Abstract: OBJECTIVE: This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study (CAPRA 1) investigated the long-term safety and efficacy of prednisone chronotherapy with a novel modified-release (MR) prednisone for up to 12 months. METHODS: Of 288 patients with rheumatoid arthritis originally randomised to MR or immediate-release (IR) prednisone, 249 continued with prednisone chronotherapy (2-10 mg/day) in the 9-month open-label extension. Duration of morning stiffness of the joints (MS), disease activity scores (DAS28), American College of Rheumatology (ACR20) responses and plasma levels of interleukin 6 (IL-6) were assessed. Safety was analysed from adverse event reports and laboratory investigations. RESULTS: During the 3-month double-blind phase, patients in the MR group achieved a reduction in MS of 33.1% while no change was observed in the IR group. After 6 months of treatment, MS was reduced in the IR/MR group by 54% and in the MR/MR group by 56%. MS reduction after 12 months was 45% (IR/MR group) and 55% (MR/MR group). Plasma levels of IL-6 declined on MR treatment. DAS28 was reduced from 5.8 to 4.8 (MR/MR group) and 4.9 (IR/MR group), respectively. 37% of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria. Adverse events did not differ from the known profile of low-dose prednisone. CONCLUSIONS: Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which resulted in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months.
Abstract: OBJECTIVE: To determine the efficacy and safety of pamapimod in adult patients with active rheumatoid arthritis (RA) who had an inadequate clinical response to methotrexate (MTX). METHODS: Patients receiving stable doses of MTX were randomised to one of six dose groups and received 12 weeks of double-blind pamapimod (up to 300 mg once daily) or matching placebo. The primary efficacy measure was the proportion of patients with > or =20% improvement in RA based on the American College of Rheumatology criteria (ACR20) at 12 weeks. Secondary measures were ACR50, Disease Activity Score (DAS)/European League Against Rheumatism (EULAR) responses and the individual ACR core set of parameters. Safety measures included adverse events (AEs), laboratory testing and immunology assessments. RESULTS: On a background of MTX, the percentage of patients with an ACR20 response at week 12 in the pamapimod groups (31% to 43%) was not significantly different from placebo (34%). Secondary efficacy end points showed a similar pattern. AEs were typically mild and included infections, gastrointestinal disturbances, dizziness and rashes; AEs resulting in discontinuation of study drug were primarily attributed to infections. CONCLUSION: In patients with active RA receiving stable doses of MTX, pamapimod showed non-significant improvement in efficacy outcomes compared to placebo.
Abstract: INTRODUCTION: Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries. METHODS: The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses. RESULTS: At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score. CONCLUSIONS: Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.
Abstract: OBJECTIVE: Use of the American College of Rheumatology classification criteria for the clinical diagnosis of fibromyalgia syndrome (FMS) is under debate. The Regional Pain Scale (RPS) had been developed for the diagnosis of FMS in clinical practice and in survey settings (survey criteria of FMS). So far a German version has not been validated. METHODS: A total of 216 patients with FMS, 53 with active rheumatoid arthritis (RA) and 60 with depressive disorder, recruited from clinical institutions completed the RPS. Forty-three patients with FMS filled in the RPS within 8 weeks a second time. RESULTS: The intraclass coefficient of FMS diagnosis after 8 weeks was 0.78 (test-retest reliability). The 7-day interval of pain was criticized by physicians. The absence of some articular pain regions was criticized by patients (face validity). The concordance of FMS diagnoses to survey and ACR criteria was 84.7% (+/-1.1); 45.3% of the patients with RA and 38.3% of the patients with depressive disorder met the survey criteria of FMS (discriminant validity). CONCLUSION: The RPS has good reliability and convergent validity, but limited discriminant validity. The RPS is suited as a screening instrument for the diagnosis of FMS in clinical practice.
Abstract: OBJECTIVES: The Internet supports interactive patient assessments, online documentation and access to online electronic health records (EHRs), but little is known about the acceptance of these features and trends in rheumatology patients. Therefore, we studied patients' attitudes and willingness to participate in online patient (self-)documentation. METHODS: We interviewed 153 consecutive outpatients with rheumatoid arthritis, systemic lupus erythematosus or spondyloarthritis using a paperbased self-administered questionnaire. To detect recent trends in patients' perception we compared our 2006 data to the results of our survey conducted in 2001. P-values provided in the abstract reflect the comparisons from 2001 and 2006. RESULTS: Patients were predominantly female (69.3%; n.s.), mean age was 45.7+/-14.4 years (n.s.), and 68.6% (+18.6% compared to 2001; p<0.001) reported regular Internet use. Confidence in the Internet and reliability of online information were rated unchanged to 2001. Internet users appreciated to access their EHR online in 68.6% (+13.8% compared to 2001; p<0.01), (self-)monitor the course of their disease online in 80.0%, and answer outcome questionnaires online in 67.6%. Internet users considered computers as valuable instruments in the patient-doctor relationship (88.4%), 58.8% were not convinced that computer use influences the relationship positively. CONCLUSIONS: Attitudes of patients with rheumatic disorders (Internet users and non-users) towards online EHRs have improved since 2001, online applications for patient assessments and disease (self-)management in rheumatology seem feasible now. Nevertheless, unchanged low confidence rates in the Internet and in the reliability of medical information derived from the Internet should sound a note of caution regarding the implementation of such services.
Abstract: OBJECTIVE: Exploring patients' Internet use, their online needs and requirements, expectations and attitudes towards the Internet is mandatory to effectively provide interactive online applications and information. METHODS: Within a prospective study, 153 consecutive outpatients with rheumatoid arthritis, systemic lupus erythematosus or spondyloarthritis answered a paper-based questionnaire investigating their Internet use, interests, pattern and degree of utilization. Sociodemographic and functional disability data were collected. The data were compared with our survey of 2001 and to the normal German population. RESULTS: Patients were predominantly female (69.3%; n.s.). Mean age was 45.7+/-14.4 years (n.s.). 68.6% (+18.6%, p=0.0027) reported regular Internet use for 5.0+/-2.6 yrs. Internet use in 2006 is still age- and education-dependent (p<0.001, p=0.003). Differences by gender observed in 2001 no longer existed as women increased their Internet use from 2.9 to 6.1 hours/week (p=0.001, p=0.0006). Searching for health-related information remained an important topic. Interest in e-communication and interactive applications strongly increased. Independently of gender and functional disability, patients' future online interests focussed on information on diseases, medications, health care providers and patient education. Confidence in the Internet and reliability of information were rated unchanged since 2001. CONCLUSION: Gender no longer has significant impact on Internet use. The great potentials of Internet services-well accepted by patients and contributing substantially to more effective and improved disease (self-) management strategies-should encourage rheumatologists to provide interactive applications and high-quality information on Internet platforms and in routine patient care. Continuous research to explore the effects of Internet-delivered information on patients' attitudes,expectations, behaviour and outcome is required.
Abstract: Abstract
Background: Since the mid 70s most rheumatologists prefer a circadian administration regimen with one morning dose of glucocorticoids (GC) in the treatment of rheumatoid arthritis (RA). It is not known whether an ultradian regimen with administration intervals of less than 24 h will yield better therapeutic results, but will probably cause a more pronounced suppression of the hypothalamus-pituitary-adrenal (HPA) axis. This open question was the objective for this monocentric, randomised, single-blind study.
Patients and Methods: 60 patients with active RA were treated with prednisolone given either in a circadian or an ultradian regimen. Treatments started with a daily dose of 40 mg which was down-titrated over 40 days to 5 mg. Before and after treatments with prednisolone, the HPA axis function was tested by corticotropin-releasing hormone (CRH) tests.
Results: Clinical efficacy and safety were found to be comparable for both schemes. Cortisol concentrations after the CRH tests revealed a slightly more pronounced suppression of the HPA axis function (p=0.07) in the ultradian treatment group of patients.
Conclusions: In general, concerning efficacy as well as safety, our study supports a circadian administration of GC in the treatment of RA.
Abstract: INTRODUCTION: Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA). METHODS: The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents. RESULTS: Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies. CONCLUSIONS: In this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.
Abstract: The pro-inflammatory cytokine TNF alpha (TNF) has a key position in the pathogenesis of various infectious and inflammatory diseases. Clarification of its pivotal role in the pathogenesis of rheumatoid arthritis, spondyloarthritis, uveitis, psoriasis and inflammatory bowel disease has resulted in the successful development of TNF- blocking therapies, which have disease-modifying properties that exceed the effects of conventional therapeutic options. For this reason data on the concurrence of several chronic inflammatory diseases have led to the hypothesis of common pathogenetic processes of cytokine dysregulation. The acronym TRECID describes this concept of "TNF RElated Chronic Inflammatory Diseases". Physicians of different specialties have integrated new therapeutic options with TNF-blocking therapies into their strategies for the management of the affected patients. Thus the concept of TRECID can be regarded as a role model for a dynamic, interdisciplinary cooperation based on shared pathophysiological aspects.
Abstract: OBJECTIVE: Traditional outcome measures in randomized controlled trials (RCT) include well-established response criteria as well as ACR EULAR responses using Disease Activity Score 44 (DAS44)/DAS28 to assess improvement; however, a measure to assess worsening of disease has yet to be developed. This special interest group (SIG) was established to develop an evidence-based, consensus-driven standard definition of "flare" in rheumatoid arthritis (RA). METHODS: At OMERACT 8, the need for a standardized definition of RA flare was recognized; interested individuals developed a proposal to form a SIG. A literature review was performed to identify publications and abstracts with flare definitions applied in RA, JIA, and lupus RCT as well as concerning patient perspectives on disease worsening. A SIG was held at OMERACT 9 with breakout sessions for patients and investigators. RESULTS: The RA flare SIG was attended by about 120 participants, including 11 patients. Patients and investigators held separate breakout sessions to discuss various aspects of disease worsening. The following consensus was obtained at OMERACT 9: a working definition of flare should indicate worsening of disease activity (88%), persistence, and duration as critical elements (77%), and consideration of change or increase in therapy (74%). CONCLUSION: A working definition of RA flare was developed based on these votes: flare is any worsening of disease activity that would, if persistent, in most cases lead to initiation or change of therapy; and a flare represents a cluster of symptoms of sufficient duration and intensity to require initiation, change, or increase in therapy. Using this working definition, evaluation of candidate domains will be conducted via Delphi exercise and further informed by patient focus groups. Validation of candidate definitions in appropriate RCT will be required.
Abstract: 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.
Abstract: OBJECTIVE: Regular physical activity is associated with decreased morbidity and mortality. Traditionally, patients with rheumatoid arthritis (RA) have been advised to limit physical exercise. We studied the prevalence of physical activity and associations with demographic and disease-related variables in patients with RA from 21 countries. METHODS: The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST-RA) is a cross-sectional study that includes a self-report questionnaire and clinical assessment of nonselected consecutive outpatients with RA who are receiving usual clinical care. Frequency of physical exercise (>or=30 minutes with at least some shortness of breath, sweating) is queried with 4 response options: >or=3 times weekly, 1-2 times weekly, 1-2 times monthly, and no exercise. RESULTS: Between January 2005 and April 2007, a total of 5,235 patients from 58 sites in 21 countries were enrolled in QUEST-RA: 79% were women, >90% were white, mean age was 57 years, and mean disease duration was 11.6 years. Only 13.8% of all patients reported physical exercise>or=3 times weekly. The majority of the patients were physically inactive with no regular weekly exercise: >80% in 7 countries, 60-80% in 12 countries, and 45% and 29% in 2 countries, respectively. Physical inactivity was associated with female sex, older age, lower education, obesity, comorbidity, low functional capacity, and higher levels of disease activity, pain, and fatigue. CONCLUSION: In many countries, a low proportion of patients with RA exercise. These data may alert rheumatologists to motivate their patients to increase physical activity levels.
Abstract: BACKGROUND: There is insufficient evidence for the long-term efficacy and safety of anti-tumour necrosis factor therapy in patients with ankylosing spondylitis (AS). This is the first report on the treatment with infliximab over 5 years. METHODS: As part of a multicentre randomised trial, 69 patients with active AS at baseline (BL) have been continuously treated with infliximab (5 mg/kg i.v. every 6 weeks)--except for a short discontinuation after 3 years (FU1). The primary outcome of this extension was remission according to the ASsessment in Ankylosing Spondylitis (ASAS) criteria at the end of year 5 of the study (FU2). RESULTS: Of the 43 patients who completed year 3, 42 agreed to continue, 38 of which (90.5%) finished year 5 (55% of 69 initially). Partial clinical remission was achieved in 13 of 38 patients (34.2%) at FU1 and FU2. At FU2, the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 2.5+/-1.9 (BL:6.4, FU1:2.5). BASDAI values <4 were seen in 79% of patients at both, FU1 and FU2. ASAS 20% and 40% responses were seen in 32 (84%) and 24 (63%) patients at FU2, respectively. Most patients classified as non-responders at FU2 were part-time responders, as all but one patient achieved an ASAS 20% response at least once within the last 2 years. Three types of responders were identified. No major side effects occurred during years 4 and 5 of infliximab therapy. CONCLUSIONS: Infliximab is safe and efficacious in AS patients over 5 years. The majority of the patients remained on treatment and had rather persistent levels of low disease activity. Different response types could be identified.
Abstract: BACKGROUND: Circadian rhythms are changed in patients with rheumatoid arthritis. A new modified-release delivery system has been developed which adapts the release of the administered glucocorticoid to the circadian rhythms of endogenous cortisol and disease symptoms to improve the benefit-risk ratio of glucocorticoid therapy in rheumatoid arthritis. We aimed to assess the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with this disease. METHODS: In a 12-week, multicentre, randomised, double-blind trial, 288 patients with active rheumatoid arthritis were randomly assigned to either a modified-release prednisone tablet (n=144) or to an immediate-release prednisone tablet (n=144). The modified-release tablet was taken at bedtime and prednisone was released with a delay of 4 h after ingestion. This treatment was compared with morning administration of immediate-release prednisone as an active comparator. The primary outcome measure was duration of morning stiffness of the joints. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00146640. FINDINGS: The mean relative change in duration of morning stiffness of the joints from baseline to end of treatment was significantly higher with modified-release prednisone than with immediate-release prednisone (-22.7%vs -0.4%; difference=22.4% [95% CI 0.49-44.30]; p=0.045). Patients in the prednisone modified-release group achieved a mean reduction of 44.0 (SD 136.6) min compared with baseline. The absolute difference between the treatment groups was 29.2 min (95% CI -2.59 to 61.9) in favour of modified-release prednisone (p=0.072). The safety profile did not differ between treatments. INTERPRETATION: Modified-release prednisone is well tolerated, convenient to administer, and produces a clinically relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone.
Abstract: BACKGROUND: Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses. Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis. METHODS: In this double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis were randomly assigned with an interactive voice response system, stratified by site with a randomisation list provided by the study sponsor, to receive tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable pre-study doses (10-25 mg/week). Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20% improvement in both swollen and tender joint counts. The primary endpoint was the proportion of patients with 20% improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria (ACR20 response) at week 24. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00106548. FINDINGS: The intention-to-treat analysis population consisted of 622 patients: one patient in the 4 mg/kg group did not receive study treatment and was thus excluded. At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4.0 [95% CI 2.6-6.1], p<0.0001 for 8 mg/kg vs placebo; and 2.6 [1.7-3.9], p<0.0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group. INTERPRETATION: Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis. FUNDING: F Hoffmann-La Roche, Chugai Pharmaceutical.
Abstract: OBJECTIVE: We evaluated the feasibility of electronic data capture of self-administered patient questionnaires using a Tablet PC for integration in routine patient management; we also compared these data with results received from corresponding paper-pencil versions. METHODS: Standardised patient questionnaires (FFbH/HAQ, BASDAI, SF-36) were implemented in our documentation software. 153 outpatients (rheumatoid arthritis, systemic lupus erythematosus, spondyloarthritis) completed sets of questionnaires as paper-pencil and electronic versions using a Tablet PC. The quality and validity of data obtained using a Tablet PC and the capability of disabled patients to handle it were assigned; patients' experiences, preferences and computer/internet use were also assessed. RESULTS: Scores obtained by direct data entry on the Tablet PC did not differ from the scores obtained by the paper-pencil questionnaires in the complete group and disease subgroups. No major difficulties using the Tablet PC occurred. 62.1% preferred remote data entry in the future. Seven (4.6%) patients felt uncomfortable with the Tablet PC due to their rheumatic disease. CONCLUSIONS: Self-administered questionnaires via Tablet PC are a facile and capable option in patients with rheumatic diseases to monitor disease activity, efficacy and safety assessments continuously. Tablet PC applications offers directly available data for clinical decision-making improves quality of care by effective patient monitoring, and contributes to patients' empowerment.
Abstract: INTRODUCTION: IL-1beta is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production. METHODS: ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1beta, was generated to study the potent and long-lasting neutralization of IL-1beta in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA). RESULTS: The mouse IL-1 receptor cross-reacts with human IL-1beta, and it was demonstrated that ACZ885 can completely suppress IL-1beta-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study--the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study. CONCLUSION: ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00619905.
Abstract: BACKGROUND: Several clinical and experimental lines of evidence suggest that leucotriene B4 (LTB4), an arachidonic acid derivative with potent proinflammatory properties, plays a key role in the pathophysiology of rheumatoid arthritis (RA). OBJECTIVE: To evaluate the efficacy and safety of BIIL 284, an oral long-acting LTB4 receptor antagonist, as monotherapy for the treatment of patients with active RA. METHODS: This was a multi-centre, randomised, double-blind, placebo-controlled trial of patients with active RA of 3 months' duration. A total of 342 patients were randomised to receive 5 mg, 25 mg or 75 mg of BIIL 284 or placebo. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR) 20. RESULTS: Although a higher percentage of ACR 20 responders was observed in the groups treated with 25 mg and 75 mg of BIIL 284 compared with those treated with placebo, no statistically significant differences were found between any of the three active treatment groups compared with the placebo group with regard to the primary or secondary end points. All trial treatments were safe and well tolerated. CONCLUSIONS: This clinical trial demonstrates that treatment of patients with active RA with a potent oral long-acting LTB4 receptor antagonist produced only modest improvements in disease activity. The results of this trial support the conclusion that LTB4 is not a major contributor to the inflammatory process in RA.
Abstract: OBJECTIVE: To analyze the safety and efficacy of the anti-tumor necrosis factor agent infliximab in patients with ankylosing spondylitis (AS) after discontinuation of longterm therapy over 1 year and readministration, using clinical and laboratory assessments including serum levels of antibodies to infliximab (ATI). METHODS: Altogether 42/43 patients with AS in a 3-year multicenter trial discontinued therapy after continuous treatment with infliximab (5 mg/kg/6 wks). Infliximab was only readministered in case of a clinical relapse [judged by Bath AS Disease Activity Index (BASDAI) and physician global assessment > 4]. ATI were measured at different timepoints. The primary outcome was safety, and efficacy outcomes were secondary. RESULTS: One patient dropped out after the eighth infusion after retreatment due to repeated local infections. ATI were detected in this patient only. No other relevant adverse events were observed. One patient remained in clinical remission without therapy for more than 1 year. The other 40 patients (97.6%) were reinfused because of clinical relapse. There was no correlation between ATI and clinical measures. BASDAI 50% responses were seen in 25 (63%) and partial remission in 12 (30%) patients. The mean (+/- SD) BASDAI score dropped from 6.0 +/- 1.4 at the time of relapse to 2.6 +/- 2.0, and the median C-reactive protein from 11.2 to 1.8 mg/l after 1 year (all p < 0.05). CONCLUSION: Readministration of infliximab after discontinuation of longterm treatment was generally safe and efficacious. Ongoing remission after discontinuation was rare. There was only one patient with relevant adverse events. ATI were detected only in this patient, but there was no correlation to clinical data. Formation of ATI seems to be rare after longterm infliximab therapy in AS.
Abstract: OBJECTIVE: The OMERACT Drug Safety Working Group focuses on standardization of assessment and reporting of adverse events in clinical trials and longitudinal and observational studies in rheumatology. This group developed the Rheumatology Common Toxicity Criteria (RCTC) in 1999, building on the Oncology Common Toxicity Criteria. At OMERACT 8, a workshop group reviewed the use of the RCTC and other instruments in rheumatology clinical trials to date, to revise and to stimulate its implementation. METHODS: The Working Group drafted a revision of the RCTC after an iterative examination of its contents, terms, and definitions. The RCTC were compared with the Oncology Common Toxicity Criteria (CTC v.2.0), and the Common Terminology Criteria for Adverse Events (CTCAE v.3.0). In addition a pharmaceutical company focus group met to clarify the challenges of application of RCTC terms and definitions, relative to the standard in pharmaceutical clinical trials, i.e., verbatim recording of adverse events followed by mapping to Medical Dictionary of Drug Regulatory Activities (MedDRA) terms. The workshop focused on the proposed revision of RCTC to version 2.0 and on the research agenda, including a validation of the RCTC in future trials. RESULTS: At OMERACT 8, breakout groups amended the contents of the 4 current and 2 new categories of adverse event terms within the draft RCTC v.2.0. Participants recognized the need to standardize the definitions for disease flares, infection, malignancy, and certain syndromes such as drug hypersensitivity and infusion reactions. Moderate consensus (62%) was reached in the final plenary session that the amended RCTC v.2.0 should be promulgated and tested in available trials of anti-tumor necrosis factor agents. CONCLUSION: The RCTC has face validity and construct validity. However, documentation of discrimination and feasibility (the other elements of the OMERACT filter) is needed. Collaboration with drug safety working groups in rheumatology professional organizations is necessary to enable this project.
Abstract: OBJECTIVE: To identify the most relevant problems to be addressed in the multi-disciplinary care of patients with acute arthritis using focus groups of health professionals followed by a Delphi process. METHODS: Focus group and Delphi methodology were applied. The focus groups were conducted at three specialist rheumatology hospital clinics in Germany, each group comprising rheumatologists, nurses, physiotherapists, occupational therapists, psychologists and social workers. The participants were asked to decide which categories of the International Classification of Functioning, Disability and Health (ICF) are relevant to the care of patients with acute inflammatory arthritis. The results from the focus groups were then followed by an anonymous Delphi process. RESULTS: Twenty-six health professionals participated in the 3 focus groups. 167 of the second-level ICF categories (63% of all second-level categories) were considered as relevant by the rheumatology health professionals. Items from all four components, Body Functions, Body Structures, Activities and Participation and Environmental Factors were represented. Agreement between focus groups and between different health professional groups was substantial for all components with the exception of Environmental Factors (Cohen's kappa 0.23). CONCLUSION: The involvement of experts from different health professions is a valuable tool to identify typical patient characteristics, expressed as distinct ICF categories, to aid in patient care in the acute rheumatology setting. Acute patient care cannot and should not be separated from ongoing long-term management.
Abstract: The success of the treatment of rheumatoid arthritis depends primarily on early diagnosis. In most cases, basic therapy begins with methotrexate. Depending on the stage and course of the disease (radiographically detected early erosion and/or progression), basic immunosuppressive therapy can be combined or supplemented with cytokine antagonists. Furthermore, for specific indications, several alternative active substances (DMARD monotherapies) are available. Today the goal of therapy is always remission.
Abstract: OBJECTIVES: To assess the effect of sulfasalazine (SSZ) on inflammatory back pain (IBP) due to active undifferentiated spondyloarthritis (uSpA) or ankylosing spondylitis in patients with symptom duration <5 years. METHODS: Patients with IBP and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >3 from 12 centres were randomly assigned to 24 weeks' treatment with SSZ 2 g/day or placebo. The primary outcome variable was the change in BASDAI over 6 months. Secondary outcomes included measures of spinal pain, physical function and inflammation. RESULTS: 230 patients (50% men, age range 18-64 years, 67% human leucocyte antigen B27 positive) were treated with either SSZ 2x1 g/day or placebo for 6 months. Enthesitis was found in 50%, and peripheral arthritis in 47% of the patients. The mean (SD) BASDAI dropped markedly in both groups: by 3.7 (2.7) and 3.8 (2.4), respectively, as did most secondary outcome measures. No noticeable difference in treatment was observed between groups. Patients with IBP and no peripheral arthritis had significantly (p = 0.03) more benefit with SSZ (BASDAI 5.1 (1.3) to 2.8 (2.3)) than with placebo (5.2 (1.6) to 3.8 (2.4)). Spinal pain (p = 0.03) and morning stiffness (p = 0.05) improved with SSZ in these patients, but other secondary outcomes were not markedly different. CONCLUSION: SSZ was no better than placebo for the treatment of the signs and symptoms of uSpA; however, SSZ was more effective than placebo in the subgroup of patients with IBP and no peripheral arthritis.
Abstract: OBJECTIVE: Infliximab, a monoclonal antibody against tumour necrosis factor alpha (TNF-alpha), is approved in Europe for the treatment of patients with active ankylosing spondylitis (AS) who have responded inadequately to conventional therapy. This report provides analyses from a 3-yr extension study, as a follow-up to both the 1- and 2-yr open label extensions of the original 3-month randomized controlled trial of infliximab in patients with AS. METHODS: Of the 49 patients with AS who completed the second year of the study, 46 continued treatment with infliximab 5 mg/kg every 6 weeks up to week 156. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index, the Bath AS Metrology Index, patient's and physician's global assessments, quality of life (Short Form-36), C-reactive protein (CRP) and erythrocyte sedimentation rate were assessed throughout the study period. RESULTS: The improvement of signs and symptoms observed in the majority of the patients during the first and second year was sustained throughout the third year of the study. Forty-three patients (62% of the 69 patients enrolled at baseline and 93% of the patients who started the third year) completed week 156. In the intention-to-treat analysis, an ASAS '5 out of 6' and ASAS 40% response was seen by 46% and 50% of the patients, respectively. The scores for other efficacy assessments were similar to the values observed at weeks 54 and 102. Median CRP levels remained low (1.5 mg/l at week 156). There were no relevant side-effects and no discontinuation because of drug-related adverse events during the third year of the study. CONCLUSIONS: Patients with AS receiving infliximab for 3 yr showed a durable clinical response without loss of efficacy. Long-term infliximab treatment was well tolerated by patients in this study.
Abstract: We analyzed the clinical response and the time to relapse after discontinuation of continuous long-term infliximab therapy in patients with ankylosing spondylitis (AS). After 3 years of infliximab therapy, all AS patients (n = 42) discontinued treatment (time point (TP)1) and were visited regularly for 1 year in order to assess the time to relapse (TP2). Relapse was defined as an increase to a value >or= 4 on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and a physician's global assessment >or= 4 according to the recommendations of the Assessments in Ankylosing Spondylitis (ASAS) working group. After 52 weeks, 41 of the 42 patients (97.6%) had to be reinfused because of relapse. The mean change in the BASDAI between TP1 and TP2 was 3.6 +/- 1.7 and that in the physician's global assessment was 4.4 +/- 1.8 (both P < 0.001). The mean time to relapse was 17.5 weeks (+/- 7.9 weeks, range 7 to 45). Ten patients (24%) showed a relapse within 12 weeks and 38 patients (90.5%), within 36 weeks. After 52 weeks, only one patient had remained in ongoing remission without further treatment with anti-tumor-necrosis factor. Patients who were in partial remission according to the ASAS criteria and those with normal C-reactive protein levels at the time point of withdrawal had longer times to relapse after discontinuation of the treatment. Retreatment with infliximab was safe and resulted in clinical improvement in all patients to a state similar to that before the treatment was stopped. Discontinuation of long-term therapy with infliximab eventually led to relapse of disease activity in all patients but one.
Abstract: OBJECTIVE: To obtain results of the second year extension of an original 3 month randomised, placebo controlled trial (and the 1 year extension study) assessing the use of infliximab, a monoclonal antibody to tumour necrosis factor alpha, for the treatment of patients with ankylosing spondylitis (AS). METHODS: Of the 54 patients with AS who completed the first year of the study, 52 continued to receive infliximab 5 mg/kg every 6 weeks up to week 102. The primary end point was the proportion of patients achieving at least 50% improvement from baseline in the Bath AS Disease Activity Index (BASDAI) at week 102. Other assessments included patient and physician global assessments, quality of life as assessed by Short Form-36, Bath AS Functional Index, Bath AS Metrology Index, and C reactive protein (CRP). RESULTS: Improvement in signs and symptoms of AS seen during the first year of the study was sustained during the second year. Forty nine patients (71% of 69 enrolled patients and 49/52 (94%) patients who started year 2) completed the study up to week 102. Thirty (58%) patients achieved at least 50% improvement from baseline in the BASDAI score at week 102. Scores for other efficacy assessments were similar at weeks 54 and 102. Median CRP levels remained low at weeks 54 and 102 (3.9 and 4.3 mg/l, respectively). Side effects during the second year of the study were similar to those of the first year of treatment with infliximab. CONCLUSIONS: Patients with AS treated for 2 years with infliximab 5 mg/kg exhibited a good and durable clinical response.
Abstract: BACKGROUND: Leukotriene B4 (LTB(4)) has a key role in the pathophysiology of rheumatoid arthritis (RA). OBJECTIVE: To investigate the inhibition of ex vivo LTB(4)-induced Mac-1 (CD11b/CD18) expression in leucocytes of patients with RA by the new oral LTB(4) receptor antagonist BIIL 284. METHODS: The pharmacokinetics and inhibition of LTB(4)-induced Mac-1 expression of BIIL 284 were characterised in 26 adult patients with RA who were treated with BIIL 284 25 mg, 150 mg, or placebo given once a day for 14 days according to a double blind, randomised, parallel group design. RESULTS: T(max) of BIIL 315 in plasma (main metabolite and active principle of BIIL 284 in plasma) was achieved about four hours after drug administration, and C(max,ss) and AUC(0-6h,ss) increased in proportion to the dosage. 100% inhibition of LTB(4)-induced MAC-1 expression was reached after two hours (150 mg) or four hours (25 mg), showing a statistically significant difference in comparison with placebo (p<0.005). A longlasting dynamic effect was seen consistently even when plasma concentrations declined to very low values 24 hours after administration. Secondary clinical efficacy end points remained unchanged probably owing to the short duration of treatment. Adverse events (AEs) were reported in 12 patients during the study. No serious AEs or laboratory AEs were seen. CONCLUSIONS: Both the 25 mg and 150 mg doses of BIIL 284 safely and effectively inhibit Mac-1 expression on neutrophils; thus longer treatment with BIIL 284 may result in clinical benefit for patients with RA.
Abstract: A randomised, double-blind study was performed to assess the efficacy and tolerability of lumiracoxib in patients with rheumatoid arthritis (RA). Patients received lumiracoxib 200mg once daily (o.d.) (n= 280), lumiracoxib 400mg o.d. (n= 281), naproxen 500 mg twice daily (n= 279) or placebo (n= 284) for 26 weeks. The primary efficacy variable was response to treatment according to ACR20 criteria (adjusted for prohibited concomitant or excessive rescue medication use and discontinuations due to unsatisfactory therapeutic response) at week 13. Safety and tolerability was also assessed. Significantly more patients receiving lumiracoxib than placebo were responders according to ACR20 criteria at week 13 (41.1 and 42.7% for lumiracoxib 200 and 400 mg o.d., respectively; 32.4% for placebo; both p < 0.05). The proportion responding to naproxen (39.1%) was not significantly different from placebo. Prespecified gastrointestinal adverse events were more frequent with naproxen than with either lumiracoxib dose or placebo. Lumiracoxib is therefore an effective and well-tolerated therapy for RA.
Abstract: Our aim was to analyze the existing body of evidence about inpatient care of patients suffering from rheumatoid arthritis (RA). The report was induced by the executive board of the German Society of Rheumatology which assigned the "Oliver-Sangha committee" to dissect and point out the tasks of inpatient care during the next few years. A systemic search of the literature was performed covering the years 1966 to 2001. A total of 16 studies were selected and thoroughly appraised in a systematic way. Four randomized controlled trials addressing the question could be identified. All of them included only patients in a clinical condition allowing outpatient care as well. Two studies indicate some advantage of inpatient care in comparison to outpatient treatment. Two studies, both equivalence studies from design, reveal that RA patients do not generally experience additional benefit from hospitalization. Consideration of two additional cohort studies demonstrates the increased need of inpatient care in RA patients. None of the studies was derived from the German health care system. Emergency cases were not the subject of any of these trials. General statements about the value of inpatient care of RA patients can not be drawn from the analyzed studies. The committee makes suggestions for future investigations that may help to answer this important question considering the special circumstances of the German health care system.
Abstract: OBJECTIVE: Treatment of ankylosing spondylitis (AS) with infliximab, an anti-tumor necrosis factor alpha monoclonal antibody, was shown to be efficacious in patients with active disease during a 3-month treatment period. The purpose of this study was to evaluate the efficacy and safety of infliximab treatment of AS for a 1-year period. METHODS: This study was an open, observational, extension study of a 3-month, randomized, placebo-controlled trial. All patients who had tolerated infliximab (infliximab/infliximab group) or placebo (placebo/infliximab 12-week crossover group) therapy for 3 months entered the open extension trial (n = 65). Infliximab was administered at a dosage of 5 mg/kg every 6 weeks after the induction phase (weeks 0, 2, and 6). The primary end point was a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). RESULTS: At week 54, a total of 54 of the 69 patients (78%) continued to take infliximab. The intent-to-treat primary efficacy analysis at week 54 showed that 47% of patients in the infliximab/infliximab group (95% confidence interval 31-63) and 51% of the patients in the placebo/infliximab group (95% confidence interval 36-67) achieved 50% improvement in BASDAI scores. In the analysis of those who completed the study, the mean BASDAI scores improved between weeks 0 and 54 in both treatment groups: from 6.6 to 2.4 in the infliximab/infliximab group and from 6.3 to 2.6 in the placebo/infliximab group. The dosage of nonsteroidal antiinflammatory drugs was reduced in approximately 70% of the patients. There were significant improvements in measures of functioning, metrologic parameters, and quality of life. Between weeks 12 and 54, a total of 4 patients had serious adverse events that were possibly related to infliximab and resulted in their discontinuing the study. CONCLUSION: Infliximab therapy in AS patients resulted in a rapid and significant improvement in BASDAI scores (>50% improvement) and a durable response for 1 year. The safety profile of infliximab in AS was comparable to that observed in the postmarketing experience for the approved indications.
Abstract: BACKGROUND: Effective new therapies are needed for rheumatoid arthritis. Current therapies target the products of activated macrophages; however, T cells also have an important role in rheumatoid arthritis. A fusion protein--cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis. CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells, blocking the engagement of CD28 on T cells and preventing T-cell activation. A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis. METHODS: We randomly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig per kilogram of body weight (105 patients), 10 mg of CTLA4Ig per kilogram (115 patients), or placebo (119 patients) for six months. All patients also received methotrexate therapy during the study. The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology (ACR), which define the response according to its extent: 20 percent (ACR 20), 50 percent (ACR 50), or 70 percent (ACR 70). Additional end points included measures of the health-related quality of life. RESULTS: Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo (60 percent vs. 35 percent, P<0.001). Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group. The group given 10 mg of CTLA4Ig per kilogram had clinically meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey. CTLA4Ig was well tolerated, with an overall safety profile similar to that of placebo. CONCLUSIONS: In patients with active rheumatoid arthritis who were receiving methotrexate, treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life. CTLA4Ig is a promising new therapy for rheumatoid arthritis.
Abstract: BACKGROUND Treatment options for patients with ankylosing spondylitis are few. We aimed to assess the effectiveness of infliximab, an antibody to tumour necrosis factor (TNF)-alpha, in treatment of such patients. METHODS: In this 12-week placebo-controlled multicentre study, we randomly assigned 35 patients with active ankylosing spondylitis to intravenous infliximab (5 mg/kg) and 35 to placebo at weeks 0, 2, and 6. One patient in the infliximab group was withdrawn from the study. Our primary outcome was regression of disease activity of at least 50%. To assess response, we used validated clinical criteria from the ankylosing spondylitis assessment working group, including disease activity (BASDAI), functional indices (BASFI), metrology (BASMI), and quality of life (short form 36). Analyses were done by intention to treat. FINDINGS: 18 (53%) of 34 patients on infliximab had a regression of disease activity at week 12 of at least 50% compared with three (9%) of 35 on placebo (difference 44% [95% CI 23-61], p<0.0001). Function and quality of life also improved significantly on infliximab but not on placebo (p<0.0001 and p<0.0001, respectively). Treatment with infliximab was generally well tolerated, but three patients had to stop treatment because of systemic tuberculosis, allergic granulomatosis of the lung, or mild leucopenia. INTERPRETATION: Our results show that treatment with infliximab is effective in patients with active ankylosing spondylitis. Since there are some potentially serious adverse effects, we recommend that this treatment mainly be used in co-operation with rheumatological centres.
Abstract: BACKGROUND: The prevalence of atopic disorders in ankylosing spondylitis (AS) is unknown. AS and rheumatoid arthritis (RA) exhibit divergent T helper (Th) cell cytokine patterns. OBJECTIVE: To test the hypothesis that Th2 polarised atopic disorders may be decreased in Th1 polarised RA but increased in AS, which is characterised by an impaired Th1 cytokine pattern, by assessing the prevalence of atopic disorders in AS and RA. METHODS: 2008 subjects (380 patients with AS, 728 patients with RA, 900 controls) from Berlin, Germany, were considered in this cross sectional study. A questionnaire incorporating questions from the European Community Respiratory Health Service (ECRHS) and the International Study of Asthma and Allergies in Childhood (ISAAC) protocol was mailed to all subjects. Disease severity was assessed by the modified Health Assessment Questionnaire (mHAQ). RESULTS: 1271 (63.3%) people responded to the questionnaire. The prevalence of any atopic disorder was 24.6% (61/248) in patients with AS, 20.7% (111/536) in controls, and 13.1% (64/487) in patients with RA (p=0.0009 for AS v RA; p=0.001 for controls v RA). Hay fever was reported by 40/248 (16.1%) patients with AS, 82/536 (15.3%) controls, and 42/487 (8.6%) patients with RA (p=0.002 for AS v RA; p=0.001 for controls v RA). Atopic dermatitis was reported by 19/248 (7.7%) patients with AS, 26/536 (4.9%) controls, and 14/487 (2.9%) patients with RA (p=0.003 for AS v RA), and asthma by 18/248 (7.3%) patients with AS, 35/536 (6.5%) controls, and 21/487 (4.3%) patients with RA. The differences were related neither to age nor to drugs. Disease severity was less in atopic patients with RA who had the atopic disorder before the onset of RA (median mHAQ 0.75) than in patients in whom RA preceded the atopic disorder (median mHAQ 1.75; p=0.027). CONCLUSIONS: Atopic disorders are decreased in RA but only slightly and non-significantly increased in AS. This may imply that atopy confers some protection from RA but only little if any susceptibility to AS. It may further indicate that the cytokine deviation towards an impaired Th1 pattern in AS is less strong than the cytokine deviation towards Th1 in RA, a finding which may affect future therapeutic approaches.
Abstract: OBJECTIVE: T cells are involved in the pathogenesis of rheumatoid arthritis (RA). In animal models of autoimmune diseases, blockade of costimulatory molecules on antigen-presenting cells has been demonstrated to be effective in preventing or treating this disease by preventing T cell activation. To date, the effect of costimulatory blockade in patients with RA is unknown. The goal of this multicenter, multinational study was to determine the safety and preliminary efficacy of costimulatory blockade using CTLA-4Ig and LEA29Y in RA patients who have been treated unsuccessfully with at least 1 disease-modifying agent. METHODS: CTLA-4Ig, LEA29Y (0.5, 2, or 10 mg/kg), or placebo was administered intravenously to 214 patients with RA. Patients received 4 infusions of study medication, on days 1, 15, 29, and 57, and were evaluated on day 85. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (ACR20). All patients were monitored for treatment safety and tolerability. RESULTS: CTLA-4Ig and LEA29Y infusions were well tolerated at all dose levels. Peri-infusional adverse events were carefully monitored, and showed similar incidence across all dose groups with the exception of headaches, which were slightly more frequent in the 2 treatment groups. The incidence of discontinuations due to worsening of RA was 19%, 12%, and 9% at 0.5, 2, and 10 mg/kg, respectively, in the CTLA-4Ig-treated patients and 3%, 3%, and 6% at 0.5, 2, and 10 mg/kg, respectively, in the LEA29Y-treated patients (versus 31% in the placebo group). ACR20 responses on day 85 had increased in a dose-dependent manner (23%, 44%, and 53% of CTLA-4Ig-treated patients and 34%, 45%, and 61% of LEA29Y-treated patients at 0.5, 2.0, and 10 mg/kg, respectively, versus 31% of placebo-treated patients). CONCLUSION: Both of the costimulatory blocking molecules studied were generally safe and well tolerated. As compared with placebo, both CTLA-4Ig and LEA29Y demonstrated efficacy in the treatment of RA.
Abstract: OBJECTIVE: Based on a potential role for serotonin receptors in fibromyalgia, we investigated the efficacy and tolerability of treatment with tropisetron, a highly selective, competitive inhibitor of the 5-HT3 receptor. METHODS: In this prospective, multicenter, double-blind, parallel-group, dose-finding study, 418 patients suffering from primary fibromyalgia (ACR criteria) were randomly assigned to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily, respectively. The duration of treatment was 10 days. The clinical response was measured by changes in pain-score, visual analog scale (VAS), and the number of painful tender-points. RESULTS: Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) when compared with placebo (26.2%) (p=0.033). The absolute reduction in pain-score was -13.5% for 5 mg tropisetron, -13.0% for 10 mg tropisetron, and -6.3% for placebo (p<0.05). The effects of 15 mg tropisetron were similar to placebo, thus suggesting a bell-shaped dose-response curve. Compared with placebo, treatment with 5 mg tropisetron led to a significant improvement (p<0.05) in VAS, while a clear trend in terms of clinical benefit was seen with 10 mg tropisetron. The number of painful tender-points was also reduced significantly (p=0.002) in the 5 mg tropisetron group. Of interest, during the 12-month follow-up period, pain intensity of responders on 5 mg and 10 mg tropisetron was still markedly below baseline. The treatment was well tolerated, with gastro-intestinal complaints being the most frequently reported side effects, in keeping with the known safety profile for 5-HT3 receptor antagonists. CONCLUSIONS: This study demonstrates the efficacy of short-term treatment with 5 mg tropisetron once daily in primary fibromyalgia. Treatment was well tolerated and prolonged clinical benefits were seen.
Abstract: OBJECTIVE: To evaluate the prognostic value of HLA-DRB1 antigens, rheumatoid factor (RF), and C-reactive protein (CRP) with the radiographic outcome of rheumatoid arthritis (RA). METHODS: In total, 139 patients with early RA (< 2 years) were followed up. At the end of 3 year treatment with disease modifying antirheumatic drugs (DMARD) HLA genotyping and external radiographic scoring were performed. The time up to the first development of erosive disease [Ratingen radiographic score (RS) > 0, > 5, > 10] was compared by methods of survival analysis. RESULTS: At 4 years' disease duration, DRB1*04 or DRB1*01 positive patients had RS > 0 or > 10 (73% and 27%, respectively) significantly more frequently than DRB1*04 or DRB1*01 negative patients (37% and 7%, respectively). Nearly independently of the genetic predisposition, RF and elevated CRP at the start of DMARD treatment were predictive for erosive RA at 4 years. Elevated CRP (> or = 15 mg/l) increased the probability of erosive RA in DRB1*04 or DRB1*01 positive patients from 64.0% (in patients with CRP < 15 mg/l) to 83.9%, and in DRB1*04 and DRB1*01 negative patients from 18.8% to 70.1%. The corresponding figures for RF+ and RF- patients were 58.2% and 82.5% in HLA predisposed patients and 23.5% and 60.2% in those who were negative for DRB1*04 and DRB1*01. The probability of a RS > 10 was 40.9% for HLA predisposed patients with elevated CRP. In contrast, no case with RS > 10 was found in 43 patients who had neither of these 2 risk factors. CONCLUSION: Our findings support that HLA predisposition plays an important role with regard to radiographic progression. However, this effect is modified by RF serum concentration and disease activity.
Abstract: Increasing interest in the functional consequences of differential expression of MHC class II molecules prompted us to examine the surface expression of HLA class II molecules on fresh peripheral blood mononuclear cells. Differential regulation of DR4 and DRB4 was shown for peripheral blood monocytes. In addition, DR4 expression is upregulated on B cells of patients suffering from chronic inflammation and is reduced under prednisolone-treatment. The expression levels of total DR molecules on a given cell type are almost identical comparing different haplotypes among non-RA controls, suggesting that the alpha-chain determines the level of surface expression. The present findings fit the hypothesis that the differential expression of HLA class II molecules is involved in regulation of the immune response and may thus contribute to determining susceptibility to immunological diseases.
Abstract: OBJECTIVE: To investigate the effect of long-term antibiotic treatment in patients with reactive arthritis (ReA) and undifferentiated oligoarthritis. METHODS: One hundred twenty-six patients were treated with ciprofloxacin (500 mg twice a day) or placebo for 3 months, in a double-blind, randomized study. Of these patients, 104 (48 treated with ciprofloxacin and 56 treated with placebo) were valid for clinical evaluation: 55 were diagnosed as having ReA with a preceding symptomatic urogenic or enteric infection and 49 as having undifferentiated oligoarthritis. These 2 groups were randomized separately. The triggering bacterium was sought by serology and/or culture. The percentage of patients in remission after 3 months of treatment was chosen as the primary efficacy parameter. RESULTS: A triggering bacterium could be identified in 52 patients (50%): Chlamydia trachomatis in 13, Yersinia in 14, and Salmonella in 25. No patient was positive for Campylobacter jejuni or for Shigella. No difference in outcome was found between treatment with ciprofloxacin or placebo in the whole group or in subgroups of patients with ReA or undifferentiated oligoarthritis. No difference was seen in patients with a disease duration <3 months. Ciprofloxacin was not effective in Yersinia- or Salmonella-induced arthritis but seemed to be better than placebo in Chlamydia-induced arthritis. This difference was not significant, however, which might be due to the small sample size. CONCLUSION: Long-term treatment of ReA with ciprofloxacin is not effective; however, it might be useful in the subgroup of patients who have Chlamydia-induced arthritis. This has to be proven in a bigger study focusing on patients with Chlamydia-induced arthritis.
Abstract: OBJECTIVE: To estimate the frequency of and to identify possible risk factors involved with terminating an initial disease modifying antirheumatic drug (DMARD) therapy. We hypothesized that treatment termination depends not only on side effects and inefficacy but also on the therapeutic setting and the health beliefs of the patient. METHODS: We observed an inception cohort of 302 patients with early rheumatoid arthritis (< 2 years) and first prescription of DMARD for 3 years. Survival analysis was used to estimate treatment continuation under rheumatological care. The study group comprised 4 rheumatological outpatient clinics and 7 private practices in Berlin. RESULTS: Of the initial cohort 80% continued the same drug or were in remission after one year, 70% after 2 years. Within the first 2 years, methotrexate therapy was terminated in 15% of the cases and sulfasalazine therapy in 40%, respectively. In both forms of therapy, the discontinuation rate was dependent on initial disease activity. However, the influence of the patient's psychological status at baseline was equally strong. DMARD treatment was terminated earlier and more frequently in patients with poor psychological well being. These findings hold true after controlling for disease activity or severity. CONCLUSION: Patient psychological well being and disease activity at start of initial DMARD therapy are important predictors of early drug discontinuation. By influencing psychological well being (e.g., by patient education programs), continuation of DMARD therapy might be further improved.
Abstract: OBJECTIVE: (1) To characterize potential changes in diclofenac pharmacokinetics and renal function in patients with rheumatoid arthritis (RA) treated with diclofenac and cyclosporine; (2) to prospectively collect longitudinal safety data during use of this drug combination. METHODS: Twenty patients with severe, treatment refractory RA were sequentially treated with stable doses of diclofenac (100-200 mg/day) for one month followed by diclofenac combined with cyclosporine (3 mg/kg/day) for one month. Pharmacokinetic profiles of diclofenac were obtained at the end of each treatment period. Combined therapy was continued for an additional 5 months, during which doses of both drugs could be individually titrated and safety data collected. RESULTS: During co-administration, diclofenac exposure doubled, as shown by an average 104% increase in the area-under-the-curve. Diclofenac half-life was not altered. Serum creatinine was significantly elevated from a baseline value of 0.8 +/- 0.1 mg/dl on diclofenac alone to 1.0 +/- 0.3 mg/dl after one month co-administration with cyclosporine. The magnitude of creatinine elevation was not correlated with that of change in diclofenac exposure, suggesting the pharmacokinetic interaction per se may not additionally contribute to the effect on renal function resulting from this drug combination. During longterm treatment with both medications, prospectively collected safety data indicated that renal function could be stabilized when drug doses were individually titrated in response to serial clinical and laboratory evaluations. The overall pattern of adverse events and laboratory abnormalities in the study population were similar to those reported in patients with RA treated with other nonsteroidal antiinflammatory agents and concomitant cyclosporine. CONCLUSION: Diclofenac can be safely combined with cyclosporine in the management of RA when appropriate clinical monitoring and dose titrations are performed. Due to the pharmacokinetic interaction that increases diclofenac systemic exposure, it would be prudent to start combination therapy with diclofenac doses at the lower end of the therapeutic dose range.
Abstract: OBJECTIVE: To investigate the efficacy of oral type II collagen in the treatment of early rheumatoid arthritis (RA). METHODS: Ninety patients with RA (disease duration < or = 3 years) were treated for 12 weeks with oral bovine type II collagen at 1 mg/day (n = 30) or 10 mg/day (n = 30) or with placebo (n = 30), in a double-blind randomized study. RESULTS: There were no significant difference between the 3 groups in terms of response to treatment. However, we observed a higher prevalence of responders in the type II collagen-treated groups: 7 responders in the 10-mg type II collagen group and 6 in the 1-mg group, versus 4 in the placebo group. Furthermore, 3 patients in the 10-mg type II collagen group and 1 patient in the 1-mg type II group, but no patients in the placebo group, had very good response. A total of 14 patients had to be withdrawn from the study: 2 because of side effects (nausea) and 12 because of lack of efficacy. CONCLUSION: Only a minority of patients responded to treatment with oral type II collagen. These results justify further efforts to identify which patients will have good response to such therapy.
Abstract: The following pages contain summaries and short statements on chronic pain providing further material for reflection and debate, namely: a) synopses of recent findings on: the physiology and biochemistry of pain; the contribution of psychoneuroimmunology; b) some views on a sociology of pain; c) analysis of various concepts and approaches which consider pain as: a symptom of disease a form of behaviour a psychosomatic reaction and a social learning process a communication phenomenon a symptom of disintegrated life a disruption in the integrity of the system a signal of broken unity a breach in the wholeness of the individual; d) a holistic approach in pain therapy; e) some unanswered questions.
Abstract: Microangiopathic changes in capillary architecture associated with collagen diseases can be visualized by vital capillary microscopy. In our study of 100 patients with collagen disease we found typical capillaroscopic images in 64%. Differentiation in subclasses showed the highest diagnostic value of this method in systemic sclerosis (77%) and rheumatoid arthritis (68%). It was lower in patients with Sharp- and CREST-syndrome (55%) and very low in systemic lupus erythematosus (33%). In summary, vital capillary microscopy is a valid method in non-invasive diagnostic of collagen diseases.
Abstract: Summary The postnatal development of the ovary of the heterozygous nude (nu/+) mouse with the genetic background BALB/c is very similarâif not identicalâto that of other mouse strains. As other BALB/c mice, the nu/+ females become sexually mature during the 5th week post partum (p.p.). At this age the ovaries contain corpora lutea at various stages of differentiation.
In the ovaries of newborn and 1 week-old homozygous (nu/nu) mice, the differentiation of oocytes into primary and secondary follicles is delayed. In the third postnatal week, the ovaries of homozygous females contain more atretic follicles than those of their heterozygous littermates. This increased degeneration of follicles may account for the greater mass of secondary interstitial tissue, which is observed in the ovaries of adult nu/nu females. In nine out of ten of the 5 to 7 week-old nu/nu mice studied, the ovaries contained no-/or only very few corpora lutea. Thus in homozygous nude females, the onset of sexual maturity is delayed. This ovarial immaturity may persist throughout life. In other animals development may become normal.
In addition to the impaired postnatal development of the ovary, unspecific inflammation of the uterine wall (endo- and/or myometritis) was detected in 47% of nu/nu animals older than five weeks. No direct correlation was, however, found between the delay of sexual maturation and the inflammatory changes in the uterus as many of the animals with an endo-or myometritis possessed mature ovaries. The low fertility of the female homozygous nude mouse seems, therefore, to be caused not only by an impaired differentiation of the ovary but also by inflammatory processes in the uterus.
