Anakinra for rheumatoid arthritis (Protocol)

Transcription

1 Mertens MT, Singh JA This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2008, Issue 4 1

2 T A B L E O F C O N T E N T S ABSTRACT BACKGROUND OBJECTIVES CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW SEARCH METHODS FOR IDENTIFICATION OF STUDIES METHODS OF THE REVIEW POTENTIAL CONFLICT OF INTEREST ACKNOWLEDGEMENTS SOURCES OF SUPPORT REFERENCES COVER SHEET i

3 Mertens MT, Singh JA This record should be cited as: Mertens MT, Singh JA. Anakinra for rheumatoid arthritis. (Protocol) Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD DOI: / CD pub2. This version first published online: 23 April 2008 in Issue 2, Date of most recent substantive amendment: 06 February 2008 A B S T R A C T This is the protocol for a review and there is no abstract. The objectives are as follows: The aim of this review is to provide a systematic evaluation of the clinical effectiveness of anakinra in adult patients (18 years and older) who have not responded to conventional DMARD treatments. This review will address the following questions: 1. What is the clinical effectiveness of anakinra for the treatment of RA in terms of: a. relieving symptoms? b. delaying disease progression? 2. What are the risks (frequency and severity of adverse events) associated with anakinra treatment in these patients? B A C K G R O U N D Rheumatoid arthritis (RA) is the most common inflammatory arthritis in adults. It is a chronic systemic inflammatory disease with a particular predilection to the joint synovium. Subsequently, the clinical hallmark of RA is polyarticular synovial inflammation of peripheral joints - typically in the hands (MCP, PIPs), causing pain, stiffness, and - for many - some degree of irreversible joint damage and disability. In addition, there is also a significant systemic inflammatory state present, leading to a number of other possible extra-articular effects - including coronary artery disease, pulmonary fibrosis, osteoporosis, and vasculitis(o Dell 2004). RA affects 0.5 to 1% of the population worldwide, of which 75% of affected patients are female. RA is associated with a high degree of disability, leading to an estimated 50% of affected patients toward work disability within ten years. In patient with rheumatoid arthritis, there is an estimated 2.5-fold increase in mortality rate, with life expectancy shortened by an average of 3-7 years (Lipsky 2005). The exact cause of RA remains unclear. It is likely a multi-factorial disease in which there are a number of genetic and environmental influences (Lipsky 2005). There is significant evidence that the pathogenesis of RA is largely immune-mediated (O Dell 2004). The activation of T-cells and macrophages with the consequent release of a number of inflammatory cytokines play a key role in the initiation and maintenance of both the systemic and local synovial inflammation present in RA (Lipsky 2005). In particular, tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6 are considered pivotal synovial and systemic inflammatory mediators in RA. However, a large number of other mediators are also likely contributing to its pathogenesis. The American College of Rheumatology (ACR) guidelines for the effective management of patients with RA require a multidisciplinary approach coordinated with a rheumatologist. The objectives of treatment are to control joint inflammation and to reduce joint damage, minimize loss of function, improve quality of life and reduce pain, and treat extra-articular complications (ACR 2002). Medical therapy for RA falls into two categories: symptomatic treatment and disease-modifying anti-rheumatic drugs (DMARDs). Symptomatic treatment for patients with RA may be achieved with the use of analgesics, most commonly non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs may reduce early morning stiffness and pain and improve quality of life, though have no effect on long-term outcomes of RA. Corticosteroids are also commonly used to acutely reduce inflammation with active disease. They are generally used in short courses for flares or during the initiation of DMARD therapy and generally are not used on a long-term basis 1

4 due to significant side effects. Local therapy - typically with corticosteroid injections to affected joints - have also been found to be beneficial. Other options for symptomatic improvement in RA may also include resting acutely inflamed joints, local application of heat or cold, and regular exercises to help strengthen muscles and improve range of motion in affected joints (ACR 2002). DMARDs are the main-stay for therapy of rheumatoid arthritis. They are a group of medications designed to inhibit specific mediators of inflammation and have been found to significantly reduce and prevent damage to joints (radiographic and clinical) and improve/maintain function of joints in patients with RA. ACR guidelines recommend initiation of DMARD therapy within three months of the diagnosis of rheumatoid arthritis. The most commonly used medication for initiation of RA therapy is methotrexate, though others may include hydroxychloroquine, sulfasalazine, and leflunamide. In the last decade, the Biologics, a new class of DMARDs, has been developed for the treatment of rheumatoid arthritis. These medications act as selective inhibitors to specific cytokines - including TNF-a (etanercept, infliximab, adalimumab) and IL-1 (anakinra) - and have been found to further suppress inflammation and reduce joint damage if previously unresponsive to standard DMARD therapy (ACR 2002). Anakinra (tradename: Kineret) is a recombinant form of a human interleukin-1 receptor antagonist (IL-1ra) and is the first biologic agent designed specifically to modify the biological immune response of IL-1. It has been found in a number of studies to significantly improve clinical signs of RA and was FDA approved in 2001 for moderately-severe RA whom failed at least one DMARD therapy (FDA 2003). It is administered as a daily subcutaneous injection and adverse effects primarily include injection-site reactions, recurrent infections - notably pulmonary infections with history of asthma/copd - and possible risk of malignancy (ACR 2002). O B J E C T I V E S The aim of this review is to provide a systematic evaluation of the clinical effectiveness of anakinra in adult patients (18 years and older) who have not responded to conventional DMARD treatments. This review will address the following questions: 1. What is the clinical effectiveness of anakinra for the treatment of RA in terms of: a. relieving symptoms? b. delaying disease progression? 2. What are the risks (frequency and severity of adverse events) associated with anakinra treatment in these patients? C R I T E R I A F O R C O N S I D E R I N G S T U D I E S F O R T H I S R E V I E W Types of studies All randomised controlled trials (RCTs) comparing anakinra alone or in combination with DMARDs or biologics to placebo or other DMARDs or biologics in patients with Rheumatoid arthritis will be considered. Types of participants Adults aged 18 years and above meeting the ACR 1987 revised criteria for rheumatoid arthritis (Arnett 1988). Types of intervention Anakinra alone or in combination with other drugs. Types of outcome measures A. Primary outcomes Efficacy: a. An ACR20 response rate to treatment with anakinra as defined by the American College of Rheumatology (ACR) (Felson 1995). The variables included in this definition are: tender joint count swollen joint count patient s assessment of pain (VAS or Likert scale) patient and physician assessment of disease activity (VAS or Likert scale) patient assessment of functional ability (HAQ, AIMS, MAC- TAR) inflammatory markers, such as erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) An ACR20 response is defined as a 20 per cent improvement in tender and swollen joints counts and the same level of improvement in three of the five following variables: patient/physician global assessments, pain scores, HAQ score, and laboratory acute phase reactants. b. Improvement in Disease Activity Score (DAS)/DAS28 score - The DAS is a composite index that includes the combination of the values of tender and swollen joints counts, patient s global assessment of disease activity, and ESR value (Van der Heijde 1993). A DAS28 score is used when a twenty-eight joint count is used as the index (Prevoo 1995). Safety: Adverse events, including allergic reactions, injection site reactions Serious adverse events, including serious infections Withdrawals due to lack of efficacy 2

5 Withdrawals due to adverse events Total Withdrawals Number of Deaths B. Secondary outcomes An ACR50 and 70 response criteria as outlined above. Proportion achieving the European League Against Rheumatism (EULAR) Response: EULAR criteria defines responses (good, moderate and none) according to relative changes in the Disease Activity Score (DAS) (Van Gestel 1996) o A good response is defined as a decrease in the DAS or DAS 28 >1.2 from baseline with a final DAS < 2.4 (or DAS 28 < 3.2) (Van Gestel 1996; Fransen 2005) o A none response is defined as a decrease in DAS or DAS 28 < 0.6 or a decrease >0.6 and < 1.2 with a final DAS > 3.7 (or DAS 28 > 5.1) (Van Gestel 1996; Fransen 2005) o Any other scores are regarded as moderate response Low disease activity as defined by DAS score <2.4 or DAS28 <3.2 (Van Gestel 1996; Fransen 2005) Disease remission as defined by DAS <1.6 or DAS28 <2.6 (Prevoo 1996; Fransen 2005) Radiographic progression, as measured by the Sharp, modified Sharp or Larsen methods (Sharp 1971;Larsen 1977; van der Heijde 1989) Recently revised ACR criteria (Felson 2007): e.g.. Nominal measure of improvement such as ACR Step: 0 if ACR20 = 0, 1 if ACR20 but not ACR50, 2 if ACR50 but not ACR70, 3 if ACR70 Health-related quality of life (HRQoL) as measured by the Short Form (SF)-36 or other instruments:(kosinski 2000; Tugwell 2000) o Change in SF-36 Physical and Mental Component Summary (PCS and MCS) scores o Change in SF-36 subscale scores o Proportion achieving the population norms for PCS and MCS (Mean of 50) o Proportion achieving the Minimal Clinical Important Change (MCID) in SF-36 PCS and MCS - defined as a change of on each summary score (Samsa 1999; Kosinski 2000; Tugwell 2000) Function Change, as measured by Composite Function scales: Stanford Health Assessment Questionnaire (HAQ), modified HAQ or others. - HAQ is a self-report questionnaire aimed for assessment of effect of disease on 8 basic categories of functions (dressing, standing, eating, walking, toileting, reach, grip, and instrumental activities) (Fries 1980) - mhaq is modified and simplified version of this scale utilizing the above categories (Pincus 1983) o Proportion achieving a Minimal Clinical Important Change (MCID) in HAQ (defined as change >=0.22) (Wells 1993) or in a similar functional assessment o Proportion achieving HAQ of 0 o Proportion achieving the population norm for HAQ (0.25) (Krishnan 2004) S E A R C H M E T H O D S F O R I D E N T I F I C A T I O N O F S T U D I E S See: Cochrane Musculoskeletal Group methods used in reviews. See: Cochrane Musculoskeletal Group methods used in reviews. The following electronic bibliographic databases will be searched: Cochrane Library and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index (SCI), National Research Register (NRR), NHS Database of Reviews of Effectiveness (DARE), NHS Economic Evaluation Database (NHS EED) and Dissertation Abstracts. The following search strategy has been developed for MEDLINE and was adapted for the other electronic databases: 1 exp arthritis, rheumatoid/ 2 (felty$ adj2 syndrome).tw. 3 (caplan$ adj2 syndrome).tw. 4 rheumatoid nodule.tw. 5 (sjogren$ adj2 syndrome).tw. 6 (sicca adj2 syndrome).tw. 7 still$ disease.tw. 8 bechterew$ disease.tw. 9 (arthritis adj2 rheumat$).tw. 10 or/ Interleukin 1 Receptor Antagonist Protein/ 12 anakinra.tw. 13 kineret.tw. 14 interleukin-1.tw. 15 IL-1ra.tw. 16 Il-a.tw. 17 or/ and clinical trial.pt. 20 randomized.ab. 21 placebo.ab. 22 dt.fs. 23 clinical trial/ 24 randomly.ab. 25 trial.ti. 26 groups.ab. 3

6 27 or/ animals/ 29 humans/ and not not and 32 FDA submissions for new drug applications ( European Public Assessment Reports from the European Evaluation Agency ( the Australian Adverse Drug Reactions Bulletin ( and UK Current Problems in Pharmacovigilance ( Quality assessment strategy will be reviewed for adverse effects. The reference lists of identified publications, including previous meta-analyses, will be reviewed to identify any additional studies and/or citations. No language restrictions will apply and translations will be obtained where necessary. Where information is missing, further information will be sought from the authors or industry. Data from studies with multiple publications will be extracted and reported as a single study. M E T H O D S O F T H E R E V I E W Details of individual outcomes measured through tools above, such as: - Changes in disease activity e.g. ACR improvement criteria, DAS/DAS28 scores, swollen joint count, pain scales, radiographic joint space narrowing and erosion. - Changes in quality of life e.g. HRQoL scores - SF-36 - Changes in function e.g. HAQ or mhaq scores - Adverse events, including serious adverse events - number of deaths Results will be extracted, where possible for the intention to treat population, as raw numbers, plus any summary measures with standard deviations, confidence intervals and p-values where given. Two reviewers will independently, using a structured form, undertake quality assessments. Disagreements will be resolved by discussion, with reference to a third party if there remains disagreement. The information on quality assessment will be presented in table form and summarized within the text of the report. The validity of included studies will be assessed by looking at the method of randomization, the concealment of allocation, the comparability of baseline characteristics between the different arms, blinding, withdrawals and losses to follow-up for each patient. Each criteria will be assessed and graded as yes, no, or unclear. The use of Risk of Bias tables and Selective Outcome reporting per RevMan 5 will be utilized for qualification of assessments. Methods of analysis/synthesis Two reviewers will independently apply the following inclusion/exclusion criteria to all potential studies. Any disagreements will be resolved by discussion, referring to a third party if necessary. Reviewers will not be blinded to any features of the report including authorship however inclusion/exclusion decisions will be made prior to detailed scrutiny of the results. Data extraction strategy Two reviewers will independently extract data using a pre-designed data extraction form. Disagreements will be resolved by discussion, consulting with a third party if there is still disagreement. The following data will be extracted: Details of the study population and baseline characteristics of the intervention and control groups, with particular reference to disease characteristics and previous treatment history. Details of the intervention, including dose, mode of administration, frequency of administration, duration of treatment, and co-administered medications. Details of completion rates across the groups, reasons for withdrawal, frequency of loss to follow up. Clinical relevance tables Clinical relevance tables will be compiled under additional tables to improve the readability of the review. For dichotomous outcomes, the weighted absolute risk difference will be calculated using the risk difference (RD) statistic in RevMan. RR-1 calculates the weighted relative percent change. The number needed to treat (NNT) will be calculated from the control group event rate (unless the population event rate is known) and the relative risk using the Visual Rx NNT calculator (Cates 2003). Continuous outcome tables will also be presented under additional tables. Weighted absolute change will be calculated from the weighted mean difference (WMD) statistic in RevMan when trials using the same scale are pooled. For outcomes pooled on different scales, the standardized mean difference (SMD) is multiplied by the baseline standard deviation in the control group to obtain the weighted absolute change. Relative percent change from baseline will be calculated as the absolute benefit divided by the baseline mean of the control group. NNT is calculated using the Wells calculator software available at the CMSG editorial office. The minimal clinically important difference (MCID) for each outcome will be determined for input into the calculator. Heterogeneity 4

7 In addition to reviewing forest plots, heterogeneity of the data will be formally tested using the chi-square with a p-value <0.10 indicating significant heterogeneity. The I 2 statistic will also be assessed (Higgins 2004). A value greater than 50% may indicate substantial heterogeneity. In the case of substantial heterogeneity, the data will be explored further, including sub-group analyses, in an attempt explain the heterogeneity. Data synthesis In the absence of significant heterogeneity, a fixed effects model will be used. However, if significant heterogeneity is demonstrated, a random effects model will be used for analysis. Where available, the analyses will be based on intention-to-treat data from the individual studies. Publication bias A funnel plot will be performed to assess the possibility of publication bias. Sub-group analysis The following sub-group analyses are planned to explore possible effect size differences: 1. Intervention - variable dosage or duration of treatment 2. Characteristics of participants - severity of baseline disease; age; disease duration; sex; disease with or without peripheral joint involvement. 3. Adult patients with rheumatoid arthritis who have had an inadequate response to methotrexate or patients in whom anakinra is being prescribed in combination with methotrexate. Sensitivity analysis The following sensitivity analyses are planned to explore effect size differences and the robustness of conclusions: 1. Effect of study quality - defined as adequate allocation concealment and outcome assessor blinding 2. Effect of imputation of missing data or statistical transformations. Grading of the evidence In addition, a further ranking based on the level of evidence will be performed in the manner described by Tugwell and approved by the CMSG editorial team (Tugwell 2004). A simplified ranking scale will be used to grade the strength of scientific evidence for the trial intervention. The scale is as follows, in decreasing order: Platinum: A published systematic review that has at least two individual controlled trials each satisfying the following : Sample sizes of at least 50 per group - if these do not find a statistically significant difference, they are adequately powered for a 20% relative difference in the relevant outcome. Blinding of patients and assessors for outcomes. Handling of withdrawals >80% follow up (imputations based on methods such as Last Observation Carried Forward (LOCF) are acceptable). Concealment of treatment allocation. Gold: At least one randomised clinical trial meeting all of the following criteria for the major outcome(s) as reported: Sample sizes of at least 50 per group - if these do not find a statistically significant difference, they are adequately powered for a 20% relative difference in the relevant outcome. Blinding of patients and assessors for outcomes. Handling of withdrawals > 80% follow up (imputations based on methods such as LOCF are acceptable). Concealment of treatment allocation. Silver: A randomized trial that does not meet the above criteria. Silver ranking would also include evidence from at least one study of non-randomised cohorts that did and did not receive the therapy, or evidence from at least one high quality case-control study. A randomised trial with a head-to-head comparison of agents would be considered silver level ranking unless a reference were provided to a comparison of one of the agents to placebo showing at least a 20% relative difference. Bronze: The bronze ranking is given to evidence if at least one high quality case series without controls (including simple before/after studies in which patients act as their own control) or if the conclusion is derived from expert opinion based on clinical experience without reference to any of the foregoing (for example, argument from physiology, bench research or first principles). P O T E N T I A L I N T E R E S T None known. C O N F L I C T O F A C K N O W L E D G E M E N T S We thank Louise Falzon for her support with electronic searches. S O U R C E S O F S U P P O R T External sources of support No sources of support supplied Internal sources of support Minneapolis VA Medical Center USA National Institute of Health USA NIH CTSA Award 1 KL2 RR (Mayo Clinic Center for Clinical and Translational Research) USA 5

8 R E F E R E N C E S Additional references ACR 2002 American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis & Rheumatism 2002;46(2): Arnett 1988 Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al.the American Rheumatism Association revised criteria for the classification of rheumatoid arthritis. Arthritis and Rheumatism 1988;31: Cates 2003 Dr. Christopher Cates EBM website. Available from: URL: http: // visularx@nntonline.net. Visual Rx version 2.0. Dr. Christopher Cates EBM website. Available from: URL: visularx@nntonline.net, FDA 2003 FDA website. Product approval information: Anakinra Felson 1995 Felson DT, et. al. American college of rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis & Rheumatism 1995;38(6): Felson 2007 Felson, et. al, American College of Rheumatology Committee to Reevaluate Improvement Criteria. A Proposed Revision to the ACR20: The Hybrid Measure of American College of Rheumatology Response. Arthritis & Rheumatism 2007;57(2): Fransen 2005 Fransen J, van Riel PLCM. The disease activity score and the EULAR response criteria. Clinical and Experimental Rheumatology 2005;23 (S39):S93 9. Fries 1980 Fries JF, Spitz PW, Kraines RG, Holman HRFries JF, Spitz PW, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis & Rheumatism 1980;23: Higgins 2004 Higgins JPT, Thompson SG. Controlling the risk of spurious findings from meta-regression. Statistics in Medicine 2004;23: Kosinski 2000 Kosinski M, Zhao SZ, Dedhiya S, et al.determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis. Arthritis & Rheumatism 2000;43: Krishnan 2004 Krishnan E, Sokka T, Häkkinen A, Hubert H, Hannonen P. Normative values for the Health Assessment Questionnaire Disability Index: benchmarking disability in the general population. Arthritis & Rheumatism 2004;50: Larsen 1977 Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiologic Diagnosis (Stockholm) 1977;18(4): Lipsky 2005 Lipsky RE. Rheumatoid arthritis. In: KasperDL, FauciAS, LongoDL, BraunwaldE, HauserSL, JamesonJL editor(s). Harrison s Principles of Internal Medicine. 16. McGraw-Hill, O Dell 2004 O Dell JR. Rheumatoid arthritis. Current Rheumatology Diagnosis and Treatment. Imboden J, Hellman DB, Stone JH.. Vol. 1, McGraw- Hill, Pincus 1983 Pincus T, Summey JA, Soraci SA, Jr, Wallston KA, Hummon NP. Assessment of patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire. Arthritis & Rheumatism 1983;26: Prevoo 1995 Prevoo MLL, Van t Hof MA, Kuper HH, Van Leeuwen MA, Van de Putte LBA, Van Riel PLCM. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis & Rheumatism 1995;38:44 8. Prevoo 1996 Prevoo MLL, Van Gestel AM, Van t Hof MA, Van Rijswijk MH, Van de Putte LBA, Van Riel PLCM. Remission in a prospective study of patients with rheumatoid arthritis. British Journal of Rheumatology 1996;35: Samsa 1999 Samsa G, Edelman D, Rothman ML, Williams GR, Lipscomb J, Matchar D. Determining clinically important differences in health status measures: a general approach with illustration to the Health Utilities Index Mark II. Pharmacoeconomics 1999;15: Sharp 1971 Sharp JT, Lidsky MD, Collins LC, Moreland J. Methods of scoring the progression of radiologic changes in rheumatoid arthritis. Correlation of radiologic, clinical and laboratory abnormalities. Arthritis & Rheumatism 1971;14(6): Tugwell 2000 Tugwell P, Wells G, Strand V, et al.clinical improvement as reflected in measures of function and health-related quality of life following treatment with leflunomide compared with methotrexate in patients with rheumatoid arthritis: sensitivity and relative efficiency to detect a treatment effect in a twelve-month placebo-controlled trial. Leflunomide Rheumatoid Arthritis Investigator Group. Arthritis & Rheumatism 2000;43: Tugwell 2004 Tugwell P, Shea B, Boers M, Brooks P, Simon L, Strand V, et al.evidence-based Rheumatology. BMJ Books, van der Heijde 1989 van der Heijde DMFM, van Riel PL, Nuver-Zwart IH, Gribnau FW, Van de Puttte LB. Effects of hydroxychloroquine and sulfasalazine on progression of joint damage in rheumatoid arthritis. Lancet 1989; 1: Van der Heijde 1993 van der Heijde DM, van t Hof M, van Riel PL, van de Putte LB. Development of a disease activity score based on judgment in clinical 6

9 practice by rheumatologists. Journal of Rheumatology 1993;20(3): Van Gestel 1996 van Gestel AM, Prevoo ML, van t Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis & Rheumatism 1996; 39(1): Wells 1993 Wells GA, Tugwell P, Kraag GR, Baker PR, Groh J, Redelmeier DA. Minimum important difference between patients with rheumatoid arthritis: the patient s perspective. Journal of Rheumatology 1993;20: 557. Wolfe 2005 Wolf F, Michaud K, Strand V. Expanding the definition of clinical differences from minimally clinically important differences to really important differences. Analyses of 8931 patients with rheumatoid arthritis. Journal of Rheumatology 2005;32: C O V E R S H E E T Title Authors Contribution of author(s) Anakinra for rheumatoid arthritis Mertens MT, Singh JA All reviewers contributed to the protocol. Issue protocol first published 2005/1 Date of most recent amendment 19 February 2008 Date of most recent SUBSTANTIVE amendment What s New Contact address DOI Cochrane Library number Editorial group Editorial group code 06 February 2008 This protocol was originally published in Issue 1, The authors, A Burls, WK Clark, P Jobanputra, are unable to complete the review. A new review team will complete this review. Marty Mertens Resident, Internal Medicine University of Minnesota 596 Grand Ave., Apt 1 Saint Paul Minnesota USA mtm7575@yahoo.com Tel: / CD pub2 CD Cochrane Musculoskeletal Group HM-MUSKEL 7