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Keywords:

  • Disease activity score;
  • PMR-AS;
  • Polymyalgia rheumatica

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Objective

To evaluate associations linking glucocorticoid dose changes in patients with polymyalgia rheumatica (PMR) to the PMR activity score (PMR-AS) and its components.

Methods

Nine clinical vignettes of PMR were written by a panel of experts and submitted to 35 rheumatologists, who were asked to assess disease activity using a visual analog scale (VASph) and to determine whether there was a relapse of PMR requiring an increase in the glucocorticoid dose. In 7 vignettes, >80% of the rheumatologists agreed on the diagnosis of relapse justifying the glucocorticoid dose decision. A total of 243 vignette-physician combinations were obtained. Using these vignettes, we evaluated statistical associations linking a decision to increase the glucocorticoid dose to the value of PMR-AS, of its components (VASph, visual analog scale for pain [VASp], C-reactive protein level [CRP], morning stiffness [MST], and elevation of upper limbs [EUL]), or to the difference in these variables between the last 2 visits (dPMR-AS, dVASph, dVASp, dCRP, dMST, and dEUL).

Results

The strongest associations with a decision to increase the glucocorticoid dose occurred with dPMR-AS >4.2, dMST >10 minutes, dVASph >1.55, and dCRP >4 mg/dl (99.3% sensitivity, 100% specificity for all 4 variables); MST ≥10 minutes (100% sensitivity, 99.3% specificity); PMR-AS ≥7 (98.1% sensitivity, 94.3% specificity); VASph ≥2.25 (94.2% sensitivity, 83.6% specificity); and CRP level ≥14.5 mg/liter (66.3% sensitivity, 99.3% specificity).

Conclusion

Despite inter-individual variations in VASph, PMR-AS was a good indicator of disease activity. However, MST, dMST, dVASph, dPMR-AS, and dCRP performed better than PMR-AS. These variables may be useful in tailoring the glucocorticoid dose to the individual needs of each patient.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Polymyalgia rheumatica (PMR) is a clinical syndrome of the elderly, characterized by pain and morning stiffness in the neck and limb girdles. The erythrocyte sedimentation rate (ESR) and serum C-reactive protein level (CRP) are usually elevated. The response to systemic glucocorticoid therapy is usually rapid, with resolution of the clinical symptoms and laboratory evidence of inflammation reduction occurring within a few days. To monitor disease activity and to detect relapses, clinical symptoms combined with ESR and/or CRP levels are widely used. However, PMR is a heterogeneous disease, and ESR elevation may be lacking. The risk of a relapse may be difficult to predict, especially in patients with low baseline ESR or CRP values. Concern about unexpected relapses may lead physicians to delay glucocorticoid tapering, thereby unnecessarily prolonging patient exposure to the adverse effects of glucocorticoid therapy. In addition to their classic adverse effects, glucocorticoid therapy may increase the risk of cardiovascular disease, a major concern in elderly patients, although inadequate control of inflammation may also induce adverse cardiovascular effects (1). Therefore, carefully tailoring the glucocorticoid dose to the patient needs is an important objective when treating patients with PMR.

Leeb and Bird (2) recently developed a disease activity score for PMR (PMR-AS) based on 5 variables: morning stiffness in minutes (MST), ability to elevate the upper limbs (EUL, on a scale from 0–3), physician's global assessment using a 10-point visual analog scale (VASph), pain measured using a 10-point visual analog scale (VASp), and the C-reactive protein (CRP) level in mg/dl. The PMR-AS (2) is computed by summing the 5 variables after multiplying MST by 0.1 for weighting purposes: PMR−AS = CRP (mg/dl) + VASp (0–10 scale) + VASph (0–10 scale) + (MST [min]×0.1) + EUL (0–3 scale). Leeb and Bird (2) reported that PMR-AS values <7 indicated low disease activity, values 7–17 indicated moderate disease activity, and values >17 indicated high PMR activity. The PMR-AS score is well suited to everyday practice. However, the subjective nature of VASph may lead to interobserver variability, which may hamper the identification of PMR-AS cut-offs that indicate a need for changing the glucocorticoid dose.

We designed a study to evaluate the effectiveness of the PMR-AS in determining when glucocorticoid dose changes are needed in patients with PMR who are receiving glucocorticoid therapy in decreasing doses. To evaluate interobserver variability in PMR-AS values, we asked 35 rheumatologists to assess their VASph for 9 fictional scenarios depicting arguable cases of relapsing or stable PMR during glucocorticoid dose reduction. Then we evaluated the effectiveness of PMR-AS in predicting a decision to change the glucocorticoid dose during the long-term followup of patients with PMR, and we compared the performance of PMR-AS in this regard with that of each of the 5 components of the score (MST, EUL, VASph, VASp, and CRP levels). We also determined whether decisions regarding the glucocorticoid dose were more heavily dependent on the magnitude of the change in PMR-AS, or its components, from one visit to the next.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Clinical cases.

Nine clinical vignettes (Table 1) of PMR, with disease activity level ranging from low to high, were written by a panel of rheumatologist experts who were members of the Inflammatory Joint Disease Working Group of the French Society for Rheumatology (Club Rhumatismes et Inflammation). The 9 vignettes shared common features: a definitive diagnosis of PMR; initial symptoms consisting of asthenia, anorexia, weight loss, limited active range of motion of the shoulders, aching and morning stiffness in the neck and limb girdles; elevated ESR and CRP levels; a rapid response to prednisone therapy with complete resolution of clinical symptoms and normal ESR and CRP level; and initial prednisone therapy in a dosage of 0.3 mg/kg/day for 15 days and 0.25 mg/kg/day for the next 15 days, then 0.2 mg/kg per day followed by tapering every week or 2 weeks for ∼6 months. Recurrence of clinical symptoms or an ESR or CRP level elevation was described in the vignettes as suggestive of a relapse. The 9 vignettes were submitted to 35 office-based and hospital-based rheumatologists who were asked to determine VASph and to decide whether the disease was relapsing and whether a prednisone dose increase was indicated.

Table 1. Main clinical symptoms and laboratory test results in 9 clinical vignettes of polymyalgia rheumatica evaluated by 35 rheumatologists*
 Vignette
836271495
  • *

    Vignettes listed in the order of increasing percentage of rheumatologists diagnosing a relapse. VASp = pain measured on 0–10 visual analog scale; MST = morning stiffness; EUL = elevation of upper limbs; CRP = C-reactive protein level; VASph = physician's global assessment measured on 0–10 visual analog scale; S = scheduled; ER = emergency room.

  • Evaluated by 34 rheumatologists.

Last visit         
 VASph, 0–10 scale124112211
 MST, minutes002001001000
 EUL, degrees120120909012090120180120
 CRP, mg/liter7918971010710
 VASp, 0–10 scale113112101
 Prednisone, mg/day512151161214512
Current visit         
 VisitSERSERERSSERS
 SymptomPainAstheniaAstheniaAstheniaAstheniaAstheniaMST
 VASp, 0–10 scale312133233
 MST, minutes00001010201020
 EUL, degrees16018012090120909012090
 CRP, mg/liter7128121315171220
Rheumatologist opinions, %         
 Diagnosis of relapse06111140579197100
 Decision to increase  prednisone099113154779194

Diagnosis of relapse.

The reference standard to include a fictional case report in the statistical analysis was agreement of at least 28 (80%) rheumatologists on the diagnosis of relapse justifying the decision to increase or not increase the prednisone dose.

Statistical analysis.

Results for the quantitative variable VASph were reported as the mean ± SD, and results for qualitative variables (diagnosis of relapse and decision to increase the prednisone dose) were reported as percentages and as number of positive responses per category for each vignette. We computed PMR-AS as indicated by Leeb and Bird (2): PMR−AS = CRP (mg/dl) + VASp (0–10 scale) + VASph (0–10 scale) + (MST[min]×0.1) + EUL (0–3 scale). The 4 levels on the semiquantitative EUL scale are as follows: 3 = no upper limb elevation; 2 = elevation (<90°) below the shoulder girdle; 1 = elevation (90°) up to the shoulder girdle; and 0 = elevation (>90°) above the shoulder girdle. Patient groups were compared using chi-square tests. P values less than 0.05 were considered statistically significant.

We studied the associations linking the decision to increase the prednisone dose with the PMR-AS and with each of its 5 components (MST, EUL, VASph, VASp, and CRP) separately. We also studied the association linking the decision to increase the prednisone dose with the change in each of these 6 variables between the last 2 physician visits (dPMR-AS, dMST, dEUL, dVASph, dVASp, and dCRP). Sensitivities and specificities were calculated at different cut-off values. Receiver-operating characteristic (ROC) curves were plotted. Statistical tests were performed using the Statistical Package for the Social Sciences, version 13.0 (SPSS, Chicago, IL).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Relapse diagnosis and decision to increase prednisone.

As expected, a gradient of response for a positive diagnosis of PMR relapse and a decision to increase the prednisone dose was observed (Table 1). In vignettes 4, 5, and 9 a diagnosis of relapse and a decision to increase the prednisone dose were made by most of the rheumatologists (91%, 100%, and 97% for relapse and 77%, 94%, and 91% for dose increase, respectively). Conversely, vignettes 2, 3, 6, and 8 were usually interpreted as indicating no relapse (89%, 94%, 89%, and 100% of rheumatologists, respectively) and no need to increase the prednisone dose (89%, 91%, 91%, and 100%, respectively). Opinions of the rheumatologists were divided in vignettes 1 and 7, with 43% and 60% of rheumatologists, respectively, feeling that there was no relapse; consequently those vignettes were removed from subsequent analyses. The data from the remaining 7 vignettes were used for a statistical evaluation of the impact of disease-activity parameters on decisions to increase the prednisone dose. There were 35 responses for each of 5 vignettes and 34 responses for vignettes 3 and 5, yielding a total of 243 responses for the study.

As expected, we found a highly significant (P < 0.00001) association between diagnosing a relapse and deciding to increase the prednisone dosage. Of 243 vignette-rheumatologist combinations, 226 were concordant for both the diagnosis of relapse and the decision to increase prednisone, including 129 assigned to both the relapse group and the increase prednisone dose group, and 97 patients to both the no relapse group and the do not increase prednisone dose group. Two patients assigned to the no relapse group were assigned to the increase prednisone dosage group, and the opposite occurred for 15 patients.

Diagnostic impact of clinical and laboratory parameters.

As expected, variations occurred across rheumatologists in the evaluation of VASph, most notably for vignettes 4, 5, 6, and 9. The mean ± SD (range) VASph scores for vignettes 1 through 9 were 3.44 ± 1.28 (1–6), 2.01 ± 1.13 (1–5), 1.87 ± 0.69 (1–4), 4.18 ± 1.48 (0–8), 4.70 ± 1.76 (2–9), 2.14 ± 1.29 (0–6), 2.50 ± 1.05 (1–6), 1.50 ± 0.74 (0–4), and 4.04 ± 1.69 (0–8).

Figure 1 shows the ROC curves of associations linking a decision to increase the prednisone dose to PMR-AS, MST, EUL, VASph, VASp, and CRP levels for the 7 vignettes analyzed in the study (vignettes 2–6, 8, and 9). Figure 2 shows the ROC curves of associations linking the decision to increase the prednisone dose to the variations (d) in PMR-AS, MST, EUL, VASph, VASp, and CRP levels between the last 2 visits. The best cut-off values for the best parameters, together with their sensitivities and specificities are shown in Table 2. Strong associations with a prednisone dose increase were found for dPMR-AS >4.2, dMST >10 minutes, dVASph >1.55, and dCRP >4 mg/liter. For each of these 4 variables, sensitivity was 99.3% and specificity was 100%. A decision to increase the prednisone dose was also strongly associated with MST ≥10 minutes (sensitivity 100%, specificity 99.3%) and PMR-AS ≥7 (sensitivity 98.1%, specificity 94.3%). Lower predictive values were found for VASph ≥2.25 (sensitivity 94.2%, specificity 83.6%) and CRP levels ≥14.5 mg/liter (sensitivity 66.3%, specificity 99.3%). EUL, VASp, and dVASp showed weak associations with a decision to increase the prednisone dose (VASp ≥1.5 sensitivity 100%, specificity 49.3%; EUL ≥1 sensitivity 66.3%, specificity 74.3%; and dVASp >0.5 sensitivity 74.5%, specificity 100%).

thumbnail image

Figure 1. Receiver operating curves of the associations linking a decision to increase the prednisone dose with PMR-AS, VASp, VASph, CRP levels, MST, and EUL. PMR-AS = polymyalgia rheumatica activity score; VASp = pain measured on visual analog scale; VASph = physician's global assessment on visual analog scale; CRP = C-reactive protein; MST = morning stiffness; EUL = elevation of upper limbs; ref = reference line.

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thumbnail image

Figure 2. Receiver operating curves of the associations linking a decision to increase the prednisone dosage with variations between the last 2 visits in PMR-AS, MST, EUL, VASph, VASp, and CRP (dPMR-AS, dMST, dEUL, dVASph, dVASp, and dCRP, respectively). See Figure 1 for definitions.

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Table 2. Best cut-off values, sensitivities, and specificities of various parameters for predicting a decision to increase the prednisone dose. Data are from 7 clinical vignettes evaluated by 35 rheumatologists*
ParameterSensitivity, %Specificity, %
  • *

    d = variation between the 2 last visits in PMR-AS, MST, CRP, VASph, VASp, and EUL; PMR-AS = disease activity score for polymyalgia rheumatica. For additional definitions, see Table 1.

dPMR-AS >4.299.3100
dMST >10 minutes99.3100
dCRP >4 mg/liter99.3100
dVASph >1.5599.3100
dVASp >0.574.5100
dEUL >199.376.3
PMR-AS ≥798.194.3
MST ≥10 minutes10099.3
CRP ≥14.5 mg/liter66.399.3
VASph ≥2.2594.283.6
VASp ≥1.510049.3
EUL ≥166.374.3

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

The European Collaborating Polymyalgia Rheumatica Group developed EULAR (European League Against Rheumatism) response criteria for PMR (3) to improve the monitoring of disease activity and to accurately determine the prednisone dose requirements. However, a validated disease activity index such as the PMR-AS (2) would be extremely helpful for comparing various therapeutic options for PMR and for improving clinical practice uniformity. To investigate the usefulness of PMR-AS and its components, we used an original study design in which 9 clinical vignettes were evaluated by 35 rheumatologists. Our preliminary objective was to assess the variability in physicians' assessments of the disease (the VASph component of the PMR-AS). Our main objective was to seek a threshold of either PMR activity, assessed by PMR-AS or its components, which indicated a relapse requiring an increase in the prednisone dose. Although a relapse is usually defined as the recurrence of clinical symptoms and/or ESR or CRP level elevation, no consensus has been developed and no relapse criteria have been published. This study using fictional patients, following the example of other studies (4, 5) was a useful preliminary to a prospective study of patients with PMR aimed at using the best disease-monitoring parameters to minimize both total prednisone exposure and the relapse rate.

The panel of rheumatologists wrote several fictional case reports to cover a gradient of PMR disease activity. Agreement of at least 80% among the 35 rheumatologists who were asked to diagnose a relapse was required. As previously reported in other studies using either a questionnaire or fictional case reports (4, 6), we chose an 80% cut-off. If we had used a 50% cut-off, all the vignettes would have been included in the study. However, 2 vignettes (1 and 7) described a questionable situation in which relapse may or may not be present. With a 50% cut-off for the reference standard, the best PMR-AS cut-off determined using the ROC curve was >7.4 (95.7% sensitivity, 89.1% specificity).

The first result from this study is that the global assessment of PMR activity using an analog scale (VASph) varied widely among the 35 rheumatologists for a given vignette. Therefore, the mean ± SD ranged from a low of 1.50 ± 0.74 (vignette 8) to a high of 4.70 ± 1.76 (vignette 5). Similarly, VASph ranges varied from a low of 1–4 (vignette 3) to 0–8 (vignettes 4 and 9). Therefore, the physician's assessment alone cannot constitute the basis for therapeutic decisions.

The second conclusion is that in our study a PMR-AS cut-off of 7 had excellent sensitivity and specificity for predicting a relapse. Leeb and Bird reported that a cut-off of 7 defined the border between low and medium disease activity (2). When the magnitude of changes in PMR-AS components from one visit to the next was disregarded, 4 of the components (the exception being MST) had less diagnostic value than did the PMR-AS. However, in our study an increase >4.2 in the PMR-AS between 2 visits was even better than a PMR-AS ≥7 for predicting a decision to increase the prednisone dose. Changes between 2 visits in CRP levels, MST, and VASph also were highly sensitive and specific predictors of a decision to increase the prednisone dose. Therefore, although our results suggest that a PMR-AS ≥7 may indicate a relapse, the PMR-AS value above which the prednisone dose should be increased probably varies between patients. Combining PMR-AS with other parameters, most notably changes in PMR-AS (and/or selected individual components) between 2 visits may be better than using the PMR-AS alone. These results are very encouraging, and a prospective study in patients with PMR is needed to confirm our results obtained using fictional case reports.

Our study had a number of limitations. First, we used fictional case reports, although the reports were written by rheumatologists who had extensive experience with PMR. Second, changes in clinical symptoms and laboratory test results from one visit to the next were small, except for MST. MST was the parameter that showed the closest association with a diagnosis of relapse, suggesting that a set of vignettes describing larger variations in other parameters might have produced different results. Third, none of the 35 rheumatologists was familiar with VASph score determination, which may explain the considerable interobserver variability in the VASph score. Additionally, for 2 of the 9 vignettes (vignettes 1 and 7) fewer than 80% of the rheumatologists agreed regarding the diagnosis of relapse and prednisone requirements, and we excluded these vignettes from further analysis. However, for the remaining 7 vignettes there was strong agreement among the rheumatologists regarding the diagnosis of relapse and prednisone needs, despite the variability in VASph. This finding supports the validity of using vignettes to select a set of parameters for use in a prospective study of patients.

The final goal is to help physicians determine when a small prednisone dose increase is in order in patients with subtle signs of an impending relapse, and to determine when the prednisone dose can be left unchanged in patients with little or no evidence of relapse development (vignettes 2, 3, 6, and 8). Although isolated PMR has long been considered a benign and self-limited disease, it requires long-term systemic glucocorticoid therapy, which induces adverse effects. A recent study by Kremers et al (1) suggests that an increased risk of cardiovascular disease may deserve to be added to the list of adverse effects of long-term glucocorticoid therapy. Although the mean duration of glucocorticoid therapy in patients with PMR is 1 to 2 years (7) and the median duration is 1.83 years (8), many patients require low-dose glucocorticoid therapy for several years. It should be noted that the impact on mortality of a possible cardiovascular risk increase associated with long-term glucocorticoid therapy remains debated (9–13). However, until this issue is resolved, it makes good sense to minimize the use of glucocorticoid therapy in patients with PMR. Availability of parameters strongly associated with glucocorticoid requirements would help physicians to achieve this goal. Using the lowest possible glucocorticoid dose not only minimizes adverse effects, but also improves the annual glucocorticoid discontinuation rate (14). At present, physicians usually base their decisions about glucocorticoid dose on the clinical symptoms associated with ESR and/or CRP values. Both parameters can be misleading, and many reports have alerted physicians to the existence of PMR with low ESR (15–18) or PMR relapse with low ESR or CRP levels. For instance, Kyle et al (19) reported that ESR and CRP levels were normal in 48% and 56%, respectively, of patients experiencing PMR relapses.

The use of the PMR-AS alone or combined with other parameters may help to reduce the relapse rate. In a study by Salvarani et al, 50% of patients experienced at least 1 relapse and 25.5% at least 2 relapses (20). PMR-AS and its components may finally prove to be at least as effective as more expensive tools such as interleukin-6 or interleukin-1β assays, which are not widely available (20, 21).

Overall, our data obtained using vignettes suggest that despite significant interobserver variability in VASph, the PMR-AS is a good indicator of disease activity. However, for predicting a change in prednisone dose, the PMR-AS was not better than MST or than changes between 2 visits in PMR-AS, MST, VASph, or CRP levels. Nevertheless, as discussed in detail in previous reports (4, 22), a composite index is valuable to decrease the variance associated with each measure. A prospective study in a cohort of patients with PMR is needed to determine whether close monitoring with the PMR-AS, its components, and their changes over time predicts a need for a prednisone dose increase, as evaluated based on outcomes. A randomized controlled design with the relapse rate and total glucocorticoid dose as the key endpoints would be ideal.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Dr. Saraux had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. De Bandt, Saraux.

Acquisition of data. Binard, De Bandt, Berthelot, Saraux.

Analysis and interpretation of data. Binard, Saraux.

Manuscript preparation. Binard, De Bandt, Berthelot, Saraux.

Statistical analysis. Binard, Saraux.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

We are grateful to the physicians of the following organizations for their participation in this study: APR (Association des Rhumatologues Parisiens), ARE (Association des Rhumatologues de l'Essone), ARVM (Association des Rhumatologues du Val de Marne), ARLIF (Association des Rhumatologues du Finistère), ARVO (Association des Rhumatologues du Val d'Oise), CRI (Club Rhumatisme et Inflammation), FFR (Fédération Française de Rhumatologie), and SRO (Société de Rhumatologie de l'Ouest).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES