Indication Criteria for Total Knee Arthroplasty in Patients with Osteoarthritis - A Multi-perspective Consensus Study.

Background and Objectives Knee osteoarthritis (OA) is a significant public health burden. Rates of total knee arthroplasty (TKA) in OA vary substantially between geographical regions, most likely due to the lack of standardised indication criteria. We set out to define indication criteria for the German healthcare system for TKA in patients with knee OA, on the basis of best evidence and transparent multi-stakeholder consensus. Methods We undertook a complex mixed methods study, including an iterative process of systematic appraisal of existing evidence, Delphi consensus methods and stakeholder conferences. We established a consensus panel representing key German national societies of healthcare providers (orthopaedic surgeons, rheumatologists, pain physicians, psychologists, physiotherapists), payers, and patient representatives. A priori defined consensus criteria were at least 70% agreement and less than 20% disagreement among the consensus panel. Agreement was sought for (1) core indication criteria defined as criteria that must be met to consider TKA in a normal patient with knee OA, (2) additional (not obligatory) indication criteria, (3) absolute contraindication criteria that generally prohibit TKA, and (4) risk factors that do not prohibit TKA, but usually do not lead to a recommendation for TKA. Results The following 5 core indication criteria were agreed within the panel: 1. intermittent (several times per week) or constant knee pain for at least 3 - 6 months; 2. radiological confirmation of structural knee damage (osteoarthritis, osteonecrosis); 3. inadequate response to conservative treatment, including pharmacological and non-pharmacological treatment for at least 3 - 6 months; 4. adverse impact of knee disease on patient's quality of life for at least 3 - 6 months; 5. patient-reported suffering/impairment due to knee disease. Additional indication criteria, contraindication criteria, and risk factors for adverse outcome were also agreed by a large majority within the multi-perspective stakeholder panel. Conclusion The defined indication criteria constitute a prerequisite for appropriate provision of TKA in patients with knee OA in Germany. In eligible patients, shared-decision making should eventually determine if TKA is performed or not. The next important steps are the implementation of the defined indication criteria, and the prospective investigation of predictors of success or failure of TKA in the context of routine care provision in Germany.

German guidelines for the sequential medical treatment of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs.

The German Society of Rheumatology approved new German guidelines for the sequential medical treatment of rheumatoid arthritis (RA) based on the European League Against Rheumatism (EULAR) recommendations for the management of RA published in 2010. An update of the EULAR systematic literature research was performed in Medline, Embase, and Cochrane databases. Meta-analyses, controlled trials, cohort studies, and registry data addressing traditional and biologic disease-modifying antirheumatic drugs, glucocorticoids, and treatment strategies published between January 2009 and August 2011 were included. Two reviewers independently evaluated and compared the additional data that had been published after the time limit set by the EULAR recommendations. A national guideline working group developed an adapted set of recommendations. The new German guidelines were accepted by vote using an informal Delphi approach. Twelve recommendations and the resulting updated treatment algorithm were developed and approved as a practical orientation for rheumatologists. These recommendations are based on a successive treatment with traditional and biologic disease-modifying drugs depending on the individual progress of the disease and distinct patient characteristics. The German guidelines have been developed on the basis of the internationally well-recognized EULAR recommendations. In addition, more recent evidence from a systematic literature research was considered. They have been developed and approved by a group of national experts aiming at guidance for rheumatologists to reach best medical practice.

Clinical presentation, burden of disease and treatment in young-onset and late-onset rheumatoid arthritis: a matched-pairs analysis taking age and disease duration into account.

OBJECTIVES: The aim of this study is to compare clinical features and treatment of young onset rheumatoid arthritis with late-onset rheumatoid arthritis. METHODS: Nine thousand five hundred forty-one patients with rheumatoid arthritis (RA) enrolled in the national database of the German Collaborative Arthritis Centres in 2007-2009 were stratified by age at disease onset: up to 65 years (YORA), >65 years (LORA). To enable unbiased comparisons between the two groups despite their systematic differences in age and disease duration, we performed two separate matched-pairs analyses: the impact of current age was assessed by matching YORA and LORA patients for disease duration and sex (n=1,550 pairs). To identify the influence of disease duration, a second sample matched for age and sex (n=1,158 pairs) was drawn. RESULTS: At identical age, YORA patients had higher disease activity (DAS28), worse functional capacity and were less frequently in remission when compared with LORA patients. YORA patients also suffered more frequently from RA-related co-morbidities such as cardiovascular disease, chronic renal disease and osteoporosis. Matched for disease duration, there were no differences between the two groups concerning disease severity and remission rates, global health or pain intensity. Independent of age or disease duration, YORA patients reported more sleep disorders and fatigue. LORA patients received significantly fewer synthetic or biologic DMARDs than YORA patients. CONCLUSIONS: Duration of RA, rather than age, explains differences in disease burden between YORA and LORA patients. The lower prescription rates of synthetic and in particular biologic DMARDs, despite lower remission rates, indicate a potential treatment deficit in older patients.

Hypothalamus-pituitary-adrenal axis function in patients with rheumatoid arthritis treated with nighttime-release prednisone.

OBJECTIVE: To investigate the effects of longterm low-dose chronotherapy with modified-release (MR) prednisone for rheumatoid arthritis (RA) on the hypothalamus-pituitary-adrenal (HPA) axis as part of the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) study. This consisted of a 3-month active-controlled phase and a 9-month open-label extension with MR prednisone including patients previously treated with prednisone (ClinicalTrials.gov number NCT00146640). METHODS: Corticotropin-releasing hormone (CRH) tests were performed on 28 patients at 3 timepoints: at baseline on prestudy immediate-release (IR) prednisone, after the 3-month double-blind phase on either IR prednisone or MR prednisone, and after the 9-month open-label extension on MR prednisone. Changes of cortisol were assessed and compared to individual patients' efficacy and safety data. RESULTS: The increase (mean, SD) of cortisol plasma concentrations after injection of corticorelin was 5.5 (4.37) µg/dl on IR prednisone at baseline (n = 21) and 5.3 (4.07) µg/dl on MR prednisone at 12 months (n = 22). Numbers of normal/suppressed/no response reactions did not differ among treatments. Switching from IR to MR prednisone did not influence responses, nor did longterm treatment of up to 12 months with MR prednisone. No worsening of adrenal impairment was observed on treatment with nighttime-release prednisone in patients with low responsiveness to CRH testing before the treatment with MR prednisone. CONCLUSION: Treatment with nighttime-release prednisone did not change adrenocortical function over 12 months. We presume that chronotherapy with this nighttime-release prednisone may improve the efficacy of longterm low-dose glucocorticoid treatment in patients with RA.

Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis.

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.

Association of an NKG2D gene variant with systemic lupus erythematosus in two populations.

NKG2D, involved in T-cell activation and viral defense, shows a single-nucleotide polymorphism (SNP) in the transmembrane region, characterized by a substitution of alanine with threonine. We examined the association of systemic lupus erythematosus (SLE) with one of the NKG2D gene variants. We also studied the functional impact of that allele in SLE. Restriction fragment length polymorphism/polymerase chain reaction specific for the SNP rs2255336 G--> A was performed with 247 German SLE patients and 447 controls and with 284 Spanish SLE patients and 180 controls. NKG2D expression on peripheral blood lymphocytes of SLE patients was analyzed via fluorescence activated cell sorter. In addition, proliferation assays were performed. We found that the NKG2D alanine/alanine (G/G) gene variant was significantly associated with SLE in the German cohort (70.4% vs 60.8% controls; p = 0.0027) and almost significantly in the Spanish cohort (66.2% vs 62.2% controls; p = 0.054). In a pooled analysis, the prevalence of G/G was 68.2% in SLE versus 61.2% in the controls (p = 0.0024). There were no significant differences in the expression levels of NKG2D on peripheral blood lymphocytes of the different genotypes. A comparison of the coreceptor activity of the genotypes in response to CD3 and NKG2D antibodies revealed a trend toward higher proliferation in the A/A genotype. In conclusion, based on our study results, SLE is associated with the SNP rs2255336 of NKG2D.

Do temporal artery duplex ultrasound findings correlate with ophthalmic complications in giant cell arteritis?

OBJECTIVE: Ophthalmic complications are common in acute GCA. Do temporal artery ultrasound and clinical parameters correlate with the occurrence and severity of ophthalmic complications? METHODS: The results of temporal artery ultrasound examinations are compared with the occurrence of anterior ischaemic optic neuropathy (AION), central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO), diplopia and amaurosis fugax in 222 consecutive patients with newly diagnosed, active GCA. RESULTS: Temporal artery ultrasound displayed vasculitic wall swelling (halo), stenoses and/or acute occlusions in 84% (58% in 67 large-vessel GCA patients and 95% in 155 patients without proximal arm vasculitis). Ophthalmic complications occurred in 64 (29%), AION in 30 (14%), CRAO in 7 (3%), BRAO in 2 (1%), amaurosis fugax in 16 (7%) and diplopia in 9 patients (4%). Ophthalmic complications were insignificantly more common if temporal artery ultrasound was positive (31 vs 17%; P = 0.11) as a greater number of patients without arm vasculitis showed eye involvement (34 vs 18%; P = 0.02). The number of pathological temporal artery segments, presence of stenoses or bilateral findings did not correlate with ophthalmic complications. Age >or= 72 yrs at diagnosis correlated with a higher incidence of ophthalmic complications. CONCLUSION: Ophthalmic complications occurred less frequently if proximal arm vasculitis was present. Findings of temporal artery ultrasound did not correlate with eye complications.

Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system.

Clinical trials have indicated that immunoablation followed by autologous hematopoietic stem cell transplantation (ASCT) has the potential to induce clinical remission in patients with refractory systemic lupus erythematosus (SLE), but the mechanisms have remained unclear. We now report the results of a single-center prospective study of long-term immune reconstitution after ASCT in 7 patients with SLE. The clinical remissions observed in these patients are accompanied by the depletion of autoreactive immunologic memory, reflected by the disappearance of pathogenic anti-double-stranded DNA (dsDNA) antibodies and protective antibodies in serum and a fundamental resetting of the adaptive immune system. The latter comprises recurrence of CD31(+)CD45RA(+)CD4(+) T cells (recent thymic emigrants) with a doubling in absolute numbers compared with age-matched healthy controls at the 3-year follow-up (P = .016), the regeneration of thymic-derived FoxP3(+) regulatory T cells, and normalization of peripheral T-cell receptor (TCR) repertoire usage. Likewise, responders exhibited normalization of the previously disturbed B-cell homeostasis with numeric recovery of the naive B-cell compartment within 1 year after ASCT. These data are the first to demonstrate that both depletion of the autoreactive immunologic memory and a profound resetting of the adaptive immune system are required to reestablish self-tolerance in SLE.

Direct assessment of thymic reactivation after autologous stem cell transplantation.

Methods to quantify Th cell reconstitution after immunosuppressive therapies such as hematopoietic stem cell transplantation are becoming a key issue since persistent Th cell deficiencies may result in severe complications and adverse events. We employed here cytometric monitoring of CD31+ thymus-naive Th cells for the direct assessment of human thymic function in 10 patients undergoing autologous stem cell transplantation for severe autoimmune diseases. High frequencies of posttransplant recurring naive Th cells coexpressed CD31 and stable long-term reconstitution with elevated absolute counts of CD31+ thymus-naive Th cells that were enriched with T cell receptor excision circles was demonstrated. Cytometric monitoring of CD31+ thymus-naive Th cells enables to directly evaluate human thymic function ex vivo.

Ultrasonography of salivary glands -- a highly specific imaging procedure for diagnosis of Sjögren's syndrome.

OBJECTIVE: To verify ultrasonographic criteria for examination of the major salivary glands in diagnosis of primary and secondary Sjögren's syndrome (SS). METHODS: Three hundred sixteen consecutive patients with rheumatic diseases were selected according to the European Consensus Study Group diagnostic criteria for SS. Fifty-seven had primary SS, 33 had secondary SS, 78 had Sicca symptoms, and 148 patients served as asymptomatic controls. This cohort was analyzed for size and parenchymal echogenicity of the major salivary glands by ultrasonography. RESULTS: Evident parenchymal inhomogenicity in 2 or more major salivary glands was detected by ultrasonography in patients with primary and secondary SS with a sensitivity of 63.1% and 63.6%, respectively. The specificity of this imaging approach in our cohort was 98.7%. The volume of submandibular glands was reduced in patients with primary and secondary SS by about 30% compared to patients with sicca symptoms and asymptomatic controls. In receiver-operating characteristic (ROC) curve analysis, the detection of reduced volumes of both submandibular glands in patients with primary and secondary SS had a specificity of 93% and a sensitivity of 48% at the cutoff point of 3.0 ml. Of note, the volume of the parotid glands did not differ between the groups of patients. In patients with primary SS, parenchymal inhomogenicity of the salivary glands was strongly associated with positivity for anti-Ro and/or anti-La antibodies. CONCLUSION: Ultrasonographic detection of parenchymal inhomogenicity of the major salivary glands and observation of reduced volume of the submandibular glands resulted in high specificities for diagnosis of primary and secondary SS. The data indicate that ultrasonography of major salivary glands is a noninvasive imaging procedure with high diagnostic value for the diagnosis of primary and secondary SS.

Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial.

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.

Safety and efficacy of readministration of infliximab after longterm continuous therapy and withdrawal in patients with ankylosing spondylitis.

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.

The expression of collagenase 3 (MMP-13) mRNA in the synovial tissue is associated with histopathologic type II synovitis in rheumatoid arthritis.

The histopathologic analysis of the synovial tissue is important to distinguish rheumatoid arthritis (RA) from other forms of synovitis and to provide information about prognosis and therapeutic strategies at early stages of the disease. In this context, the present study was performed to investigate the correlation between immunohistopathological and morphological features of synovitis and the expression of collagenase 3 (MMP-13) known to contribute significantly to cartilage degradation in RA. In the histopathologic scoring system used in this study, type I synovitis is characterized by B lymphocyte infiltration and an intact lining, and is only mild destructive to cartilage and bone. Type II shows marked diffuse infiltrations of macrophages and T lymphocytes, an ulcerated lining, fibrin exudation, and invasive growth into cartilage and bone tissue. Investigating 36 patients with RA, 21 patients (58%) were positive for the expression of collagenase 3 mRNA in the synovial tissue. Among these patients, 19 showed a histopathologic type II synovitis and only 2 patients had undifferentiated synovitis. In contrast, synovial tissue samples from patients without collagenase 3 mRNA expression were characterized in 6 cases by type I, in 5 cases by type II and in 4 cases by undifferentiated synovitis. The analysis of the clinical data revealed that RA patients with a histopathologic type II synovitis and synovial tissue collagenase 3 mRNA expression had elevated levels of systemic markers of inflammation and received stronger therapies. The data suggest, that collagenase 3 expression and the histopathologic type II synovitis are associated with a severe and destructive course of RA.

Clinical and functional remission: even though biologics are superior to conventional DMARDs overall success rates remain low--results from RABBIT, the German biologics register.

We investigated the frequency of remission according to the disease activity score (DAS28) definition, modified American Rheumatology Association (ARA) criteria, and the frequency of an achievement of a functional status above defined thresholds ('functional remission', 'physical independence') in rheumatoid arthritis (RA) patients treated with either biologics or conventional DMARDs. We used the data of a prospective cohort study, the German biologics register RABBIT (German acronym for Rheumatoid Arthritis--Observation of Biologic Therapy) to investigate the outcomes in RA patients with two or more DMARD failures who received new treatment with biologics (BIOL; n = 818) or a conventional DMARD (n = 265). Logistic regression analysis was applied to adjust for differences in baseline risks. Taking risk indicators such as previous DMARD failures or baseline clinical status into account, we found that biologics doubled the chance of remission compared to conventional DMARD therapies (DAS28 remission, adjusted odds ratio (OR) 1.95 (95% confidenece interval (CI) 1.2-3.2)); ARA remission, OR 2.05 (95% CI 1.2-3.5)). High remission rates (DAS28 remission, 30.6%; ARA remission, 16.9%) were observed in BIOL patients with a moderate disease activity (DAS28, 3.2 to 5.1) at the start of treatment. These rates decreased to 8.5% in patients with DAS28 > 6. Sustained remission at 6 and 12 months was achieved in <10% of the patients. Severely disabled patients (< or = 50% of full function) receiving biologic therapies were significantly more likely to achieve a status indicating physical independence (> or = 67% of full function) than controls (OR 3.88 (95% CI 1.7-8.8)). 'Functional remission' (> or = 83% of full function) was more often achieved in BIOL than in controls (OR 2.18 (95% CI 1.04-4.6)). In conclusion, our study shows that biologics increase the chance to achieve clinical remission and a status of functional remission or at least physical independence. However, temporary or even sustained remission remain ambitious aims, which are achieved in a minority of patients only.

Manifestation of rheumatoid arthritis in a patient with hereditary haemochromatosis.

Articular symptoms are frequent manifestations of hereditary haemochromatosis. The clinical signs of the arthropathy of haemochromatosis are not specific and difficult to identify in case of co-incidence of haemochromatosis with Heberden's and Bouchard's osteoarthritis or rheumatoid arthritis (RA). Here the manifestation of RA in a patient is reported who was successfully treated for haemochromatosis. Six months after terminating phlebotomy, the patient presented again suffering from impressive swelling of all MCP joints, showing strong synovitis in ultrasound, and from morning stiffness longer than 1 h. ESR, CRP, IgM rheumatoid factor, and anti-cyclic citrullinated peptide antibodies were markedly elevated. Based on these findings the diagnosis of RA was made. Therefore, the high prevalence of RA and haemochromatosis in the general population underlines the usefulness of a screening for HFE gene mutations in RA patients with an atypical course of the disease as well as in patients with undifferentiated arthritis.

Healthcare and burden of disease in psoriatic arthritis. A comparison with rheumatoid arthritis and ankylosing spondylitis.

OBJECTIVE: To compare quality of life and treatment among patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), and ankylosing spondylitis (AS) treated by German rheumatologists. METHODS: Data for outpatients with PsA (n = 1863), RA (n = 9627), or AS (n = 1378) enrolled in the national database of the German collaborative arthritis centers in the year 2002 were analyzed. Among those with PsA, 2 subgroups with predominantly peripheral arthritis (n = 1612) and predominantly axial disease (n = 251) were distinguished. RESULTS: We found a high burden of illness in patients with PsA treated by rheumatologists. Among the 2 subgroups, those with axial PsA had worse outcomes (pain, function) than those with peripheral PsA. However, compared with RA and AS, physician ratings of disease activity and severity were lower in PsA. Concerning access to rheumatology care, there were similarities between AS and axial PsA, with very long disease duration at first visit (mean of about 6 yrs), versus RA and peripheral PsA, with shorter duration (1.6 and 2.5 yrs, respectively). A majority (84%) of patients with PsA were treated with disease modifying antirheumatic drugs. Thirty percent of the patients with PsA currently were under therapy with glucocorticoids, mainly (89%) with a dose < 7.5 mg. CONCLUSION: Patients with PsA seen in rheumatologic care have a burden of illness comparable to that of patients with RA or AS.

Infections in patients with rheumatoid arthritis treated with biologic agents.

OBJECTIVE: To estimate the incidence rates of serious and nonserious infections in patients with rheumatoid arthritis (RA) who start treatment with a biologic agent, and to compare these rates with those in patients with RA who receive conventional treatment. METHODS: Patients enrolled in the German biologics register between May 2001 and September 2003 were included. Treating rheumatologists assessed adverse events and serious adverse events. All adverse events and serious adverse events experienced within 12 months after study entry were analyzed. Propensity score methods were applied to estimate which part of a rate increase was likely to be attributable to differences in patient characteristics. RESULTS: Data were available for 512 patients receiving etanercept, 346 patients receiving infliximab, 70 patients receiving anakinra, and 601 control patients treated with disease-modifying antirheumatic drugs. The total number of adverse events per 100 patient-years was 22.6 (95% confidence interval [95% CI] 18.7-27.2) among patients receiving etanercept, 28.3 (95% CI 23.1-34.7) among patients receiving infliximab, and 6.8 (95% CI 5.0-9.4) among controls (P < 0.0001). Significant differences in the rate of serious adverse events were also observed. For patients receiving etanercept, those receiving infliximab, and controls, the total numbers of serious adverse events per 100 patient-years were 6.4 (95% CI 4.5-9.1), 6.2 (95% CI 4.0-9.5), and 2.3 (95% CI 1.3-3.9), respectively (P = 0.0016). After adjusting for differences in the case patient mix, the relative risks of serious adverse events were 2.2 (95% CI 0.9-5.4) for patients receiving etanercept and 2.1 (95% CI 0.8-5.5) for patients receiving infliximab, compared with controls. CONCLUSION: Patients treated with biologic agents have a higher a priori risk of infection. However, our data suggest that this risk is increased by treatment with tumor necrosis factor inhibitors.

Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab.

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.

Modelling cost effectiveness and cost utility of sequential DMARD therapy including leflunomide in rheumatoid arthritis in Germany: I. Selected DMARDs and patient-related costs.

OBJECTIVE: To quantify direct costs of medication and cost of illness (according to functional capacity) for patients with rheumatoid arthritis (RA) in Germany, allowing further use in a health economic evaluation of sequential therapy with disease-modifying antirheumatic drugs (DMARDs) in specialised, i.e. rheumatological, care in Germany. DESIGN AND SETTING: The analysis was conducted from the societal perspective in Germany using a modelling approach, which was based on secondary analysis of existing data and on data from a sample of 583 patients from the German rheumatological database of 1998. Functional capacity was defined by the Hannover Functional Ability Questionnaire (HFAQ) scores. Costs were calculated from resources utilised and patients' work capacity. Direct costs consisted of outpatient medical services, inpatient treatment, long-term care and rehabilitation treatment. Indirect costs incurred by sick leave and premature retirement were quantified according to the human-capital approach. MAIN OUTCOME MEASURES AND RESULTS: Average total direct costs (year 1998-2001 values) per patient per year for continuous treatment with the selected DMARDs comprising costs for drugs, monitoring and treatment of adverse drug reactions (ADRs) were highest for intramuscular gold (sodium aurothiomalate) [euro 2106 (euro 1 approximately equal to $US 0.91; average of the period from 2000 through 2001)] followed by leflunomide (euro 2010), azathioprine (euro 1878), sulfasalazine (euro 1190), oral methotrexate (euro 708), and lowest for the antimalarials chloroquine/hydroxychloroquine (euro 684). There were additional yearly costs for RA-related non-DMARD medication of euro 554 per patient, including management of ADRs. Mean cost of illness (year 1998 values) excluding medication cost amounted to euro 17,868 per RA patient per year. Annual costs increased with increasing disability, i.e. decreasing functional capacity, of RA patients from euro 6029 per patient with more than 94% of functional capacity to euro 28,509 per patient with <20% of functional capacity. In general, there was a predominance of indirect costs in each of the categories of functional capacity, ranging between 74% and 87% of total (direct and indirect) annual costs per RA patient. Annual direct costs increased from euro 811 to euro 7438 per patient with increasing disability. Inpatient treatment was the predominant component of direct costs. Patients in the worst category (<20%) of function experienced hospital costs that were 6.5 times higher than those of patients in the best category (>94%). CONCLUSIONS: On the basis of the data presented it can be concluded that the results of this investigation are typical for patients in rheumatological care in Germany and can therefore be used in a health economic analysis of different DMARD sequences aimed at changing disease progression over time.