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Criteria
2012 provisional classifi cation criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative Bhaskar Dasgupta,1 Marco A Cimmino,2 Hilal Maradit-Kremers,3 Wolfgang A Schmidt,4 Michael Schirmer,5 Carlo Salvarani,6 Artur Bachta,7 Christian Dejaco,8 Christina Duftner,5,9 Hanne Slott Jensen,10 Pierre Duhaut,11 Gyula Poór,12 Novák Pál Kaposi,13 Peter Mandl,14 Peter V Balint,14 Zsuzsa Schmidt,12 Annamaria Iagnocco,15 Carlotta Nannini,16 Fabrizio Cantini,16 Pierluigi Macchioni,6 Nicolò Pipitone,6 Montserrat Del Amo,17 Georgina Espígol-Frigolé,18 Maria C Cid,18 Víctor M Martínez-Taboada,19 Elisabeth Nordborg,20 Haner Direskeneli,21 Sibel Zehra Aydin,21 Khalid Ahmed,22 Brian Hazleman,23 Barbara Silverman,23 Colin Pease,24 Richard J Wakefi eld,24 Raashid Luqmani,25 Andy Abril,26 Clement J Michet,27 Ralph Marcus,28 Neil J Gonter,28 Mehrdad Maz,29 Rickey E Carter,3 Cynthia S Crowson,3,27 Eric L Matteson3,27 ABSTRACT
distal manifestations such as peripheral arthritis, The objective of this study was to develop EULAR/ hand swelling with pitting oedema and carpal tun- ACR classifi cation criteria for polymyalgia rheumatica nel syndrome.1 2 7 11 Polymyalgic presentation is (PMR). Candidate criteria were evaluated in a 6-month common in late-onset rheumatoid arthritis (RA) and prospective cohort study of 125 patients with new spondyloarthritis and is also associated with giant onset PMR and 169 non-PMR comparison subjects with cell arteritis in 10–30% of cases.1 2 Heterogeneity conditions mimicking PMR. A scoring algorithm was in the disease course, uncertainty regarding disease Correspondence to
developed based on morning stiffness >45 minutes assessment parameters, and evolution of alternative (2 points), hip pain/limited range of motion (1 point), diagnoses on follow-up complicate the manage- absence of RF and/or ACPA (2 points), and absence ment of PMR.9 12–15For the above reasons a safe and of peripheral joint pain (1 point). A score ≥4 had 68% specifi c approach preferring a relative underdiagno- 200 1st Street SW, Rochester, Minnesota, USA; sensitivity and 78% specifi city for discriminating all sis to an overdiagnosis is needed in PMR.9 11 comparison subjects from PMR. The specifi city was Uniform responsiveness to low doses of cor- higher (88%) for discriminating shoulder conditions from ticosteroids has been assumed to be a cardinal PMR and lower (65%) for discriminating RA from PMR. feature of PMR. However, there is little hard evi- Adding ultrasound, a score ≥5 had increased sensitivity dence to substantiate this assertion. A previous to 66% and specifi city to 81%. According to these report showed that 3 weeks after starting predni- provisional classifi cation criteria, patients ≥50 years solone 15 mg a day only 55% showed a complete issue of Arthritis & Rheumatism.
old presenting with bilateral shoulder pain, not better response to therapy.10 This also emphasises that explained by an alternative pathology, can be classifi ed clinical trials of novel effective agents are needed as having PMR in the presence of morning stiffness>45 minutes, elevated CRP and/or ESR and new hip pain. The lack of standardised classifi cation criteria These criteria are not meant for diagnostic purposes.
has been a major factor hampering the develop-ment of rational therapeutic approaches12 16 17 and causing diffi culties in evaluating patients in Polymyalgia rheumatica (PMR) is a common infl am- clinical studies. In response to a European League matory rheumatic disease of older individuals and Against Rheumatism (EULAR)/American College a common indication for long-term corticosteroid of Rheumatology (ACR) initiative, a criteria devel-therapy.1–3 PMR is also subject to wide variations opment work group convened in 2005.
of clinical practice, due to the considerable uncer- A systematic literature review, a three-phase tainty related to diagnosis, course, and manage- hybrid consensus process and a wider survey were ment in primary and secondary care.4–7 There is undertaken to identify candidate criteria items.18 no diagnostic laboratory test, infl ammatory mark- The fi rst stage consisted of a meeting of 27 interna- ers are not specifi c, and clinicians often turn to the tional experts who anonymously rated 68 potential corticosteroid response as a ‘test of treatment’ to criteria identifi ed through literature review. In the establish the diagnosis.1 2 8 second round the experts were provided with the Diffi culties in diagnosing and classifying patients results of the fi rst round and re-rated the criteria with PMR are inherent in its defi nitions.9 10 The items. In the third round, the wider acceptance of proximal pain and stiffness syndrome can occur at the chosen criteria (>50% support) was evaluated presentation in many other rheumatological infl am- using a survey of 111 rheumatologists and 53 non- matory illnesses in older people.1 2 7 9 Approximately rheumatologists in North America and western half of patients diagnosed with PMR may have Europe.
Ann Rheum Dis 2012;71:484–492. doi:10.1136/annrheumdis-2011-200329
Criteria
In round three, over 70% of respondents agreed on the impor- clinical and patient-based outcomes in PMR over a 6-month tance of seven core criteria (all achieving 100% support in round two). These were aged 50 years or older, symptom duration 2 weeks or longer, bilateral shoulder and/or pelvic girdle aching, Study population
duration of morning stiffness more than 45 min, elevated eryth- The study was a prospective cohort study that included a rocyte sedimentation rate (ESR), elevated C-reactive protein cohort of patients with new-onset PMR and a comparison (CRP) and rapid corticosteroid response. More than 70% agreed cohort of non-PMR patients with various conditions mimick- on assessing pain and limitation of shoulder (84%) and/or hip ing PMR. Study subjects were recruited from 21 community- (76%) on motion, but agreement was low for peripheral signs based and academic rheumatology clinics in 10 European (eg, carpal tunnel syndrome, tenosynovitis, peripheral arthritis).
countries and the USA. Inclusion criteria for PMR patients The group reached consensus on the need for a prospective were age 50 years or older, new-onset bilateral shoulder pain cohort study to evaluate the disease course from presentation and no corticosteroid treatment (for any condition) within in patients included on the basis of proximal pain and stiff- 12 weeks before study entry, fulfilling all the inclusion and ness with evaluations over a 6-month period while receiving exclusion criteria defined by our previous report and in a standardised corticosteroid treatment regimen.7 18–25 The accordance with the judgement of the participating inves- group also agreed to assess musculoskeletal ultrasound as part tigator that the patient had PMR.18 Every effort was made of the PMR classifi cation criteria. In this paper, we present the to choose patients across the spectrum of disease severity. results from this prospective study and propose new classifi ca- Corticosteroid treatment for PMR patients was initiated according to a predefined treatment protocol starting with 15 mg a day oral prednisone for weeks 1 and 2, 12.5 mg STUDY DESIGN AND METHODS
a day for weeks 3 and 4, 10 mg a day for weeks 6–11, 10 Consensus decisions about study design
mg/7.5 mg every other day for weeks 12–15, 7.5 mg a day for A priori, the work group decided that a specifi c approach weeks 16–25 and tapering according to treatment response should be adopted for classifying newly presenting patients from week 26 onwards. The gold standard for the pre-steroid with bilateral shoulder pain as PMR.18 The group agreed on the diagnosis of PMR was established as above at presentation and when the diagnosis was maintained without an alterna- 1. Patients presenting with polymyalgic syndrome should tive diagnosis at week 26 of follow-up.
have stepwise evaluation on the basis of inclusion and The non-PMR comparison cohort included conditions repre- exclusion criteria, response to a standardised corticosteroid sentative of the types that need to be distinguished from PMR, challenge and follow-up confi rmation. The criteria items in both primary and secondary care. Inclusion criteria for the would be agreed upon clinical features and laboratory non-PMR comparison cohort were age 50 years or older, new- onset bilateral shoulder pain and a diagnosis of either infl am- 2. The need to standardise response to corticosteroid therapy in matory or non-infl ammatory conditions, including new-onset PMR. Because the goal of classifi cation criteria is to identify RA, connective tissue diseases, various shoulder conditions (eg, patients for enrollment into clinical trials before any treat- bilateral rotator cuff syndrome and/or adhesive capsulitis, rota- ment, the response to corticosteroid therapy should be used tor cuff tear, glenohumeral osteoarthritis), fi bromyalgia, gen- in verifying the classifi cation of a patient as having PMR, eralised osteoarthritis and others. Patients known to have the although it should not be used as a classifi cation criterion. condition for more than 12 weeks before the baseline evalu- Because scientifi c evidence is poor as to what constitutes such ation (except fi bromyalgia and chronic pain) were not eligible a response it was agreed (>75% agreement) this response for inclusion. PMR patients with clinical suspicion of giant would be defi ned as greater than 75% global response in cell arteritis were included as part of the comparison cohort clinical and laboratory parameters within 7 days to corticos- because these patients required different corticosteroid doses. teroid challenge with oral 15 mg prednisone or prednisolone Patients in the comparison cohort were included on the basis and subsequent resolution of infl ammatory indices.18 of clinician diagnosis and not on formal criteria. No guidelines 3. That a prospective study would be needed to evaluate were provided for treatment of the conditions in the compari- the disease course from presentation in patients included on the basis of the mandatory ‘core’ criteria of proximal Ethics board approval was obtained at all participating insti- pain and stiffness. New-onset bilateral shoulder pain was tutions before initiation of the study, and all participants gave selected as the main eligibility criterion as the percentage written informed consent before enrollment.
of PMR presenting with hip pain without shoulder pain was very small (<5%), and that as hip girdle pain is due Follow-up and data collection
to a wide range of conditions it would require the enroll- PMR patients were evaluated at baseline, and at 1, 4, 12 and ment of an impracticably large number of comparator 26 weeks. At each follow-up visit, clinical evaluation included patient groups.18 The study would evaluate at prespeci- response to corticosteroid therapy and opinion on the emergence fi ed intervals symptoms, examination, investigations and of alternative diagnoses. Patients not considered as having PMR their evolution with standardised corticosteroid treatment at any time were evaluated and treated according to accepted in a prospective cohort of patients with new-onset bilat- clinical practice. They were excluded from the PMR cohort and eral shoulder pain (comparing the PMR case cohort with included in the non-PMR comparison cohort. Patients in the the comparator cohort of mimicking conditions) over a comparison cohort were evaluated at baseline and at 26 weeks.
Data were collected using standardised data collection forms 4. Musculoskeletal ultrasound should be evaluated in a substudy and questionnaires translated into national languages. Data col- as a feasible mode of investigation of possible PMR. A sec- lection included the candidate inclusion/exclusion criteria items ondary objective of this substudy would be the evaluation of for classifi cation of PMR, physical examination and assessment Ann Rheum Dis 2012;71:484–492. doi:10.1136/annrheumdis-2011-200329
Criteria
of corticosteroid response. Criteria items were age 50 years or examined and found to represent a similar domain. This tech- older, symptom duration 2 weeks or more, bilateral shoulder nique allowed a reduction of the number of variables, as one and/or pelvic girdle aching, recent weight loss greater than 2 kg, variable from each factor was examined in multivariable logistic duration of morning stiffness more than 45 min, elevated ESR, regression models. In addition, to avoid discarding a relevant elevated CRP and rapid response of symptoms to corticosteroids domain as identifi ed by expert consensus, a few of the variables (>75% global response within 1 week to prednisolone/predni- with factor loading between 0.4 and 0.5 were also considered in sone 15–20 mg a day). Pain was assessed using a horizontal 100 mm visual analogue scale (VAS) in four separate locations Classifi cation trees including the variables determined by (shoulder, pelvic, neck and overall) with zero indicating no pain the factor analysis were also considered, but were not found and 100 indicating worst pain. Morning stiffness (in the past to be optimal for distinguishing PMR from comparison sub- 24 h) was assessed in minutes; functional status and quality of jects.31 32 An integer scoring algorithm was defi ned based on the life were assessed by the modifi ed health assessment question- odds ratios in the fi nal multivariable logistic regression model. naire (MHAQ) and short form 36. A 100-mm VAS was also used Performance characteristics (sensitivity, specifi city, etc.) of this for recording global wellbeing measures (patient and physician scoring algorithm were assessed. In addition, the utility of ultra- global) and fatigue. Physical examination included the presence sound assessments for classifying PMR patients was examined or absence of tenderness, pain on movement and limitation of using factor analysis and adding potential ultrasound criteria the shoulders and hips. Aspects of corticosteroid therapy includ- to the scoring algorithm. Odds ratios for clinical criteria varied ing dose, therapeutic response and change in dose and therapy somewhat in the scoring algorithm that included ultrasound cri- teria. Scoring weights based on both models were considered Data regarding laboratory measures (including ESR, CRP, and found to perform similarly, so a common set of scoring rheumatoid factor (RF) and anticitrullinated protein antibody weights was used for the clinical items in both algorithms in (ACPA)) were obtained from clinically ordered tests performed order to ease comparison and application of the criteria.
at each study centre. As the laboratory assays used at each centre Finally, gradient boosting regression tree models, which are varied, test results were classifi ed as normal/abnormal using the a machine learning technique, were examined to determine reference ranges from each centre (see supplementary appendix whether a better prediction could be achieved using a more table S1, available online only). Both PMR and non-PMR sub- jects underwent ultrasound evaluation of shoulders and hips at baseline and at 26 weeks. Evaluations were made according to EULAR guidelines28 to assess for features previously reported to be associated with PMR, including bicipital tenosynovitis, At baseline, 128 patients were recruited into the PMR cohort subacromial and subdeltoid bursitis, trochanteric bursitis and and 184 patients were recruited into the non-PMR comparison glenohumeral and hip effusion. A rheumatologist or radiologist cohort. During follow-up, 10 PMR patients were reclassifi ed as experienced in musculoskeletal ultrasound performed the ultra- not having PMR and moved into the non-PMR cohort. Similarly, sound examination using linear probes with the frequency range eight non-PMR comparison cohort patients were reclassifi ed 6–10 MHz for shoulders and linear or curved array probes with as having PMR and moved into the PMR cohort. In addition, the frequency range 5–8 MHz for hips.
seven patients (one PMR and six non-PMR) were excluded due to missing information, and two non-PMR subjects with age less than 50 years and nine non-PMR subjects with no shoulder pain Statistical analysis
were also excluded. Therefore, the fi nal analysis was based on Descriptive statistics (means, percentages, etc.) were used to summarise the candidate criteria data. Demographics (age and The diagnoses of the 169 non-PMR subjects (see supplemen- gender) and candidate criteria were compared between PMR tary appendix table S2, available online only) were new-onset and comparison subjects using χ2 and rank sum tests. Several RA (49, 29%), new-onset other seronegative arthritis (20, 12%), statistical approaches were considered in order to develop a new-onset connective tissue diseases or vasculitis (9, 5%), scoring algorithm for PMR and to assess the proposed classifi ca- shoulder conditions (52, 31%), chronic pain (26, 15%), infection tion criteria in patients judged by expert clinician investigators (5, 3%), previously undiagnosed malignancy (4, 2%), and two each of endocrinopathy and neurological disorders.
First, logistic regression models to distinguish PMR patients The distribution of the candidate classifi cation criteria for the from all comparison subjects and each subset of comparison sub- 125 PMR patients and 169 non-PMR comparison subjects (all, jects were examined. The c-statistic, a measure of concordance RA only and shoulder condition only) is displayed in table 1. analogous to the area under the receiver operating characteristic Criteria items present in over 80% of the PMR subjects were curve, was used to assess the ability of each individual crite- 2 weeks or greater duration of symptoms, bilateral shoulder rion to distinguish between PMR and comparison subjects. The pain and elevated CRP and/or ESR. Relevant clinical features c-statistic ranges from 0.5 to 1, with 0.5 indicating a criterion that best discriminated RA from PMR were peripheral synovitis, that provides no information. The sensitivity, specifi city and the the presence of RF and/or ACPA and hip pain/limited range of positive and negative likelihood ratios were also examined.
motion. Features best discriminating shoulder conditions from Second, exploratory factor analysis was used to examine the PMR were hip pain/limited range of motion, morning stiffness interdependencies between the candidate criteria.30 Maximum likelihood factor analysis with varimax rotation was used. Maximum likelihood tests were used to examine goodness of fi t Development of a scoring algorithm
(eg, to determine the number of factors). This method is thought Table 2 shows the results of univariate logistic regression to be superior to the eigenvalue greater than 1 or Catell’s scree models to distinguish PMR from all comparison subjects, RA plot method for selecting the number of factors.30 For each only and shoulder conditions only. Criteria items related to factor, variables with factor loadings greater than 0.5 were hip involvement (pain, tenderness, limited movement) had Ann Rheum Dis 2012;71:484–492. doi:10.1136/annrheumdis-2011-200329
Criteria
Table 1 Distribution of candidate criteria for 125 PMR patients and 169 comparison subjects*
Comparison
Shoulder
PMR (N=125)
subjects (N=169)
RA (N=49)
conditions† (N=52)
Morning stiffness duration >45 min‡ tenosynovitis or arthritis)‡Other joint pain‡ Abnormal serum protein electrophoresis‡ *Values are number (percentage) unless specifi ed. Percentages for laboratory results are the number of abnormal tests results divided by the number of patients tested.
ACPA, anticitrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MHAQ, modifi ed health assessment questionnaire; PMR, polymyalgia rheumatica; RF, rheumatoid factor.
†Bilateral rotator cuff syndrome and/or adhesive capsulitis, rotator cuff tear, glenohumeral osteoarthritis.
‡Data not available on all subject.
Table 2 Univariate logistic regression models to distinguish subjects with PMR from comparison subjects
PMR vs all
PMR vs shoulder
comparison subjects
conditions*
Odds ratio
Odds ratio
Odds ratio
Variable
tenosynovitis or arthritis)Other joint pain ACPA, anticitrullinated protein antibody; c, c-statistic; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MHAQ, modifi ed health assessment questionnaire; PMR, polymyalgia rheumatica; RA, rheumatoid arthritis; RF, rheumatoid factor.
*Bilateral rotator cuff syndrome and/or adhesive capsulitis, rotator cuff tear, glenohumeral osteoarthritis.
signifi cant ability to discriminate PMR from all comparison or ESR would be included as a required criterion in the scor- subjects, RA and shoulder conditions based on the c-statistic. ing algorithm for PMR. Similarly, as all subjects in the study Early morning stiffness, MHAQ, weight loss and raised labo- were required to have shoulder pain, this was also included as ratory markers of infl ammation distinguished PMR from com- parison subjects, particularly those with shoulder conditions. Factor analysis revealed that four factors were suffi cient to The presence of ACPA and/or RF, peripheral synovitis and joint represent all the criteria (see supplementary appendix table S3, pains had signifi cant ability (with high c-statistic) to distinguish available online only). These four factors were: hip pain/tender- PMR from RA. In addition, the odds ratios for abnormal CRP ness, peripheral synovitis or other joint pain, morning stiffness and/or ESR were particularly high. This resulted because only and shoulder tenderness. Note that duration of symptoms, neck fi ve PMR patients did not have abnormal CRP and/or ESR, per- aching, carpal tunnel syndrome, weight loss, presence of RF/ haps refl ecting that the diagnosis of PMR is less certain in the ACPA and MHAQ, did not play a prominent role in any of the presence of normal CRP and ESR. Therefore, abnormal CRP Ann Rheum Dis 2012;71:484–492. doi:10.1136/annrheumdis-2011-200329
Criteria
Table 3 Multivariable logistic regression models
Model based on factors without shoulder
Model based on factors plus
Model based on factors
tenderness plus presence of RF/ACPA
presence of RF/ACPA and MHAQ
Criterion
Odds ratio (95% CI)
Odds ratio (95% CI)
Odds ratio (95% CI)
Likelihood ratio test for additional terms ACPA, anticitrullinated protein antibody; MHAQ, modifi ed health assessment questionnaire; RF, rheumatoid factor.
Table 4 Scoring algorithm with and without optional ultrasound criterion—required criteria: age 50 years or greater, bilateral shoulder aching and
abnormal CRP and/or ESR
Clinical criteria (without ultrasound)*
Criteria including ultrasound†
Ultrasound criteriaAt least one shoulder with subdeltoid bursitis and/or biceps tenosynovitis and/or glenohumeral synovitis (either posterior or axillary) and at least one hip with synovitis and/or trochanteric bursitisBoth shoulders with subdeltoid bursitis, biceps tenosynovitis or glenohumeral synovitis ACPA, anticitrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor; CI, confi dence interval.
*The optimal cut point is 4. A patient with a score of 4 or more is categorised as having polymyalgia rheumatica (PMR).
†The optimal cut point is 5. A patient with a score of 5 or more is categorised as having PMR.
§ P = 0.008. ¶ P = 0.009.
Next, multivariable logistic regression models were used included morning stiffness for more than 45 min (two points), hip to determine the importance of each criterion when assessed pain/limited range of motion (one point), absence of RF and/or simultaneously (table 3). Three models were considered: (1) ACPA (two points) and the absence of peripheral joint pain (one including the four factors identifi ed in factor analysis; (2) remov- point). The score was evaluated using all PMR subjects (includ- ing shoulder tenderness and adding presence of RF/ACPA; and ing the fi ve with normal CRP/ESR) and all comparison subjects. (3) subsequently adding MHAQ. While the subsequent addi- This was done to account properly for the infl uence of CRP/ tions appeared to be signifi cant, they also negatively impacted ESR on the performance of the scoring algorithm. A score of 4 the hip pain criteria. The utility of the inclusion of MHAQ was or greater had 68% sensitivity and 78% specifi city for discrimi- questionable, as hip pain was easier to assess than MHAQ in nating all comparison subjects from PMR. The specifi city was a clinical setting. Therefore, the second model, which included higher (88%) for discriminating shoulder conditions from PMR hip pain, other joint pain, morning stiffness and abnormal RF/ and lower (65%) for discriminating RA from PMR. The c-statis- ACPA was deemed the best multivariable model.
tic for the scoring algorithm was 81%. A total of 40 (32%) PMR Additional analyses were performed using classifi cation patients and 38 (22%) comparison subjects was incorrectly clas- trees and assessing combinations of criteria. Classifi cation trees sifi ed. The positive predictive value was 69% and the negative were examined using three sets of potential variables: (1) the predictive value was 77%. Supplementary appendix table S4 four identifi ed factors; (2) adding presence of RF/ACPA; and (3) (available online only) shows the sensitivity and specifi city for subsequently adding MHAQ. The resulting trees were deemed all possible cut points of the scoring algorithm.
inadequate. For example, the second tree, which was fi t using the Finally, gradient boosting regression tree models, which are same fi ve variables that were included in our scoring algorithm, a model averaging technique, were examined to determine had a sensitivity of 66% and specifi city of 66%. This specifi city whether a better prediction could be achieved using a more was lower than the scoring algorithm developed from the logis- complex algorithm. The resulting c-statistic from the gradient tic models. In addition, this tree only included morning stiffness boosting model was 80%, which was quite comparable to the and absence of RF and/or ACPA, so it was inadequate because results for our scoring algorithm. This indicated that we will not it excluded other domains deemed necessary for content valid- be able to make better predictions from these data with another ity. Content validity requires that the set of criteria identifi ed is comprehensive. This was the case in all three trees. Therefore, classifi cation trees were deemed to have poorer performance Ultrasound fi ndings
and content validity than the logistic regression models.
Ultrasound was performed in 120 PMR subjects, 154 of the com- A scoring algorithm was developed (table 4) based on the parison subjects (including 46 with RA and 47 with shoulder multivariable logistic regression model presented in table 3 and conditions) and 21 additional controls (not included in our study Ann Rheum Dis 2012;71:484–492. doi:10.1136/annrheumdis-2011-200329
Criteria
Table 5 Ultrasound fi ndings in 120 patients with PMR, 154 comparison subjects (including 46 with RA and
47 with shoulder conditions) and 21 subjects without shoulder conditions
Subjects without
Comparison
Shoulder
shoulder conditions
(N=120) subjects (N=154)
RA (N=46)
condition (N=47)
subdeltoid bursitis, biceps tenosynovitis or glenohumeral synovitisBoth shoulders with subdeltoid bursitis, biceps tenosynovitis or glenohumeral synovitisAt least one shoulder with subdeltoid bursitis or biceps tenosynovitisBoth shoulders with subdeltoid bursitis or biceps tenosynovitisAt least one hip with synovitis or trochanteric bursitisBoth hips with synovitis or trochanteric bursitisAt least one shoulder and one hip with fi ndings as aboveBoth shoulder and both hips with *p<0.05 compared with PMR.
**p<0.01 compared with PMR.
PMR, polymyalgia rheumatica; RA, rheumatoid arthritis.
Table 6 PMR classifi cation criteria scoring algorithm—required criteria: age 50 years or older, bilateral
shoulder aching and abnormal CRP and/or ESR*
Points without US (0–6)
Points with US† (0–8)
At least one shoulder with subdeltoid bursitis and/or biceps tenosynovitis and/or glenohumeral synovitis (either posterior or axillary) and at least one hip with synovitis and/or trochanteric bursitisBoth shoulders with subdeltoid bursitis, biceps tenosynovitis or *A score of 4 or more is categorised as PMR in the algorithm without US and a score of 5 or more is categorised as PMR in the algorithm with US.
†Optional ultrasound criteria.
ACPA, anticitrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PMR, polymyalgia rheumatica; RF, rheumatoid factor; US, ultrasound.
cohorts) who did not have shoulder conditions. Patients with but less so in discriminating PMR from RA. Table 4 also shows the PMR were more likely to have abnormal ultrasound fi ndings in scoring algorithm including the ultrasound criteria. Supplementary the shoulder (particularly subdeltoid bursitis and biceps teno- appendix table S4 (available online only) shows the sensitivity and synovitis), and somewhat more likely to have abnormal fi ndings specifi city for all possible cut points of the scoring algorithm.
in the hips than comparison subjects as a group (table 5). PMR could not be distinguished from RA on the basis of ultrasound, Response to corticosteroids in PMR
but could be distinguished from non-RA shoulder conditions Complete corticosteroid response at 4 weeks was seen in 71% and subjects without shoulder conditions.
of patients and the response was sustained in 78% of respond-ers at 26 weeks. As expected by the plan for tapering of the Assessing the utility of ultrasound in classifying PMR
corticosteroids, the median prednisone dose decreased from 15 Factor analysis (see supplementary appendix table S5, available mg at baseline to 5 mg at 26 weeks. Response to treatment (per- online only) revealed several strong factors potentially useful for clas- centage improvement in global pain VAS at weeks 4 and 26) sifying patients with PMR from the ultrasound data. The inclusion was highly correlated with percentage improvement in other of ultrasound fi ndings in the scoring algorithm resulted in improving VAS measures (correlation >0.5 and p<0.001 at weeks 4 and 26), the c-statistic to 82%. A score of 5 or greater had 66% sensitivity and but was not correlated with percentage change in corticosteroid 81% specifi city for discriminating all comparison subjects from PMR. dose (p=0.20 at week 4 and p=0.47 at week 26). There was no The specifi city was higher (89%) for discriminating shoulder condi- association between the points obtained on either scoring algo- tions from PMR and lower (70%) for discriminating RA from PMR. rithm and the response to corticosteroids at 4 weeks (Spearman A total of 41 (34%) PMR patients and 30 (19%) comparison subjects correlation coeffi cient 0.09; p=0.38 for the scoring algorithm was incorrectly classifi ed. The positive predictive value was 72% and including ultrasound) and 26 weeks (data not shown), indicat- the negative predictive value was 75%. Therefore, ultrasound fi nd- ing that corticosteroid response can not be used as part of PMR ings were useful in discriminating PMR from shoulder conditions, Ann Rheum Dis 2012;71:484–492. doi:10.1136/annrheumdis-2011-200329
Criteria
We also re-evaluated our risk score model for the scoring algo- and 0–8 (with ultrasound). In the absence of competing diagno- rithm using only the PMR subjects who responded to corticos- ses, a score of 4 or greater (without ultrasound), or 5 or greater teroids. When the fi nal risk score model was re-computed using (with ultrasound) is indicative of PMR. Patients with a score of only the subset of subjects with PMR who responded to corti- less than 4 (based on clinical plus laboratory criteria) cannot be costeroids (and all of the comparison subjects), the odds ratios considered to have PMR. Ultrasound improves the specifi city of for each of the criteria remained essentially unchanged. In addi- PMR diagnosis, and shows particularly good performance in dif- tion, the specifi city was identical and the sensitivity increased ferentiating PMR from non-infl ammatory conditions and thus is by an insignifi cant amount (0.5%).
a recommended investigation for PMR.
Classifi cation criteria for PMR should be useful for identifying patients appropriate for enrollment into clinical trials of novel Blinded re-evaluation of selected PMR patients
medications for the treatment of PMR, and studying long-term and non-PMR controls
outcomes in more homogeneous patient cohorts. Our analyses The re-evaluation exercise showed that most candidate criteria indicate that even typical PMR patients at presentation may vary items performed well in discriminating PMR patients from con- in their response to low-dose corticosteroid therapy, indicating trols. However, a third of the sample of PMR patients/compari- that corticosteroid response is not reliable as a classifi cation fea- son subjects was diffi cult to classify. The high c-statistic levels ture for PMR. This is similar to other rheumatic diseases such as associated with the corticosteroid response and post-treatment RA, in which phenotypically similar patients may exhibit differ- CRP and ESR suggested that the uncertainty originated from the ent responses to disease-modifying antirheumatic drugs.
pivotal role of corticosteroids in the investigator assessment, in deciding whether a patient does or does not have PMR. It raises Strengths and limitations
questions such as whether PMR always responds adequately The strengths of the study relate to harnessing international to corticosteroids and whether polymyalgic RF-positive dis- effort to address a disease area subject to wide variation of prac- ease without peripheral synovitis can occur (see supplementary tice; to develop agreement on the defi nition of what may or may appendix 2, available online only, for details).
not be treated as PMR and what needs further evaluation.
Our study methodology satisfi es the ACR guidelines for the DISCUSSION
development of classifi cation criteria for rheumatic diseases.35 This is the fi rst international multicentre prospective study The consensus-based candidate criteria were generated by examining consensus-based candidate classifi cation criteria for a multispecialty international group whose views were sup- PMR proposed by an international work group. Findings indi- ported by the results of a wide trans-Atlantic survey. The work cate that patients 50 years of age or older presenting with new group suggested a prospective study designed to separate PMR bilateral shoulder pain (not better explained by an alternative patients from comparison subjects in patients included on a sin- diagnosis) and elevated CRP and/or ESR can be classifi ed as hav- gle eligibility criterion (new bilateral shoulder pain in subjects ing PMR in the presence of morning stiffness for more than 45 min, and new hip involvement (pain, tenderness, limited move- This ensured an inception cohort longitudinal observational ment). The absence of peripheral synovitis or of positive RA design wherein the PMR cohort could be compared with the serology increases the likelihood of PMR. While recognising comparison cohort at similar chronological time points of dis- that RF particularly may be present in patients with PMR, the ease. All PMR patients were evaluated before treatment with absence of RF serology is useful in distinguishing PMR from RA corticosteroids, were treated with a standard corticosteroid in older patients for classifi cation purposes.18 34 Ultrasound fi nd- schedule and assessed at predetermined time points. Our study ings of bilateral shoulder abnormalities (subacromial bursitis/ is in keeping with the EULAR/ACR goal of developing rheumatic bicipital tenosynovitis/glenohumeral effusion) or abnormalities disease classifi cation criteria as opposed to diagnostic criteria. in one shoulder and hip (hip effusion, trochanteric bursitis) may We focused on subjects with new-onset/incident disease, and a signifi cantly improve the specifi city of the clinical criteria. These 6-month longitudinal follow-up allowed an accurate evaluation criteria are not meant for diagnostic purposes and have not been of the disease course and diagnoses. Previous criteria for PMR were developed using cross-sectional comparisons. Only two Newer concepts of PMR are revealed by this and other recent of the previous criteria were developed through an evaluative studies—heterogeneity at presentation and course, lack of uni- process.20 36 Neither had a defi nition of the ‘gold standard’ diag- form responsiveness to low-dose steroids and overlap with nosis other than the physician considered the patient to have infl ammatory arthritis. However, we feel that at present these classifi cation criteria provide a basic framework for developing Another strength of our proposed classifi cation criteria is the clinical trials of novel therapies in PMR.
imaging component. Musculoskeletal ultrasound has promise due to widespread availability, feasibility and good research evi- How should the PMR classifi cation criteria be applied?
dence.18 The PMR work group standardised the examination of shoulders and hips by ultrasound for the purposes of the cur- The target population will be patients aged 50 years or older rent study.37 Our fi ndings indicate that ultrasound evaluation of presenting with new-onset (<12 weeks) bilateral shoulder pain hips and shoulders adds signifi cantly to the evaluation of the and abnormal acute phase response. The criteria may only be polymyalgic syndrome. The lack of a ‘gold standard’ and the applied to those patients in whom the symptoms are not bet- challenge of circularity was addressed through a blinded multi- ter explained by an alternative diagnosis. Mimicking conditions rater re-evaluation exercise in selected cases and comparison include the infl ammatory and non-infl ammatory conditions subjects (in supplementary appendix 2, available online only). studied as comparators in this report.
Most of the candidate criteria items performed well. The mis- Four clinical and laboratory criteria along with optional ultra- classifi cation of several subjects refl ects the diffi culty in discrimi- sound criteria (table 4 and table 6) can be applied to eligible nating PMR from other infl ammatory conditions such as RA. patients to identify patients with PMR suitable for low-dose cor- This uncertainty originates from the pivotal role of (and circular ticosteroid therapy. The scoring scale is 0–6 (without ultrasound) Ann Rheum Dis 2012;71:484–492. doi:10.1136/annrheumdis-2011-200329
Criteria
reasoning related to using) the corticosteroid response in decid- Patient consent Obtained.
ing whether a patient does or does not have PMR. Although the Provenance and peer review Not commissioned; externally peer reviewed.
proposed scoring algorithm has high specifi city for identifying Author affi liations 1Department of Rheumatology, Southend University Hospital,
PMR patients,, it is nevertheless unable to predict the subse- quent corticosteroid response, suggesting heterogeneity of dis- 2Department of Internal Medicine, University of Genova, Genova, Italy ease course and treatment response. This has also been reported 3Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA4 Department of Rheumatology, Immanuel Krankenhaus Berlin: Medical Center for Rheumatology Berlin–Buch Berlin, Berlin, Germany While we were able to scrutinise the basis for PMR diagnosis, 5Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria no formal criteria were required for diagnosis of the comparison 6Department of Rheumatology, Arcispedale S Maria Nuova, Reggio Emilia, Italy conditions. This is a limitation of the study. However, the study 7Department of Internal Medicine and Rheumatology, Military Institute of Medicine, was led in all centres by experienced rheumatologists with major clinical and research interest in PMR and related conditions. We Department of Rheumatology, Medical University Graz, Graz, Austria 9Department of Internal Medicine, General Hospital of Kufstein, Kufstein, Austria did not include hip pain without shoulder pain as an eligibility 10Gentofte Hospital, Rheumatology Division, Hellerup, Denmark criterion for reasons discussed in the ‘Methods’ section. Funding 11Service de Médecine Interne, Amiens, France constraints limited the follow-up duration to only 6 months. We 12National Institute of Rheumatology and Physiotherapy, Budapest, Hungary13 were also limited by lack of funding for the central measure- Radiology Department, National Institute of Rheumatology and Physiotherapy, ment of laboratory data. Values of ESR, CRP, RF and ACPA were 14General and Pediatric Rheumatology Department, National Institute of based on local laboratory assays. Our study approach refl ects a Rheumatology and Physiotherapy, Budapest, Hungary pragmatic view, which perhaps lends wider applicability to the 15Rheumatology Unit, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy16 Our classifi cation algorithm had a c-statistic of 81%, which Rheumatology Unit, Ospedale Misericordia e Dolce, Prato, Italy 17Center for Diagnosis Imaging, Hospital Clínic, Barcelona, Spain exceeds the threshold of 80% that is conventionally considered 18Department of Systemic Autoimmune Diseases, Hospital Clinic, University of to be useful in clinical decision-making. However, we suggest that the criteria are regarded as provisional at this point awaiting 19Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Santander, Spain20Sahlgren University Hospital, Department of Rheumatology, Göteborg, Sweden In conclusion, patients aged 50 years or older presenting 21Department of Rheumatology, Marmara University Medical School, Istanbul, Turkey with bilateral shoulder pain and elevated CRP and/or ESR can 22Department of Rheumatology, Princess Alexandra Hospital, Harlow, UK be classifi ed as having PMR in the presence of morning stiff- 23Department of Rheumatology, Addenbrookes Hospital, Cambridge, UK24 ness for more than 45 min, and new hip pain in the absence of Rheumatology and Rehabilitation Research Unit, University of Leeds, Leeds, UK peripheral synovitis or positive RA serology. Using ultrasound, Nuffi eld Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, a score of 5 or greater had 66% sensitivity and 81% specifi city 26Department of Internal Medicine, Division of Rheumatology, Mayo Clinic, for discriminating all comparison subjects from PMR. In our view, this approach can now be used to test eligibility for tri- 27Department of Internal Medicine, Division of Rheumatology, Mayo Clinic, Rochester, als with newer therapies in PMR. A number of future research Minnesota, USA28Rheumatology Associates of North Jersey, Teaneck, New Jersey, USA questions are highlighted, including: (1) Should PMR be con- 29Department of Internal Medicine, Division of Rheumatology, Mayo Clinic, Scottsdale, sidered as a part of the spectrum of late-onset infl ammatory arthritis? (2) Can polymyalgic disease without peripheral syn-ovitis occur in RF-positive disease? (3) Can we diagnose PMR in patients with normal acute phase response? (4) What is the REFERENCES
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Bhaskar Dasgupta, Marco A Cimmino, Hilal Maradit-Kremers, et al.
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