Patients' and clinicians' perspectives towards primary care consultations for shoulder pain: qualitative findings from the Prognostic and Diagnostic Assessment of the Shoulder (PANDA-S) programme.

BACKGROUND: Clinical management of musculoskeletal shoulder pain can be challenging due to diagnostic uncertainty, variable prognosis and limited evidence for long-term treatment benefits. The UK-based PANDA-S programme (Prognostic And Diagnostic Assessment of the Shoulder) is investigating short and long-term shoulder pain outcomes. This paper reports linked qualitative research exploring patients' and clinicians' views towards primary care consultations for shoulder pain. METHODS: Semi-structured interviews were conducted with 24 patients and 15 primary care clinicians. Twenty-two interviews (11 patients, 11 clinicians) were conducted as matched patient-clinician 'dyads'. Data were analysed thematically. RESULTS: Clinicians reported attempts to involve patients in management decisions; however, there was variation in whether patients preferred treatment choice, or for decisions to be clinician-led. Some patients felt uncertain about the decisions made, due to a lack of discussion about available management options. Many General Practitioners expressed a lack of confidence in diagnosing the underlying cause of shoulder pain. Patients reported either not being given a diagnosis, or receiving different diagnoses from different professionals, resulting in confusion. Whilst clinicians reported routinely discussing prognosis of shoulder pain, patients reported that prognosis was not raised. Patients also expressed concern that their shoulder pain could be caused by serious pathology; however, clinicians felt that this was not a common concern for patients. CONCLUSIONS: Findings showed disparities between patients' and clinicians' views towards shoulder pain consultations, indicating a need for improved patient-clinician communication. Findings will inform the design of an intervention to support treatment and referral decisions for shoulder pain that will be tested in a randomised controlled trial.

An evidence-based approach to laboratory tests in usual care of patients with rheumatoid arthritis.

Laboratory tests often are regarded as the most important information in clinical care by patients and doctors, and dominate clinical decisions in many chronic diseases such as diabetes and hyperlipidemia. Most patients with rheumatoid arthritis (RA) have a positive test for rheumatoid factor or anti-cyclic citrullinated peptide antibodies (ACPA), or an elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). However, about a third of RA patients, have negative tests for rheumatoid factor or ACPA, and more than 40% have a normal ESR or CRP at presentation ('false-negative' results). Furthermore, many normal people have a positive test for rheumatoid factor or ACPA but do not have RA, even among those with extensive musculoskeletal pain ('false-positive' results). Abnormal laboratory tests are the most significant predictor of high levels of radiographic progression, and therefore regarded as indicators of 'poor prognosis RA'. By contrast, laboratory tests are far less predictive of severe long-term outcomes such as work disability and premature mortality than functional difficulties reported on a patient questionnaire. A patient questionnaire score is abnormal in 89% of RA patients at presentation, and therefore more useful than ESR or CRP to document subsequent clinical improvement or deterioration. In clinical practice, patient questionnaire scores and RAPID3, an index of physical function, pain, and patient global estimate of status, identify incomplete responses to methotrexate more effectively than ESR. Improved understanding of the limitations of laboratory tests in diagnosis and management of individual patients with RA (and all rheumatic diseases) could improve patient care and outcomes.

Relative efficiencies of the 7 rheumatoid arthritis Core Data Set measures to distinguish active from control treatments in 9 comparisons from clinical trials of 5 agents.

The 7 Core Data Set measures to assess rheumatoid arthritis (RA) were analysed for their relative efficiencies to distinguish active from control treatments in 9 comparisons of 5 agents, methotrexate, leflunomide, infliximab, adalimumab, and abatacept, in 8 clinical trials. Among the 7 measures, levels of relative efficiencies were in a similar range, highest for the physician global estimate, followed by, in order, patient global estimate, physical function on a health assessment questionnaire (HAQ), pain, swollen joint count (SJC), an acute phase reactant laboratory test - erythrocyte sedimentation (ESR) or C-reactive protein (CRP), and tender joint count (TJC). Comparisons of only 3 measures, SJC and ESR/CRP (regarded as optimal indicators of inflammation) and HAQ function (regarded as most likely to be affected by joint damage and therefore least reversible) indicated relative efficiencies for HAQ function at least as great as for SJC or ESR/CRP, although 8 of the nine comparisons involved patients with disease duration > 6.9 years. The findings indicate a strong rationale for a Core Data Set of 7 measures, as no single measure was clearly superior in relative efficiency in all clinical trials. At the same time, 'objective' laboratory ESR/CRP, TJC and SJC were not superior to 'subjective' global estimates of the physician or patient or patient self-report measures of physical function or pain, to differentiate active from control treatments. The findings challenge a traditional view that laboratory and clinical examination findings are more robust than patient self-report scores and physician global estimates to assess and monitor RA patients.

Will shared decision making between patients with chronic musculoskeletal pain and physiotherapists, osteopaths and chiropractors improve patient care?

BACKGROUND: Chronic musculoskeletal pain (CMP) is treated in primary care by a wide range of health professionals including chiropractors, osteopaths and physiotherapists. AIMS: To explore patients and chiropractors, osteopaths and physiotherapists' beliefs about CMP and its treatment and how these beliefs influenced care seeking and ultimately the process of care. METHODS: Depth interviews with a purposive sample of 13 CMP patients and 19 primary care health professionals (5 osteopaths, 4 chiropractors and 10 physiotherapists). RESULTS: Patients' models of their CMP evolved throughout the course of their condition. Health professionals' models also evolved throughout the course of their treatment of patients. A key influence on patients' consulting behaviour appeared to be finding someone who would legitimate their suffering and their condition. Health professionals also recognized patients' need for legitimation but often found that attempts to explore psychological factors, which may be influencing their pain could be construed by patients as delegitimizing. Patients developed and tailored their consultation strategies throughout their illness career but not always in a strategic fashion. Health professionals also reflected on how patients' developing knowledge and changing beliefs altered their expectations. Therefore, overall within our analysis, we identified three themes: 'the evolving nature of patients and health professionals models of understanding CMP'; 'legitimating suffering' and 'development and tailoring of consultation and treatment strategies throughout patients' illness careers'. CONCLUSIONS: Seeking care for any condition is not static but a process particularly for long-term conditions such as CMP. This may need to be taken into account by both CMP patients and their treating health professionals, in that both should not assume that their views about causation and treatment are static and that instead they should be revisited on a regular basis. Adopting a shared decision-making approach to treatment may be useful particularly for long-term conditions; however, in some cases, this may be easier said than done due to both patients' and health professionals' sometimes discomfort with adopting such an approach. Training and support for both health professionals and patients may be helpful in facilitating a shared decision-making approach.

The clinical efficacy of 3 mg/day prednisone in patients with rheumatoid arthritis: evidence from a randomized, double-blind, placebo-controlled withdrawal clinical trial.

A randomised, double-blind, placebo-controlled, withdrawal clinical trial was conducted of prednisone <5 mg/ day versus placebo in 31 patients with rheumatoid arthritis (RA). These patients had been treated with long-term 1-4 mg/day of prednisone, 22 with 3 mg/day, in usual clinical care at a single academic clinical setting. Stable clinical status over 12 weeks prior to screening for the trial was documented quantitatively by patient questionnaire scores. The protocol involved three phases: a) 'equivalence' - 1-4 study prednisone 1-mg tablets taken for 12 weeks, to ascertain their efficacy versus the patient's usual prednisone tablets prior to randomisation; b) 'transfer' - substitution of a 1-mg prednisone or identical placebo tablet at a rate of a single 1-mg tablet every 4 weeks (over 0-12 weeks) to the same number as baseline prednisone; c) 'comparison' - observation over 24 subsequent weeks taking the same number of either placebo or prednisone tablets as at baseline. The primary outcome was withdrawal due to patient-reported lack of efficacy versus continuation in the trial for 24 weeks. Thirty-one patients were randomised, 15 to prednisone and 16 to placebo, with 3 administrative discontinuations. In 'intent-to-treat' analyses, 3/15 prednisone and 11/16 placebo participants withdrew (p=0.03). Among participants eligible for the primary outcome of withdrawal for lack of efficacy, 3/13 prednisone versus 11/15 placebo participants withdrew (p=0.02). No meaningful adverse events were reported, as anticipated. These data document statistically significant differences between the efficacy of 1-4 mg prednisone vs. placebo in only 31 patients, which may suggest a robust treatment effect.

Long-term prednisone in doses of less than 5 mg/day for treatment of rheumatoid arthritis: personal experience over 25 years.

This article summarises the experience of one academic rheumatologist in treatment of patients with rheumatoid arthritis (RA) over 25 years from 1980-2004 with low-dose prednisone, most with <5 mg/day over long periods. A database was available which included medications and multidimensional health assessment questionnaire (MDHAQ) scores for physical function, pain, and routine assessment of patient index data (RAPID3), completed by all patients at all visits in the infrastructure of care. Most patients were treated with long-term low-dose prednisone, often from the initial visit and indefinitely, and with methotrexate after 1990. The mean initial prednisone dose declined from 10.3 mg/day in 1980-1984 to 3.6 mg/day in 2000-2004. Although no formal criteria were used to determine the initial dose, prednisone doses were higher in patients who had more severe MDHAQ/RAPID3 scores, as expected, reflecting confounding by indication. Similar improvements were seen in clinical status over 12 months in patients treated with <5 vs. ≥ 5 mg/day prednisone, and maintained for >8 years. Adverse effects were primarily bruising and skin-thinning, with low levels of hypertension, diabetes, and cataracts, although this information was based only on self-report rather than systematic assessment by a health professional. These data reflect limitations of observational data. However, a consecutive patient database may provide long-term information not available from clinical trials. The data document that prednisone at doses <5 mg/day over long periods appears acceptable and effective for many patients with RA at this time. Further clinical trials and long-term observational studies are needed to develop optimal treatment strategies for patients with RA with low-dose prednisone.

Evidence that endogenous ecotropic virus is not expressed in AKR thymic lymphoid cells of chimeric hosts.

AKR/J thymocytes derived from fetal liver cells do not produce virus when they differentiate in lethally irradiated B10.K mice, whereas spleen and bone marrow cells are virus producers. In contrast, B10.K thymocytes that differentiate in lethally irradiated AKR mice become virus producers. These results suggest that infection of the thymus in AKR mice is initiated in thymic stromal cells.

Quantitative studies of naturally occurring murine leukemia virus infection of AKR mice.

Quantitative studies were made of the organ distribution of murine leukemia virus in AKR mice of various ages. Infectious virus first appeared shortly before or after birth and was continuously present in all mice thereafter. Highest infectivity titers were found in uterus and bone, with spleen slightly lower. Virus titers in normal thymus were relatively low, but increased significantly with the development of thymic lymphoma. The level of viremia decreased after the 1st month of life, but increased sharply in lymphomatous mice.

Experimental chronic glomerulitis.

Three of 16 rabbits injected (intravenously) daily with crystalline bovine serum albumin (BSA) for periods in excess of 10 wk developed chronic glomerulonephritis. In vivo, animals with chronic proteinuria formed variable quantities of soluble complex after injection of antigen while animals without proteinuria exhibited rapid removal of the injected BSA. In vitro studies demonstrated that a major part of the antibodies produced by rabbits with chronic nephritis lacked precipitating properties. Interpretations of these observations were presented in the discussion. It is suggested that, in addition to quantity, quality of antibody plays an important role in the development of chronic serum sickness. Complexes formed with nonprecipitating antibody, which are less rapidly removed from circulation, would have a greater opportunity to deposit in glomeruli and induce inflammation.

A major genetic locus affecting resistance to infection with murine leukemia viruses. I. Tissue culture studies of naturally occurring viruses.

Previous studies have indicated that all naturally occurring murine leukemia viruses propagate significantly more efficiently on embryo cells of either NIH Swiss or BALB/c mice. Studies of the plaquing efficiency of representative viruses on embryo cells of various inbred and hybrid mice indicate that the pattern of sensitivity of the cells is genetically determined. All of 23 strains tested were found to resemble either NIH Swiss (N-type) or BALB/c (B-type) with respect to plaquing efficiency of these viruses. Virus growth on embryo cells derived from (N-type x B-type)F(1) hybrids indicated dominance of resistance to both types of viruses. Backcross hybrid studies indicated that a single locus is the primary determinant of the host-range patterns observed. This locus has no effect on growth of certain laboratory-passaged leukemia viruses which propagate equally well on embryo cells of all mouse strains, F(1), and backcross hybrids. Though other genetic and nongenetic factors influence viral growth or expression in vitro and in vivo, the genetic locus described appears of major significance in the biology of murine leukemia.

A major genetic locus affecting resistance to infection with murine leukemia viruses. II. Apparent identity to a major locus described for resistance to friend murine leukemia virus.

The N-B locus affecting tissue culture infectivity with naturally occurring murine leukemia viruses appears to be identical to the Fv-1 locus described for sensitivity to Friend leukemia virus. Results of tissue culture studies were parallel to results of studies in vivo and indicate that the F-S virus is N-tropic and the F-B virus is NB-tropic. Inbred and partially congenic mouse strains sensitive at Fv-1 show N-type sensitivity; strains resistant at Fv-1 show B-type sensitivity. The Fv-2 locus does not appear to exert significant effect in tissue culture. Knowledge of N-B type has been useful in predicting Fv-1 sensitivity.

Active and latent forms of transforming growth factor beta activity in synovial effusions.

We have evaluated the possible involvement of TGF-beta in rheumatoid arthritis by assay of 16 cell-free synovial fluids for the presence of its active and "latent" forms. Evidence has been obtained for TGF-beta-like activity in synovial effusions by four criteria: (a) TGF-beta receptor competition, (b) soft-agar colony formation of AKR-2B and NRK-49F indicator cells, (c) immunological neutralization of the biological activity, and (d) biochemical activation of a latent form.

Underestimation of the efficacy, effectiveness, tolerability, and safety of weekly low-dose methotrexate in information presented to physicians and patients.

Ten specific examples of the underestimation of the efficacy, effectiveness and tolerability, and overestimation of adverse events of weekly, low-dose methotrexate, administered with folic acid, in treatment of rheumatic diseases are summarised. These examples include: 1) meta-analyses of clinical trials suggest that methotrexate has an efficacy similar to other disease-modifying anti-rheumatic drugs (DMARDs); 2) information in textbooks and websites may overstate adverse events and drug interactions associated with weekly low-dose methotrexate; 3) information presented to patients when filling a prescription for methotrexate understates 'side effects' of RA and overstates those of methotrexate; 4) an admonition to patients to refrain entirely from consumption of alcohol while taking methotrexate may be unnecessary; 5) frequent blood testing in patients who take methotrexate may be overused; 6) eligibility of only a small minority of patients for clinical trials to compare biologic agents and methotrexate; 7) Step-up design in most comparisons of biologic agents with methotrexate includes only patients who had experienced an incomplete response to methotrexate; 8) in parallel design trials, the efficacy of biologic agents is not substantially greater than that of methotrexate; 9) low, inflexible dosage schedules of methotrexate and requirement for withdrawal with minimal liver function abnormalities in many clinical trials may underestimate efficacy, effectiveness, tolerability and safety; 10) interpretation of clinical trial results may overstate the clinical significance of lower radiographic progression in patients treated with biologic agents versus patients treated with methotrexate. More accurate interpretation of information for physicians and other health professionals, as well as patients, concerning use of weekly low-dose methotrexate in contemporary care could improve care and outcomes for patients with RA and other rheumatic diseases.

Test-retest reliability of disease activity core set measures and indices in rheumatoid arthritis.

AIM: To examine the test-retest reliability of the rheumatoid arthritis (RA) core disease activity measures and derived composite indices. METHODS: A total of 28 stable patients with RA had 2 complete assessments within 1 week, which included the 7 RA core disease activity measures and derived disease activity indices (28-joint Disease Activity Score (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), RA Disease Activity Index (RADAI) and Routine Assessment of Patient Index Data (RAPID3)). The intraclass correlations (ICC), the smallest detectable difference (SDD) and minimal detectable change as percentage of the maximum score (MDC%) were estimated as measures of test-retest reliability. RESULTS: Correlations for the disease activity indices were high. SDDs (MDC%) to detect a true improvement or deterioration with 95% confidence were: DAS28 1.32 (14.4%), SDAI 8.26 (9.6%), CDAI 8.05 (10.6%), RAPID3 1.48 (14.8%) and RADAI 1.49 (14.9%). Thus, SDDs were rather high, and the MDC% values were of a similar magnitude of 10% to 15% for all seven core data set measures. CONCLUSIONS: SDDs of the DAS28, SDAI and CDAI were close to limits to detect important improvement. Clinicians should be aware of measurement error. Nonetheless, RA core data set measures and indices obtained from a health professional, laboratory and patient self-report had similar reliability.

Efficacy of prednisone 1-4 mg/day in patients with rheumatoid arthritis: a randomised, double-blind, placebo controlled withdrawal clinical trial.

OBJECTIVE: A randomised double-blind placebo controlled withdrawal clinical trial of prednisone versus placebo in patients with rheumatoid arthritis (RA), treated in usual clinical care with 1-4 mg/day prednisone, withdrawn to the same dose of 1 mg prednisone or identical placebo tablets. METHODS: All patients were from one academic setting and all trial visits were conducted in usual clinical care. Patients were taking stable doses of 1-4 mg prednisone with stable clinical status, documented quantitatively by patient questionnaire scores. The protocol included three phases: (1) equivalence: 1-4 study prednisone 1 mg tablets taken for 12 weeks to ascertain their efficacy compared with the patient's usual tablets before randomisation; (2) transfer: substitution of a 1 mg prednisone or identical placebo tablet every 4 weeks (over 0-12 weeks) to the same number as baseline prednisone; (3) comparison: observation over 24 subsequent weeks taking the same number of either placebo or prednisone tablets as at baseline. The primary outcome was withdrawal due to patient-reported lack of efficacy versus continuation in the trial for 24 weeks. RESULTS: Thirty-one patients were randomised, 15 to prednisone and 16 to placebo, with three administrative discontinuations. In "intent-to-treat" analyses, 3/15 prednisone and 11/16 placebo participants withdrew (p = 0.03). Among participants eligible for the primary outcome, 3/13 prednisone and 11/15 placebo participants withdrew for lack of efficacy (p = 0.02). No meaningful adverse events were reported, as anticipated. CONCLUSION: Efficacy of 1-4 mg prednisone was documented. Evidence of statistically significant differences with only 31 patients may suggest a robust treatment effect.

Disparities in rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the QUEST-RA database.

OBJECTIVE: To analyse associations between the clinical status of patients with rheumatoid arthritis (RA) and the gross domestic product (GDP) of their resident country. METHODS: The Quantitative Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST-RA) cohort includes clinical and questionnaire data from 6004 patients who were seen in usual care at 70 rheumatology clinics in 25 countries as of April 2008, including 18 European countries. Demographic variables, clinical characteristics, RA disease activity measures, including the disease activity score in 28 joints (DAS28), and treatment-related variables were analysed according to GDP per capita, including 14 "high GDP" countries with GDP per capita greater than US$24,000 and 11 "low GDP" countries with GDP per capita less than US$11,000. RESULTS: Disease activity DAS28 ranged between 3.1 and 6.0 among the 25 countries and was significantly associated with GDP (r = -0.78, 95% CI -0.56 to -0.90, r(2) = 61%). Disease activity levels differed substantially between "high GDP" and "low GDP" countries at much greater levels than according to whether patients were currently taking or not taking methotrexate, prednisone and/or biological agents. CONCLUSIONS: The clinical status of patients with RA was correlated significantly with GDP among 25 mostly European countries according to all disease measures, associated only modestly with the current use of antirheumatic medications. The burden of arthritis appears substantially greater in "low GDP" than in "high GDP" countries. These findings may alert healthcare professionals and designers of health policy towards improving the clinical status of patients with RA in all countries.

Demonstration of biological activity of a murine leukemia virus of New Zealand black mice.

Although New Zealand Black mouse embryo and adult tissues show evidence of murine leukemia viral particles and antigens, efforts to demonstrate biological activity of a murine leukemia virus by standard methods have proved negative. Cocultivation of tissues of these mice with non-virus-yielding hamster cells transformed by Moloney sarcoma virus, however, has resulted in the rescue of a pseudotype sarcoma virus, presumably carrying the New Zealand Black mouse leukemia virus coat. This virus has an unusual host restriction, producing foci of cell alteration only in rat cells.

Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardised operating procedures, which use a three-step approach: (1) expert-based definition of relevant research questions (November 2006); (2) systematic literature search (November 2006 to May 2007); and (3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature the expert panel recommended that each trial should report the following items: (1) disease activity response and disease activity states; (2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; (3) baseline disease activity levels (in general); (4) the percentage of patients achieving a low disease activity state and remission; (5) time to onset of the primary outcome; (6) sustainability of the primary outcome; (7) fatigue. CONCLUSIONS: These recommendations endorsed by EULAR and ACR will help harmonise the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Ascendancy of weekly low-dose methotrexate in usual care of rheumatoid arthritis from 1980 to 2004 at two sites in Finland and the United States.

OBJECTIVES: To analyse consecutive patients with RA in usual rheumatology care between 1980 and 2004 at two settings for the proportion of patients taking MTX, interval from patient presentation to MTX prescription and radiographic and functional status outcomes. METHODS: Longitudinal study of all patients seen in usual care between 1980 and 2004, 1982 consecutive patients in Jyväskylä, Finland and 738 consecutive patients in Nashville, TN, USA. Clinical status was assessed as Larsen radiographic scores in Jyväskylä and modified health assessment questionnaire (MHAQ) in Nashville. RESULTS: The probability of initiating MTX within 5 yrs after presentation increased from <5% in Jyväskylä before 1989 to >90% in 2000-04, and from 25% in Nashville in 1980-84 to >90% since 1995. The median interval from presentation to MTX initiation in Jyväskylä was 14 yrs in 1980-84 vs 8.6 in 1985-89, 4.5 in 1990-94, 1.8 in 1995-99 and <1 yr in 2000-05; in Nashville, median intervals were 8.6 yrs in 1980-84, 4.4 years in 1985-89, and <2 months in 1990-95, 1995-2000 and 2000-05. Patient outcomes were substantially improved in both settings: in Jyväskylä, mean 5-yr Larsen radiographic scores (0-100) were 15.7 in 1980-84 vs 4.0 in 1995-99; in Nashville, mean MHAQ scores (0-3) for physical function were 1.13 in 1980-84 vs 0.57 in 2000-04. CONCLUSION: Early MTX in usual clinical care of RA increased from <5% in 1980 to >90% in 2004. Over this period, substantially improved outcomes were seen, most of which antedated biological agents.