (DXR) for estimating cortical bone loss seems to be promising in clinical practice. Investigators in several studies have not only reported a significant correlation between BMD peripherally measured by dual x-ray absorptiometry (DXA) and BMD estimated by DXR in postmenopausal women, but they have also determined normative values for DXR (24–26). Although BMD measurement by DXR was not performed on areas of high fracture incidence, Bouxsein et al (27) documented in a prospective study over an observation period of 5 years that DXR was as good as single-photon absorptiometry for predicting the risk of fracture of the wrist, spine, and femur. In addition, postmenopausal women receiving hormone replacement therapy showed a significant increase in the MCI as calculated by DXR (28).

The Radiogrammetry Kit (version 1.3.5; Sectra Pronosco) is a separate software program implemented for semiautomated measurements of the metacarpophalangeal (MCP) joint space width (JSW) in the second through the fifth fingers, and our results using the Radiogrammetry Kit program have proved to be consistent with the results of different scoring methods. Previous techniques used for joint space analysis have not been able to provide consistently accurate estimates of JSW in finger joints with distinctive disease-related abnormalities (21). Furthermore, measurements of JSW in the proximal interphalangeal (PIP) joints seem to be complicated, because these joints show a bicompartmental configuration, which result in a varied width of each compartment according to minor rotations of the hand (especially the PIP joints of the first, fourth, and fifth fingers).

In this cross-sectional and longitudinal study using digitized hand radiographs, we evaluated the ability to make precise measurements of the radiographically detectable MCP JSW for any grade of RA with the Radiogrammetry Kit, and we evaluated the ability to quantify periarticular demineralization by DXR for different scoring methods. Our longitudinal data showed notable reductions in the mean BMD and MCI estimated by DXR and in the mean MCP JSW in the course of active RA over a period of 6 years and revealed accentuated periarticular demineralization and MCP JSN within the first year after disease onset. Our technique should help to identify patients with aggressive RA who are going to develop joint damage before major erosions occur and, consequently, should help to optimize individual therapeutic strategies.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients.

Two hundred fifty-eight Caucasian patients (189 women and 69 men) were enrolled without preselection regarding the grade of RA. Our study population comprised only patients with active RA who fulfilled the following conditions at disease onset: erythrocyte sedimentation rate (ESR) >20 mm in the first hour (mean ± SD 49 ± 29; estimated by the Westergren method) and C-reactive protein (CRP) level >25 mg/liter (mean ± SD 41 ± 37; measured by nephelometric assay). The patients' ages ranged from 18 to 83 years (mean ± SD 60.9 ± 11.2 years), and RA was diagnosed according to the 1987 revised criteria of the American College of Rheumatology (formerly, the American Rheumatism Association) (29). Since all patients had established RA during the 6 years of the longitudinal component, after 3 years, we focused on obtaining cross-sectional data regarding RA severity–dependent periarticular demineralization and JSN.

Patients were not preselected on the basis of whether they had previously received or were currently receiving steroid therapy. Forty-five patients were treated with methotrexate and 138 with other disease-modifying antirheumatic drugs (DMARDs), respectively, in combination with nonsteroidal antiinflammatory drugs. Seventy-one patients had been receiving long-term, low-dose prednisolone therapy (5 mg/day over a 6-month period). The remaining 4 patients had not received systemic corticosteroids, DMARDs, or immunomodulating agents. We excluded patients with abnormal renal function (serum creatinine >130 μmoles/liter), those receiving hormone replacement therapy/bisphosphonates, and those with other conditions known to affect bone metabolism. Informed consent was obtained, and the study received approval from the local ethics committee.

This retrospective study consisted of a cross-sectional component and a longitudinal component. In the cross-sectional component, which was performed 3 years after the onset of RA, we quantified RA severity–dependent periarticular demineralization and JSN. In the longitudinal (6-year) component, we determined changes in BMD and the MCI estimated by DXR as well as changes in MCP JSW, differentiating early (duration <1 year) and established (duration ≥1 year) RA.

Cross-sectional component.

We reviewed digital radiographs of the nondominant hand taken 3 years after the onset of RA. Exclusion criteria were signs of fracture and visible osteosynthetic material in the right and left upper extremities (including the ulna, radius, and hand).

Each radiograph was scored by 2 trained observers working independently using the following 4 methods: 1) the Steinbrocker criteria for RA stage and functional class (30), which were used to evaluate only the most affected joints of the hands; 2) the Larsen scale (31), which was used to evaluate 32 joints of the feet and hands (total of 160 points); 3) the Sharp erosion score (32), which was used to evaluate 34 joints of the hands (total of 170 points); and 4) the Sharp JSN score (32), which was used to evaluate 36 joints of the hands (total of 144 points). In cases of ambiguity, a third radiologist reviewed the radiographs; the individual sums of the points scored were then divided by the numbers of joints evaluated, and the patients were subgrouped according to the scores.

Longitudinal component.

The longitudinal component included the 6-year period after the onset of RA, during which all patients underwent annual digital radiographs of the nondominant hand. The same exclusion criteria as for the cross-sectional component were used. We were therefore able to distinguish between early (duration <1 year) and established (duration ≥1 year) RA in all patients.

Calculation of BMD and the MCI by DXR.

The Pronosco X-Posure System was used to determine BMD and the MCI based on DXR results, which required radiographs of the nondominant hand. All plain radiographs of the hand were acquired with a Polydoros SX 80 device (Siemens, Munich, Germany) under the following standardized conditions: x-ray aluminum-related filter with 1-mm thickness, film focus distance 1 meter, tube voltage 42 kV, exposure 4 mA, using a Scopix Laser 2B 400 (Agfa, Cologne, Germany).

The digital radiographs were printed and subsequently scanned into the system. The system itself checked the quality of the scanned images and interrupted the examination in case of inadequate quality (i.e., technical lack of exposure and focus as well as incorrect illustration of the relevant anatomic structures). The computer algorithms automatically defined regions of interest (ROIs) around the narrowest parts of the second, third, and fourth metacarpal bones and subsequently determined the outer and inner cortical edges of the cortical bone parts studied. Apart from placing the radiograph on the charge-coupled device–based desktop flatbed scanner (resolution of 300 dots per inch, corresponding to 5.5 line pairs/mm), there was no operator interaction associated with the DXR measurement. The analyzed images and their ROIs were displayed on the computer monitor.

The mean of the cortical thickness and overall bone cortical thickness of the second, third, and fourth metacarpals were estimated. Subsequently, the cortical volume per area (VPA) was calculated for each bone. The DXR estimation of BMD, based on the mean VPA, was computed with a correction for the estimated porosity index. The porosity index is a technical parameter with a value between 1 and 19 which is derived from the area percentage of local intensity minima found in the cortical part of the bone relative to the entire cortical area (24). The DXR estimation of the MCI obtains the mean cortical thickness normalized to the mean outer bone diameter (24). It should be noted that for clinical purposes, the manufacturer recommends restrictions on the scanning of printed digital radiographs and subsequent DXR measurements of BMD using the X-Posure System, since the printing process may influence the sharpness of the image and, thereby, the BMD measured by DXR.

Measurement of JSW by the Radiogrammetry Kit program.

The Radiogrammetry Kit program could estimate almost all visible MCP JSW, including severely altered joints with subluxation and partial ankylosis; only joints with complete ankylosis could not be considered. Using this technique, one could perform a joint space analysis of a finger joint by detection of the joint edges within a rectangular ROI defined by the user. The positioning of the ROI to identify the favored joint represented the only operator-dependent interaction during the entire measurement. The software was based on an edge filtering of the ROI and automatically detected the tips of the 2 involved bones. A 1.5-cm edge path across each bone was further determined, and the distance between the 2 edges was measured as a function of the horizontal position. The mean and SD distance over a moving interval of 0.8 cm was calculated. The distance between the bones was defined to be over the edge interval, for which the SD was minimal. Specifically, the measurement of joint spaces was methodically established for the second through the fifth MCP joints, and distances were given in cm.

In the present study, the coefficients of variation (CVs; %) representing the short-term precision achieved using DXR and the Radiogrammetry Kit (10 repeated measurements of 10 single sets of the same images with repositioning of the same radiograph) were as follows: for BMD estimated by DXR, 0.19%; for the MCI estimated by DXR, 0.24%; for MCP2 JSW, 0.59%; for MCP3 JSW, 0.85%; for MCP4 JSW, 0.99%; for MCP5 JSW, 0.98%; for PIP2 JSW, 2.03%; for PIP3 JSW, 2.49%; for PIP4 JSW, 3.27%; and for PIP5 JSW, 3.78%.

Statistical analysis.

Results are expressed as the mean and SD. The normality of the data was checked using the Kolmogorov-Smirnov test. Comparison of parameters measured using the Radiogrammetry Kit with the results of the scoring methods and parameters estimated using DXR was performed by linear regression analysis. (P values less than 0.05 were considered significant.) The significance of severity-dependent bone loss and reduction in MCP JSW was calculated with the Mann-Whitney U test. The statistical analysis was performed using SPSS software, version 10.13 (SPSS, Chicago, IL).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Cross-sectional study.

Comparisons between DXR and Radiogrammetry Kit parameters and scoring methods (Table 1).

Measurements of BMD and the MCI using DXR were retrospectively performed on all patients. Similarly, all calculations of MCP JSW were obtained using the Radiogrammetry Kit program.

Table 1. Coefficients of correlation of the Steinbrocker rheumatoid arthritis stage, Larsen score, Sharp erosion score, Sharp JSN score, and DXR parameters with the MCP JSW estimated by the Radiogrammetry Kit program in 258 patients*
 JSW estimated by the Radiogrammetry Kit program
MCP2MCP3MCP4MCP5Mean
  • *

    JSN = joint space narrowing; DXR = digital x-ray radiogrammetry; MCP = metacarpophalangeal; JSW = joint space width; BMD = bone mineral density (gm/cm2); MCI = metacarpal index.

  • P < 0.01.

  • P < 0.05.

BMD estimated by DXR0.520.580.540.510.63
MCI estimated by DXR0.460.430.360.400.44
Steinbrocker stage−0.54−0.50−0.47−0.36−0.55
Larsen score−0.67−0.65−0.40−0.58−0.66
Sharp JSN score−0.56−0.57−0.35−0.50−0.58
Sharp erosion score−0.49−0.46−0.29−0.46−0.45

All correlations between the different parameters of both techniques (DXR and the Radiogrammetry Kit) were significant, while BMD measured by DXR always showed stronger correlations with Radiogrammetry Kit parameters than did the MCI measured by DXR. The strongest correlation was observed between mean MCP JSW and BMD measured by DXR (R = 0.63, P < 0.01).

A significant negative association was shown between the different MCP JSW results and the results of all scoring methods (−0.67 ≤ R ≤ −0.29). Pronounced negative associations were documented for the Larsen score with JSW in the second and third fingers, while the Sharp JSN score was more negatively associated with JSW than was the Sharp erosion score, as expected.

Severity-dependent periarticular demineralization and JSN according to the Steinbrocker criteria for RA stage and functional class (Table 2).

For the Steinbrocker RA stage, the mean ± SD BMD measured by DXR decreased significantly (by 32.7%), from 0.55 ± 0.08 gm/cm2 for stage I to 0.37 ± 0.10 gm/cm2 for stage IV. The relative reduction in the MCI measured by DXR was 36.6%. In this context, overall (mean) MCP JSW showed a significant narrowing of 52.9% (from 0.17 ± 0.02 cm [stage I] to 0.08 ± 0.05 cm [stage IV]). Regarding the various joints, relative decreases were observed ranging between 40.0% (MCP5 JSW) and 63.2% (MCP2 JSW).

Table 2. Reduction in values of the DXR and Radiogrammetry Kit parameters in 258 patients with rheumatoid arthritis progressing from Steinbrocker stage I through Steinbrocker stage IV*
 Stage I (n = 22)Stage II (n = 128)Stage III (n = 84)Stage IV (n = 24)Relative reduction from stage I to stage IV, %P (stage IV vs. stage I)
  • *

    Except where indicated otherwise, values are the mean ± SD. Values were calculated after 3 years of the observation period. See Table 1 for definitions.

BMD estimated by DXR, gm/cm20.55 ± 0.080.47 ± 0.090.44 ± 0.060.37 ± 0.1032.7<0.01
MCI estimated by DXR0.41 ± 0.110.36 ± 0.050.31 ± 0.080.26 ± 0.0736.6<0.01
MCP2 JSW, cm0.19 ± 0.060.17 ± 0.040.11 ± 0.060.07 ± 0.0963.2<0.01
MCP3 JSW, cm0.17 ± 0.050.15 ± 0.050.13 ± 0.040.07 ± 0.0458.8<0.01
MCP4 JSW, cm0.17 ± 0.030.15 ± 0.020.12 ± 0.040.10 ± 0.0441.2<0.01
MCP5 JSW, cm0.15 ± 0.020.14 ± 0.020.11 ± 0.040.09 ± 0.0540.0<0.01
MCP JSW, overall mean, cm0.17 ± 0.020.16 ± 0.030.12 ± 0.040.08 ± 0.0552.9<0.01
Severity-dependent periarticular demineralization and JSN according to the Larsen score.

BMD measured by DXR decreased significantly (by 25.5%), from 0.55 ± 0.09 gm/cm2 for a Larsen score of 1 to 0.41 ± 0.07 gm/cm2 for a Larsen score of 5, and the MCI measured by DXR showed a significant reduction (26.8%), from 0.41 ± 0.07 for a Larsen score of 1 to 0.30 ± 0.05 for a Larsen score of 5. JSN varied from 25.0% (MCP4 JSW) to 44.4% (MCP2 JSW). A reduction of 35.3% for the overall (mean) MCP JSW of from 0.17 ± 0.03 cm for a Larsen score of 1 to 0.11 ± 0.05 cm for a Larsen score of 5 was observed.

Severity-dependent periarticular demineralization and JSN according to the Sharp erosion score and Sharp JSN score.

For both Sharp scores, BMD measured by DXR diminished considerably (by 28.6% for Sharp JSN score and by 22.1% for Sharp erosion score), while the significant reduction in the MCI measured by DXR was similar (31.0%). Also, the overall (mean) MCP JSW showed an expected narrowing of 41.2% for the JSN segment of the score, while the Sharp erosion score revealed a lesser decline in overall (mean) MCP JSW (29.6%). For the respective joints, the relative reduction ranged between 16.5% (MCP4 JSW, Sharp erosion part) and 52.6% (MCP2 JSW, Sharp JSN part). Generally, the reductions in JSW values were more pronounced for the Sharp JSN part than for the Sharp erosion part.

Longitudinal study.

Changes over a period of 6 years (Table 3 and Figure 1).

All DXR and Radiogrammetry Kit parameters decreased significantly between the time of entry into the study (i.e., onset of RA) and the end of observation. Reductions of 32.1% and 33.3% were observed for BMD and the MCI, respectively, as measured by DXR. The relative JSN ranged from 18.8% (MCP5 JSW) to 31.6% (MCP2 JSW). The overall (mean) MCP JSW showed a relative reduction of 23.5%. On average, our study verified an annual loss of 3.6% in BMD measured by DXR, an annual reduction of 3.2% in the MCI measured by DXR, and an annual overall (mean) narrowing of 2.0% in MCP JSW.

Table 3. Reduction in values of the DXR and Radiogrammetry Kit parameters in 258 patients during the observation period of 6 years*
 Baseline1 year3 years6 yearsRelative reduction from baseline to year 6, %P (year 6 vs. baseline)
  • *

    Except where indicated otherwise, values are the mean ± SD. See Table 1 for definitions.

BMD estimated by DXR, gm/cm20.56 ± 0.090.50 ± 0.100.47 ± 0.100.38 ± 0.0832.1<0.01
MCI estimated by DXR0.42 ± 0.100.36 ± 0.110.34 ± 0.090.28 ± 0.0733.3<0.01
MCP2 JSW, cm0.19 ± 0.040.16 ± 0.040.14 ± 0.030.13 ± 0.0331.6<0.01
MCP3 JSW, cm0.17 ± 0.020.15 ± 0.020.14 ± 0.030.12 ± 0.0229.4<0.01
MCP4 JSW, cm0.17 ± 0.030.15 ± 0.020.14 ± 0.030.13 ± 0.0323.5<0.01
MCP5 JSW, cm0.16 ± 0.030.15 ± 0.020.13 ± 0.020.13 ± 0.0218.8<0.01
MCP JSW, overall mean, cm0.17 ± 0.020.15 ± 0.020.14 ± 0.030.13 ± 0.0223.5<0.01
thumbnail image

Figure 1. Changes (expressed as percentage of the baseline value) in digital x-ray radiogrammetry (DXR) and Radiogrammetry Kit parameters over the observation period of 6 years. DXR-BMD = bone mineral density (gm/cm2) as estimated by DXR; DXR-MCI = metacarpal index as estimated by DXR; MCP = metacarpophalangeal; JSW = joint space width (cm).

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Differences between the early RA and the prolonged course of RA groups (Table 4 and Figure 1).

In the first year of clinical RA manifestation, BMD and the MCI as measured by DXR revealed accentuated decreases (of 10.7% and 14.3%, respectively). Similar to the findings with the DXR parameters, the Radiogrammetry Kit demonstrated a pronounced reduction in JSW in the first year of RA. Specifically, MCP2 JSW showed a maximal narrowing of 15.8%, while MCP5 JSW showed a minor narrowing of 6.3%. After a disease duration of >1 year, we observed more flattened declines in BMD and the MCI as measured by DXR as well as in the overall (mean) MCP JSW.

Table 4. Reduction in values of the DXR and Radiogrammetry Kit parameters in 258 patients with an early or a prolonged course of rheumatoid arthritis (RA)*
 Early RAProlonged RA
Relative reduction from baseline to year 1, %P (year 1 vs. baseline)Relative reduction from year 1 to year 6, %P (year 6 vs. year 1)
  • *

    See Table 1 for other definitions.

BMD estimated by DXR, gm/cm210.7<0.0121.4<0.01
MCI estimated by DXR14.3<0.0119.0<0.01
MCP2 JSW15.8<0.0115.8<0.01
MCP3 JSW11.8<0.0117.6<0.01
MCP4 JSW11.8<0.0111.7<0.01
MCP5 JSW6.3<0.0512.5<0.01
MCP JSW, overall mean11.8<0.0111.7<0.01

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Most patients with early RA are characterized by apparently normal findings on hand radiographs despite clinical involvement of the small joints of the hand. Also, acute-phase responses (i.e., CRP level and ESR), which are known to correlate with disease activity, are not sensitive enough to diagnose early RA, because differences exist between clinical as well as biochemical disease activity and the degree to which they are correlated with the delayed occurrence of bony defects (8). Since many patients develop destructive joint alterations within the first 2 years after onset of RA and since metacarpal osteopenia precedes periarticular erosions, the early quantification of periarticular RA-related demineralization implies an important prognostic benefit for the patient. Osteoporosis occurs more frequently in patients with RA than in healthy individuals and represents the earliest radiographic feature of RA (10). Recent studies have verified the coexistence of periarticular and generalized demineralization in RA (33). Periarticular osteoporosis has been shown to have a close association with the level of disease activity, but not with the disease duration, and even indicates maximal demineralization in early, active RA (34–36). Kalla et al (37) also verified significantly reduced metacarpal osteopenia in patients receiving antirheumatic therapy.

Using a longitudinal study design, our data confirmed accentuated periarticular demineralization combined with pronounced narrowing of the MCP JSW in early RA (Table 4), along with continuous declines in BMD and the MCI as measured by DXR, as well as in the MCP JSW in established RA over an observation period of 6 years (Table 3 and Figure 1). Using DXR, the cross-sectional component of the present study also revealed a significant reduction in periarticular cortical bone mass according to the severity of RA (Table 2), a finding comparable with recently reported results (38, 39). In a recent study (40), we found a marked severity-dependent decline in cortical BMD measured by DXR in patients with different stages of RA and no significant loss of BMD as estimated by DXA in the total femur and the lumbar spine.

DXR is ideal for the quantification of periarticular demineralization without interference from soft tissue, because this technique uses the metacarpals as the measurement site. Because of a frequent and severe involvement of metacarpal joints in the rheumatoid inflammatory process, a higher degree of bone loss was seen in the subregions of phalanges and metacarpals compared with whole-hand BMD reduction in another recent study (36). The influence of disease-related bony defects and erosions on the DXR calculations can be minimized by DXR measurements of the diaphyseal part of the metacarpal bones. In addition, the short-term precision of DXR (i.e., intraradiograph reproducibility of <0.40%) is very low (41), indicating that estimated demineralization is in fact disease-related and is not based on the precision error of the densitometric method itself.

A possible limitation of DXR may be its measurement of BMD in only the cortical partition, because the cortical bone matrix involves minor bone metabolism compared with that in trabecular bone tissue. Otherwise, cortical thinning of periarticular bone, enhanced by the inflammation process, is a typical phenomenon of bone destruction in RA (37), which can be assumed to take place because of very high bone turnover on the inner bone surface (42). It is well known that osteoporosis in postmenopausal women is characterized both by a reduction in cortical thickness and by a decrease in trabecular bone volume, and that renal transplant recipients as well as children with depletion of calcium intake have shown cortical bone loss (43, 44). Otherwise, hormone effects and steroids have only a minor influence on cortical bone tissue (45).

Early diagnosis of RA is essential not only for the optimal and well-timed treatment of osteoporosis, but also for delaying or stopping inflammatory damage of the affected joints (7). In a prospective, longitudinal study of patients with early RA, Hulsmans et al (12) verified a linear course of progression over the first 6 years, and therefore, recommended conventional imaging of the hands and feet every year during the first period after the onset of RA.

Different scoring methods have been validated and established (30–32) which are based on conventional radiography as the common imaging technique for evaluating the progression of RA. Scoring methods are designed to semiquantitatively measure radiographically visible degeneration, particularly erosions and JSN caused by cartilage damage, depending on the experience of the scoring physician.

The first scoring method, as devised by Steinbrocker et al (30), divides radiographic changes of the hand skeleton into 4 stages but grades only the most serious joint destruction. The Larsen scale and its modified version evaluate 32 joints of the hands and feet (31, 46). In addition to the refinements of the Larsen scale by Rau and Herborn (47), Scott et al (48), and Edmonds et al (49), a separate evaluation of erosions and JSN of the hand and finger joints was introduced by the Sharp score (32).

A frequent limitation of scoring methods that assess joint alterations by small lesions is that these lesions frequently cannot be visualized if the erosion is not located at the margin of the bone or if other bony structures are superimposed on it (50).

Recently, Stewart et al (51) verified that DXR significantly predicted the degree of erosive disease in individuals. In that study, the reduction in BMD measured by DXR after 1 year was very specific (100%) and highly sensitive (63%) in detecting patients who developed accelerated progression of RA with occurrence of erosions after a 4-year observation period. In addition, BMD measured by DXR was independently associated with radiographic hand joint damage (52).

Estimation of JSN is hindered by the asymmetry, subluxation, and overlying soft tissue often seen in inflamed joints (17). The computerized technique for estimating JSW, which was evaluated for the first time in the present study, reveals severity-dependent narrowing of the MCP JSW with high reproducibility. Independent of the scoring method used, our results show preferential narrowing of the MCP JSW in the second and third fingers.

The usual disadvantages of joint space measurements on serial radiographs, such as different positions of the hands during imaging, variations in x-ray beam angle, and disease-related limitations (particularly destruction and subluxation of joints), can be avoided by sampling a large portion of each joint space, as was done using our new technique, and as recommended by Sharp et al (21). Furthermore, the constancy of image-capturing parameters provides the high reproducibility of the DXR and Radiogrammetry Kit results (41). To achieve reliable data, our group will use (until further notice) only the MCP joint for joint space calculations, since this facilitates edge detection by the computerized program via more effective visualization of the ridge of the joint margin.

Additionally, our software was able to estimate the JSW of the PIP joints (Figure 2). The intraradiograph reproducibility (mean CV 2.89%) was comparatively limited because the PIP joints showed a bicompartmental configuration, resulting in a varied width of each compartment depending on minor rotation of the hand (especially in PIP4 and PIP5). Therefore, the reliable estimation of marginal disease-related changes is still restricted; consequently, we have decided not to present the results related to the PIP joints without further refinement of this technique for the PIP articulation. Aside from this issue, most inflammatory alterations caused by RA were detected at the MCP joint (14). Finally, this computerized, operator-independent calculation of the JSW for the 4 MCP joints as well as the BMD and the MCI as measured by DXR for one hand requires no more than 4 minutes, and thus, requires less time compared with the scoring methods.

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Figure 2. Measurement of MCP and proximal interphalangeal JSW analyzed by the Radiogrammetry Kit program (after manual positioning of the rectangular landmarks). Positioning of the region of interest to identify the favored joint represented the only operator-dependent interaction during the entire measurement. The mean and SD distance over a moving interval of 0.8 cm was calculated. See Figure 1 for definitions.

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The combined application of DXR and the Radiogrammetry Kit program seems to be promising in the early detection and quantification of JSN and periarticular disease-related osteoporosis in patients with RA. Further prospective studies will evaluate these techniques in greater detail, along with the benefits they confer by enabling us to obtain quantitative information about reparative and therapy-induced changes. Finally, the Radiogrammetry Kit program must be further refined in order to obtain a complete assessment of all hand joints, including the PIP joints as well as the wrist joints.

The development of digital imaging technology has promoted the precise measurement of several radiographic features (53, 54). While DXR can quantify disease-related demineralization and reduction of cortical thickness that depends on the severity of RA, the clinical use of the Radiogrammetry Kit allows the reliable calculation of the MCP JSW in patients with different stages of RA independently of the scoring method used. In the longitudinal component of the present study, we were able to verify that significant periarticular bone loss, as well as marked reductions in MCP JSW, were accentuated early in the course of RA. Possible clinically important applications of DXR and the Radiogrammetry Kit might include a BMD calculation and a quantification of JSN in routinely performed followup radiographs used for monitoring the progression of RA and for confirming reparative changes after drug treatment. Therefore, the operator-independent and computerized DXR and Radiogrammetry Kit technology could be an important diagnostic tool in RA by which the clinician can target those patients who require more aggressive management of their disease in order to prevent the joint destruction that will inevitably lead to disability.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We would like to thank Mrs. M. Arens (Arewus GmbH, Mainz, Germany). We would also like to thank Mr. G. Wolf (Jena, Germany), D. Felsenberg, MD (Berlin, Germany), and C. C. Gluer, PhD (Kiel, Germany) for their comments regarding our study.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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