Long-term clinical and radiological effectiveness and safety of ultralow doses of rituximab in rheumatoid arthritis: observational extension of the REDO trial.

BACKGROUND: The REDO trial (REtreatment with Rituximab in RhEmatoid arthritis: Disease Outcome after Dose Optimisation) showed similar disease activity for retreatment with ultralow doses (200 mg and 500 mg per 6 months) compared with standard low-dose rituximab (RTX, 1000 mg per 6 months). We performed an observational extension study of the REDO trial to assess long-term effectiveness. METHODS: Patients from the REDO trial were followed from start of the trial to censoring in April 2021. RTX use was at the discretion of patient and rheumatologist using treat to target. The primary outcome was disease activity (disease activity score in 28 joints C-reactive protein (DAS28-CRP)), analysed using a longitudinal mixed model by original randomisation and time-varying RTX dose. The original DAS28-CRP non-inferiority (NI) margin of 0.6 was used. RTX dose and persistence, safety and radiological outcomes were also assessed. FINDINGS: Data from 126 of 142 REDO patients was collected from 15 December 2016, up to 30 April 2021. Drop-outs continued treatment elsewhere (n=3) or did not consent (n=13).Disease activity did not differ by original randomisation group: 1000 mg mean DAS28-CRP (95% CI) of 2.2 (2.0 to 2.5), 500 mg 2.3 (2.1 to 2.4) and 200 mg 2.4 (2.2 to 2.5). Lower time-varying RTX dose was associated with higher DAS28-CRP (0.22 (95% CI 0.05 to 0.40) higher for 200 mg/6 months compared with 1000 mg/6 months), but remained within the NI-margin. RTX persistence was 93%. Median RTX dose was 978 mg (IQR 684-1413) per year, and no association was found between RTX dose and adverse events or radiological damage. INTERPRETATION: Long-term use of ultralow doses of RTX is effective in patients with rheumatoid arthritis responding to standard dose RTX.

Nailfold capillaroscopy and candidate-biomarker levels in systemic sclerosis-associated pulmonary hypertension: A cross-sectional study.

Objectives: Pulmonary hypertension is one of the leading causes of death in systemic sclerosis. Early detection and treatment of pulmonary hypertension in systemic sclerosis is crucial. Nailfold capillaroscopy microscopy, vascular autoantibodies AT1R and ETAR, and several candidate-biomarkers have the potential to serve as noninvasive tools to identify systemic sclerosis patients at risk for developing pulmonary hypertension. Here, we explore the classifying potential of nailfold capillaroscopy microscopy characteristics and serum levels of selected candidate-biomarkers in a sample of systemic sclerosis patients with and without different forms of pulmonary hypertension. Methods: A total of 81 consecutive systemic sclerosis patients were included, 40 with systemic sclerosis pulmonary hypertension and 41 with no pulmonary hypertension. In each group, quantitative and qualitative nailfold capillaroscopy microscopy characteristics, vascular autoantibodies AT1R and ETAR, and serum levels of 24 soluble serum factors were determined. For evaluation of the nailfold capillaroscopy microscopy characteristics, linear regression analysis accounting for age, sex, and diffusing capacity of the lungs for carbon monoxide percentage predicted was used. Autoantibodies and soluble serum factor levels were compared using two-sample t test with equal variances. Results: No statistically significant differences were observed in quantitative or qualitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibody ETAR and AT1R titer between systemic sclerosis-pulmonary hypertension and systemic sclerosis-no pulmonary hypertension. In contrast, several serum levels of soluble factors differed between groups: Endostatin, sVCAM, and VEGFD were increased, and CXCL4, sVEGFR2, and PDGF-AB/BB were decreased in systemic sclerosis-pulmonary hypertension. Random forest classification identified Endostatin and CXCL4 as the most predictive classifiers to distinguish systemic sclerosispulmonary hypertension from systemic sclerosis-no pulmonary hypertension. Conclusion: This study shows the potential for several soluble serum factors to distinguish systemic sclerosis-pulmonary hypertension from systemic sclerosis-no pulmonary hypertension. We found no classifying potential for qualitative or quantitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibodies.

Treat-to-target dose reduction and withdrawal strategy of TNF inhibitors in psoriatic arthritis and axial spondyloarthritis: a randomised controlled non-inferiority trial.

OBJECTIVES: Tumour necrosis factor inhibitors (TNFi) are effective in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), but are associated with a small (0.6%) increase in serious infection risk, patient burden due to need for self-injection and high costs. Treat-to-target (T2T) tapering might ameliorate these drawbacks, but high-quality evidence on T2T tapering strategies is lacking in PsA and axSpA. METHODS: We performed a pragmatic open-label, monocentre, randomised controlled non-inferiority (NI) trial on T2T tapering of TNFi. Patients with PsA and axSpA using a TNFi with ≥6 months stable low disease activity (LDA) were included. Patients were randomised 2:1 to disease activity-guided T2T with or without tapering until withdrawal and followed-up to 12 months. Primary endpoint was the difference in proportion of patients having LDA at 12 months between groups, compared with a prespecified NI margin of 20%, estimated using a Bayesian prior. RESULTS: 122 patients (64 PsA and 58 axSpA) were randomised to a T2T strategy with (N=81) or without tapering (N=41). The proportion of patients in LDA at 12 months was 69% for the tapering and 73% for the no-tapering group: adjusted difference 5% (Bayesian 95% credible interval: -10% to 19%) which confirms NI considering the NI margin of 20%. The mean percentage of daily defined dose was 53% for the tapering and 91% for the no-tapering group at month 12. CONCLUSIONS: A T2T TNFi strategy with tapering attempt is non-inferior to a T2T strategy without tapering with regard to the proportion of patients still in LDA at 12 months, and results in a substantial reduction of TNFi use. TRIAL REGISTRATION NUMBER: NL 6771.

Discovery of Arthritis in Psoriasis Patients for Early Rheumatological Referral (DAPPER): Protocol for a Longitudinal Observational Study.

BACKGROUND: One in three patients with psoriasis will develop psoriatic arthritis (PsA). If left untreated, this can lead to pain, impaired function, and irreversible joint damage. Timely recognition and referral to a rheumatologist are therefore key. However, current methods used to screen patients with psoriasis for those who might benefit from referral to a rheumatologist are not performing well enough. OBJECTIVE: The Discovery of Arthritis in Psoriasis Patients for Early Rheumatological Referral (DAPPER) study is designed to determine the prevalence of PsA in a psoriasis population and to find parameters that can be used to develop a new or enhance an existing instrument for a rheumatological referral. METHODS: DAPPER is a longitudinal observational study with a 1-year follow-up. Patients with psoriasis (N=300) who are treated at an outpatient dermatological clinic will be screened extensively for signs and symptoms of PsA by a trained rheumatologist. If there is clinical suspicion of PsA and the patient is not yet treated by a rheumatologist, referral to the Department of Rheumatology will follow for confirmation of the diagnosis and further care. After 1 year, data on changes in quality of life and PsA and psoriasis disease activity will be collected from the referred patients. The screening visit will be used to gather demographical and medical data, which can later be used to develop the aforementioned screening instrument. RESULTS: Inclusion started in June 2019 and finished in June 2021. Follow-up with newly discovered patients with PsA is ongoing. CONCLUSIONS: The DAPPER study is specifically designed to improve the detection of existing PsA in a dermatologic outpatient setting. Although internal validity will be tested, external validity will have to be checked using a second validation cohort. To predict the development of PsA in the future, longitudinal/prospective data collection is required and will be performed in a follow-up study (DAPPER-i). TRIAL REGISTRATION: Dutch Trial Register NTR7604; https://www.trialregister.nl/trial/7397. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31647.

Predictive factors for treatment-related mortality and major adverse events after autologous haematopoietic stem cell transplantation for systemic sclerosis: results of a long-term follow-up multicentre study.

BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) improves survival in systemic sclerosis (SSc) with poor prognosis, but is hampered by treatment-related mortality (TRM). OBJECTIVE: To evaluate event-free survival (EFS), TRM, response to treatment, disease progression and patient characteristics associated with events. METHODS: All patients treated with HSCT for SSc in The Netherlands until 2017 (n=92) were included. Data on skin involvement (modified Rodnan skin score (mRSS), pulmonary function (forced vital capacity (FVC) and diffusion capacity of the lungs for carbon monoxide (DLCO)), extent of interstitial lung disease on high-resolution CT using Goh scores and left ventricular ejection fraction (LVEF) were collected at baseline, 1, 2 and 5 years. Occurrence of events, defined as death or major organ failure, were collected until 2019. As control, a comparison between patients treated with cyclophosphamide (CYC) and patients with HSCT who participated in the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial was performed. RESULTS: Median follow-up was 4.6 years. EFS estimates at 5, 10 and 15 years were 78%, 76% and 66%, respectively. Twenty deaths occurred. Mean FVC, DLCO, mRSS and Goh scores all improved significantly. Disease progression occurred in 22 patients. Frequency of TRM decreased over time and occurred more often in males. Events were independently associated with male sex, LVEF <50% and older age. In ASTIS, patients treated with HSCT (n=23) 7 events occurred versus 13 in the CYC group (n=22). CONCLUSION: Our data confirm long-term efficacy of HSCT in improving survival, skin and lung involvement in SSc. Male sex, lower LVEF and older age at baseline were identified as risk factors for events.

Prediction of organ involvement and survival in systemic sclerosis patients in the first 5 years from diagnosis.

Background: Organ involvement often occurs in early systemic sclerosis and has been related to premature death. Identifying patients at diagnosis at risk of developing early organ involvement would be useful to optimize screening and management strategies. Objective: To develop prediction models for the 5-year development of interstitial lung disease, pulmonary arterial hypertension and death. Methods: A European multicentre inception cohort was created. For modelling, predefined clinical variables with known predictive value at diagnosis were used. Univariate and multivariate regression analysis were done to select baseline predictors and build the prediction models. The models were tested using the area under the receiver operating characteristic curve comparing observed and expected frequencies. Results: Of 735 patients, 23% developed interstitial lung disease, 8% developed pulmonary arterial hypertension 12% died. The interstitial lung disease model included diffuse cutaneous systemic sclerosis (OR = 1.8), systemic sclerosis disease duration < 3 years (OR = 1.4), puffy fingers (OR = 1.6), and anti-topoisomerase-I-antibodies (OR = 1.8). The pulmonary arterial hypertension model included age > 65 years (OR = 3.2), forced vital capacity < 70% (OR = 2.5) and diffusing capacity of the lung for carbon monoxide < 55% (OR = 1.9). Death was predicted best by age > 65 years (OR = 4.1), male gender (OR = 1.9), no anti-centromere antibodies (OR = 0.5), proteinuria (OR = 1.9), forced vital capacity < 70% (OR = 1.8) and pulmonary arterial hypertension at diagnosis (OR = 10.1). The area under the receiver operating characteristic was 0.66 (95% CI 0.64-0.67), 0.66 (95% CI 0.64-0.68) and 0.70 (95% CI 0.69-0.72), respectively. Conclusion: We have shown that it is possible to predict interstitial lung disease, pulmonary arterial hypertension and death using established variables already available at the moment of systemic sclerosis diagnosis. Discriminatory performance of the models was suboptimal. Further research including new variables is necessary to improve performance.

Selexipag treatment in patients with systemic sclerosis-associated pulmonary arterial hypertension in clinical practice, a case series.

Objective: To describe the efficacy and safety in all patients with systemic sclerosis-associated pulmonary arterial hypertension who started selexipag between 09-2016 and 06-2018 in two pulmonary arterial hypertension expert centers. Methods: All patients with systemic sclerosis-associated pulmonary arterial hypertension diagnosed by right heart catheterization and treated with selexipag were included. Every 12 weeks, treatment effect was assessed by (1) the opinion of the expert team and (2) the abbreviated risk assessment, consisting of functional class, six-minute walking distance, and N-terminal prohormone of brain natriuretic peptide level at baseline and during follow-up. Side effects and adverse events were registered. Results: We included 13 systemic sclerosis-associated pulmonary arterial hypertension patients, 10 patients were female, median age (interquartile range) of 68 (58-75) years, median systemic sclerosis disease duration of 7.4 (4.7-13.5) years, and median pulmonary arterial hypertension duration of 4 (2.5-7.5) years. Two patients discontinued selexipag within 4 weeks due to side effects. The remaining 11 patients had a median follow-up duration of 48 (interquartile range = 24-72) weeks. Two patients died (one pulmonary arterial hypertension-related, the other systemic sclerosis-related). According to the expert team, 8 of 11, 9 of 10, and 5 of 7 patients stabilized or improved at 12, 24, and 48 weeks, respectively. According to the abbreviated risk assessment at study end, 3 of 11 patients had 1 low-risk criterion. No previously unrecorded side effects were reported. Conclusion: Adding selexipag to background therapy in a high-risk cohort of systemic sclerosis-associated pulmonary arterial hypertension patients provided sustained stabilization of symptoms with an acceptable safety profile. Improvement was reached in only two of our patients. Further research should focus on systemic sclerosis-associated pulmonary arterial hypertension patients treated with multiple targeted treatments, preferably these patients should be prospectively followed in international registries.

Down-titration and discontinuation strategies of tumour necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity.

BACKGROUND: Anti-tumour necrosis factor (TNF) agents are effective in treating people with rheumatoid arthritis (RA), but are associated with (dose-dependent) adverse effects and high costs. To prevent overtreatment, several trials have assessed the effectiveness of down-titration compared with continuation of the standard dose. This is an update of a Cochrane Review published in 2014. OBJECTIVES: To evaluate the benefits and harms of down-titration (dose reduction, discontinuation, or disease activity-guided dose tapering) of anti-TNF agents on disease activity, functioning, costs, safety, and radiographic damage compared with usual care in people with RA and low disease activity. SEARCH METHODS: We searched MEDLINE, Embase, Web of Science and CENTRAL (29 March 2018) and four trial registries (11 April 2018) together with reference checking, citation searching, and contact with study authors to identify additional studies. We screened conference proceedings (American College of Rheumatology and European League Against Rheumatism 2005-2017). SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing down-titration (dose reduction, discontinuation, disease activity-guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) to usual care/no down-titration in people with RA and low disease activity. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: One previously included trial was excluded retrospectively in this update because it was not an RCT/CCT. We included eight additional trials, for a total of 14 studies (13 RCTs and one CCT, 3315 participants in total) reporting anti-TNF down-titration. Six studies (1148 participants) reported anti-TNF dose reduction compared with anti-TNF continuation. Eight studies (2111 participants) reported anti-TNF discontinuation compared with anti-TNF continuation (three studies assessed both anti-TNF discontinuation and dose reduction), and three studies assessed disease activity-guided anti-TNF dose tapering (365 participants). These studies included data on all anti-TNF agents, but primarily adalimumab and etanercept. Thirteen studies were available in full text, one was available as abstract. We assessed the included studies generally at low to moderate risk of bias; our main concerns were bias due to open-label treatment and unblinded outcome assessment. Clinical heterogeneity between the trials was high. The included studies were performed at clinical centres around the world and included people with early as well as established RA, the majority of whom were female with mean ages between 47 and 60. Study durations ranged from 6 months to 3.5 years.We found that anti-TNF dose reduction leads to little or no difference in mean disease activity score (DAS28) after 26 to 52 weeks (high-certainty evidence, mean difference (MD) 0.06, 95% confidence interval (CI) -0.11 to 0.24, absolute risk difference (ARD) 1%) compared with continuation. Also, anti-TNF dose reduction does not result in an important deterioration in function after 26 to 52 weeks (Health Assessment Questionnaire Disability Index (HAQ-DI)) (high-certainty evidence, MD 0.09, 95% CI 0.00 to 0.19, ARD 3%). Next to this, anti-TNF dose reduction may slightly reduce the proportion of participants switched to another biologic (low-certainty evidence), but probably slightly increases the proportion of participants with minimal radiographic progression after 52 weeks (moderate-certainty evidence, risk ratio (RR) 1.22, 95% CI 0.76 to 1.95, ARD 2% higher). Anti-TNF dose reduction may cause little or no difference in serious adverse events, withdrawals due to adverse events and proportion of participants with persistent remission (low-certainty evidence).Results show that anti-TNF discontinuation probably slightly increases the mean disease activity score (DAS28) after 28 to 52 weeks (moderate-certainty evidence, MD 0.96, 95% CI 0.67 to 1.25, ARD 14%), and that the RR of persistent remission lies between 0.16 and 0.77 (low-certainty evidence). Anti-TNF discontinuation increases the proportion participants with minimal radiographic progression after 52 weeks (high-certainty evidence, RR 1.69, 95% CI 1.10 to 2.59, ARD 7%) and may lead to a slight deterioration in function (HAQ-DI) (low-certainty evidence). It is uncertain whether anti-TNF discontinuation influences the number of serious adverse events (due to very low-certainty evidence) and the number of withdrawals due to adverse events after 28 to 52 weeks probably increases slightly (moderate-certainty evidence, RR 1.46, 95% CI 0.75 to 2.84, ARD 1% higher).Anti-TNF disease activity-guided dose tapering may result in little or no difference in mean disease activity score (DAS28) after 72 to 78 weeks (low-certainty evidence). Furthermore, anti-TNF disease activity-guided dose tapering results in little or no difference in the proportion of participants with persistent remission after 18 months (high-certainty evidence, RR 0.89, 95% CI 0.75 to 1.06, ARD -9%) and may result in little or no difference in switching to another biologic (low-certainty evidence). Anti-TNF disease activity-guided dose tapering may slightly increase proportion of participants with minimal radiographic progression (low-certainty evidence) and probably leads to a slight deterioration of function after 18 months (moderate-certainty evidence, MD 0.2 higher, 0.02 lower to 0.42 higher, ARD 7% higher), It is uncertain whether anti-TNF disease activity-guided dose tapering influences the number of serious adverse events due to very low-certainty evidence. AUTHORS' CONCLUSIONS: We found that fixed-dose reduction of anti-TNF, after at least three to 12 months of low disease activity, is comparable to continuation of the standard dose regarding disease activity and function, and may be comparable with regards to the proportion of participants with persistent remission. Discontinuation (also without disease activity-guided adaptation) of anti-TNF is probably inferior to continuation of treatment with respect to disease activity, the proportion of participants with persistent remission, function, and minimal radiographic damage. Disease activity-guided dose tapering of anti-TNF is comparable to continuation of treatment with respect to the proportion of participants with persistent remission and may be comparable regarding disease activity.Caveats of this review are that available data are mainly limited to etanercept and adalimumab, the heterogeneity between studies, and the use of superiority instead of non-inferiority designs.Future research should focus on the anti-TNF agents infliximab and golimumab; assessment of disease activity, function, and radiographic outcomes after longer follow-up; and assessment of long-term safety, cost-effectiveness, and predictors for successful down-titration. Also, use of a validated flare criterion, non-inferiority designs, and disease activity-guided tapering instead of fixed-dose reduction or discontinuation would allow researchers to better interpret study findings and generalise to clinical practice.

Support needs for medication use and the suitability of eHealth technologies to address these needs: a focus group study of older patients with rheumatoid arthritis.

OBJECTIVE: The objectives of this study were to explore the needs of patients with rheumatoid arthritis (RA) regarding support for medication use and to gain insight into their perspective on the suitability of eHealth technologies to address these needs. METHODS: Three focus groups were conducted with 28 patients with RA. Audio recordings made during the focus groups were transcribed verbatim. Two researchers independently performed an inductive, thematic analysis on the data (ie, the transcripts and field notes). RESULTS: The following three themes that described support needs of patients with RA for medication use were identified in the data: 1) informational support; 2) practical support; and 3) emotional support. Informational support reflected the provision of information and facts, including advice, suggestions, and feedback from health care providers. Practical support included the reinforcement of practical skills as well as the provision of medication aids and pharmacy services. Emotional support reflected a trusted patient-health care provider relationship, characterized by good communication. Although potential advantages of eHealth technologies to address the patients' support needs were recognized, concerns over matters such as personal interaction with health care providers, privacy and data security, and the quality and reliability of online information were prevalent. CONCLUSION: Patients with RA have informational, practical, and emotional support needs for medication use. Informational support seems to be most important. From the patients' perspective, eHealth technologies may have the potential to address these needs. However, these technologies are regarded as a complement to, rather than a replacement of, current practices.

Long-term outcomes after disease activity-guided dose reduction of TNF inhibition in rheumatoid arthritis: 3-year data of the DRESS study - a randomised controlled pragmatic non-inferiority strategy trial.

OBJECTIVE: Tumour necrosis factor inhibitors (TNFi) are effective in rheumatoid arthritis (RA), but disadvantages include adverse events (AEs) and high costs. This can be improved by disease activity-guided dose reduction (DR). We aimed to assess long-term outcomes of TNFi DR in RA by using 3-year data from the DRESS study (Dose REduction Strategy of Subcutaneous TNF inhibitors study). METHODS: In the intervention phase (month 0-18) of the DRESS study (Dutch trial register, NTR 3216), patients were randomised to DR or usual care (UC). In the extension phase (month 18-36), treatment strategies in both groups converged to continuation of protocolised tight control and allowed dose optimisation. Intention-to-treat analyses were done on flare, disease activity (28 joint count-based disease activity score with C reactive protein (DAS28-CRP)), functioning (health assessment questionnaire-disability index (HAQ-DI)), quality of life (Euroqol 5 dimensions 5 levels questionnaire (EQ5D-5L)), medication use, radiographic progression (Sharp van der Heijde score (SvdH)) and AE. RESULTS: 172/180 patients included in the DRESS study were included in the extension phase. Cumulative incidences of major flare were 10% and 12% (-2%, 95% CI -8 to 15) in DR and UC groups in the extension phase, and 17% and 14% (3%, 95% CI -9 to 13) from 0 to 36 months. Cumulative incidences of short-lived flares were 43% (33 to 52%)%) and 35% (23 to 49%)%) in DR and UC groups in the extension phase, and 83% (75 to 90%)%) and 44% (31 to 58%)%) from 0 to 36 months. Mean DAS28-CRP, HAQ-DI, EQ5D-5L and SvdH remained stable and not significantly different between groups. TNFi use remained low in the DR group and decreased in the UC group. Cumulative incidences of AE were not significantly different between groups. CONCLUSIONS: Safety and efficacy of disease activity guided TNFi DR in RA are maintained up to 3 years, with a large reduction in TNFi use, but no other benefits. Implementation of DR would vastly improve the cost-effective use of TNFi.

Disease activity-guided dose optimisation of adalimumab and etanercept is a cost-effective strategy compared with non-tapering tight control rheumatoid arthritis care: analyses of the DRESS study.

BACKGROUND: A disease activity-guided dose optimisation strategy of adalimumab or etanercept (TNFi (tumour necrosis factor inhibitors)) has shown to be non-inferior in maintaining disease control in patients with rheumatoid arthritis (RA) compared with usual care. However, the cost-effectiveness of this strategy is still unknown. METHOD: This is a preplanned cost-effectiveness analysis of the Dose REduction Strategy of Subcutaneous TNF inhibitors (DRESS) study, a randomised controlled, open-label, non-inferiority trial performed in two Dutch rheumatology outpatient clinics. Patients with low disease activity using TNF inhibitors were included. Total healthcare costs were measured and quality adjusted life years (QALY) were based on EQ5D utility scores. Decremental cost-effectiveness analyses were performed using bootstrap analyses; incremental net monetary benefit (iNMB) was used to express cost-effectiveness. RESULTS: 180 patients were included, and 121 were allocated to the dose optimisation strategy and 59 to control. The dose optimisation strategy resulted in a mean cost saving of -€12 280 (95 percentile -€10 502; -€14 104) per patient per 18 months. There is an 84% chance that the dose optimisation strategy results in a QALY loss with a mean QALY loss of -0.02 (-0.07 to 0.02). The decremental cost-effectiveness ratio (DCER) was €390 493 (€5 085 184; dominant) of savings per QALY lost. The mean iNMB was €10 467 (€6553-€14 037). Sensitivity analyses using 30% and 50% lower prices for TNFi remained cost-effective. CONCLUSIONS: Disease activity-guided dose optimisation of TNFi results in considerable cost savings while no relevant loss of quality of life was observed. When the minimal QALY loss is compensated with the upper limit of what society is willing to pay or accept in the Netherlands, the net savings are still high. TRIAL REGISTRATION NUMBER: NTR3216; Post-results.

Anti-alpha-fodrin antibodies do not add much to the diagnosis of Sjögren's syndrome.

The presence of anti-alpha-fodrin autoantibodies has been reported to be a highly specific and sensitive test for the diagnosis of Sjögren's syndrome (SjS). We looked (in Nijmegen) for anti-alpha-fodrin, anti-Ro60, and anti-La autoantibodies in a cohort of 51 patients with rheumatic diseases (primary SjS [21], secondary SjS 6, rheumatoid arthritis [RA] 12, systemic lupus erythematosus [SLE] 6, and scleroderma 6) and in 28 healthy subjects, using ELISA, immunoblotting, and immunoprecipitation. The same samples were analyzed with an alternative anti-alpha-fodrin ELISA in Hanover. The Nijmegen ELISA of the sera from primary SjS showed sensitivities of 43% and 48% for IgA- and IgG-type anti-alpha-fodrin antibodies, respectively. The Hanover ELISA showed sensitivities of 38% and 10% for IgA- and IgG-type anti-alpha-fodrin antibodies, respectively. The ELISAs for alpha-fodrin showed six (Nijmegen) and four (Hanover) anti-alpha-fodrin-positive RA sera. IgA and IgG anti-fodrin antibodies were also present in four patients with secondary SjS. The sensitivities of Ro60 and La-antibodies in the Nijmegen ELISA were 67% and 62%, respectively. Unlike anti-alpha-fodrin antibodies, all anti-Ro60 and anti-La positive sera could be confirmed by immunoblotting or RNA immunoprecipitation. Thus, anti-Ro and anti-La autoantibodies were more sensitive than anti-alpha-fodrin autoantibodies in ELISA and were more frequently confirmed by other techniques. Anti-La antibodies appear to be more disease-specific than anti-alpha-fodrin antibodies, which are also found in RA sera. Therefore, the measurement of anti-alpha-fodrin autoantibodies does not add much to the diagnosis of Sjögren's syndrome.