Kerstin Brickmann

The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis

Background Glucocorticoids (GCs) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis (RA) and the need to start disease-modifying antirheumatic drugs (DMARDs). Objective To test the effect of GCs on patients with very early arthritis (symptom duration of <16 weeks) in a randomised controlled trial. Methods Patients received a single intramuscular injection of 120 mg methylprednisolone or placebo (PL) and were followed up for 52 weeks. Primary end point was drug-free clinical remission, both at weeks 12 and 52. Among secondary outcomes were fulfilment of remission criteria at weeks 2, 12 or 52, time course of ‘core set variables’ and proportion of patients starting DMARDs. Results 17.0% of all analysed subjects (65/383) achieved persistent remission: 17.8% (33/185) of the PL group, 16.2% (32/198) of the patients receiving methylprednisolone (OR=1.13, 95% CI 0.66 to 1.92, p=0.6847). Analyses of secondary end points showed significant clinical benefits of the GC only at week 2. These differences subsequently disappeared. DMARDs were started in 162 patients: 50.3% methylprednisolone and 56.7% PL patients had to start DMARD treatment (OR=0.78, 95% CI 0.49 to 1.22, p=0.30). Significantly more patients with polyarthritis than with oligoarthritis received DMARDs (OR=2.84, 95% CI 1.75 to 4.60, p<0.0001). Conclusions Neither remission nor development of RA is delayed by GC treatment. Remission is rare in the first year of very early arthritis, occurring in <20% of the patients. Also, the need to start DMARDs was not influenced by GC treatment.

Ultrasound for diagnosis of carpal tunnel syndrome: comparison of different methods to determine median nerve volume and value of power Doppler sonography

Objective To compare ultrasound measurement of median nerve cross-sectional area (CSA) at different anatomical landmarks and to assess the value of power Doppler signals within the median nerve for diagnosis of carpal tunnel syndrome (CTS). Methods A prospective study of 135 consecutive patients with suspected CTS undergoing two visits within 3 months. A final diagnosis of CTS was established by clinical and electrophysiological findings. CSA was sonographically measured at five different levels at forearm and wrist; and CSA wrist to forearm ratios or differences were calculated. Intraneural power Doppler signals were semiquantitatively graded. Diagnostic values of different ultrasound methods were compared by receiver operating characteristic curves using SPSS. Results CTS was diagnosed in 111 (45.5%) wrists; 84 (34.4%) had no CTS and 49 (20.1%) were possible CTS cases. Diagnostic values were comparable for all sonographic methods to determine median nerve swelling, with area under the curves ranging from 0.75 to 0.85. Thresholds of 9.8 and 13.8 mm2 for the largest CSA of the median nerve yielded a sensitivity of 92% and a specificity of 92%. A power Doppler score of 2 or greater had a specificity of 90% for the diagnosis of CTS. Sonographic median nerve volumetry revealed a good reliability with an intraclass correlation coefficient of 0.90 (95% CI 0.79 to 0.95). Conclusions Sonographic assessment of median nerve swelling and vascularity allows for a reliable diagnosis of CTS. Determination of CSA at its maximal shape offers an easily reproducible tool for CTS classification in daily clinical practice.

B lymphocyte-typing for prediction of clinical response to rituximab

IntroductionThe prediction of therapeutic response to rituximab in rheumatoid arthritis is desirable. We evaluated whether analysis of B lymphocyte subsets by flow cytometry would be useful to identify non-responders to rituximab ahead of time.MethodsFifty-two patients with active rheumatoid arthritis despite therapy with TNF-inhibitors were included in the national rituximab registry. DAS28 was determined before and 24 weeks after rituximab application. B cell subsets were analyzed by high-sensitive flow cytometry before and 2 weeks after rituximab administration. Complete depletion of B cells was defined as CD19-values below 0.0001 x109 cells/liter.ResultsAt 6 months 19 patients had a good (37%), 23 a moderate (44%) and 10 (19%) had no EULAR-response. The extent of B lymphocyte depletion in peripheral blood did not predict the success of rituximab therapy. Incomplete depletion was found at almost the same frequency in EULAR responders and non-responders. In comparison to healthy controls, non-responders had elevated baseline CD95+ pre-switch B cells, whereas responders had a lower frequency of plasmablasts.ConclusionsThe baseline enumeration of B lymphocyte subsets is still of limited clinical value for the prediction of response to anti-CD20 therapy. However, differences at the level of CD95+ pre switch B cells or plasmablasts were noticed with regard to treatment response. The criterion of complete depletion of peripheral B cells after rituximab administration did not predict the success of this therapy in rheumatoid arthritis.

The Value of Median Nerve Sonography as a Predictor for Short- and Long-Term Clinical Outcomes in Patients with Carpal Tunnel Syndrome: A Prospective Long-Term Follow-Up Study

Objectives To investigate the prognostic value of B-mode and Power Doppler (PD) ultrasound of the median nerve for the short- and long-term clinical outcomes of patients with carpal tunnel syndrome (CTS). Methods Prospective study of 135 patients with suspected CTS seen 3 times: at baseline, then at short-term (3 months) and long-term (15–36 months) follow-up. At baseline, the cross-sectional area (CSA) of the median nerve was measured with ultrasound at 4 levels on the forearm and wrist. PD signals were graded semi-quantitatively (0–3). Clinical outcomes were evaluated at each visit with the Boston Questionnaire (BQ) and the DASH Questionnaire, as well as visual analogue scales for the patient’s assessment of pain (painVAS) and physician’s global assessment (physVAS). The predictive values of baseline CSA and PD for clinical outcomes were determined with multivariate logistic regression models. Results Short-term and long-term follow-up data were available for 111 (82.2%) and 105 (77.8%) patients, respectively. There was a final diagnosis of CTS in 84 patients (125 wrists). Regression analysis revealed that the CSA, measured at the carpal tunnel inlet, predicted short-term clinical improvement according to BQ in CTS patients undergoing carpal tunnel surgery (OR 1.8, p = 0.05), but not in patients treated conservatively. Neither CSA nor PD assessments predicted short-term improvement of painVAS, physVAS or DASH, nor was any of the ultrasound parameters useful for the prediction of long-term clinical outcomes. Conclusions Ultrasound assessment of the median nerve at the carpal tunnel inlet may predict short-term clinical improvement in CTS patients undergoing carpal tunnel release, but long-term outcomes are unrelated to ultrasound findings.

The Functional Promoter Polymorphism of the Coagulation Factor XII Gene is not Associated With Peripheral Arterial Disease

Coagulation factor XII (FXII) plays a key role in both coagulation and fibrinolysis and has been associated with cardiovascular disease in some studies. Plasma FXIIa levels are strongly determined by a common functional polymorphism in the promoter of the FXII gene (F12-4C>T). To investigate the potential association of this polymorphism with peripheral arterial disease (PAD), we performed a case-control study including 668 patients with PAD and 762 controls participants without cardiovascular disease. F12 genotype frequencies were not significantly different between patients with PAD and control participants. After adjustment for classical risk factors, the odds ratio of carriers of a F12 -4T allele for PAD was 1.06 (95% confidence interval 0.86—1.32). F12 genotypes were associated with a modest increase of the mean-activated partial thromboplastin time but not with PAD stage or severity. We conclude that the functional F124C>T polymorphism is not associated with PAD.

Treatment of rheumatoid arthritis in the 21st century: targeting B-lymphocytes

SummaryRheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent inflammation of synovial tissue. Although the initiating event of RA is still unknown, recent research has demonstrated the importance of the increased production of tumor necrosis factor (TNF) alpha in the perpetuation of the inflammatory process of this disease. Targeting this molecule with soluble receptors, i.e., etanercept, or antibodies, like infliximab or adalimumab, a new class of highly effective anti rheumatic drugs has been developed. Unfortunately, not all patients respond sufficiently to TNF blockade and some of the patients become unresponsive to TNF-blocking agents. Targeting B-lymphocytes in these patients has opened a new therapeutic window. It has been demonstrated that B-lymphocytes have an important impact in the pathophysiology of RA. These cells produce not only a variety of autoantibodies, but directly stimulate autoaggressive T lymphocytes in the synovium. Furthermore, B-lymphocytes produce a variety of proinflammatory cytokines that also activate monocytes and synoviocytes. Several placebo-controlled clinical trials have demonstrated the efficacy of B-lymphocyte-directed therapy in patients that have responded poorly to conventional disease-modifying drugs or TNF blockade. In addition, several other B-cell specific antigens are potential targets in different autoimmune diseases.ZusammenfassungDie rheumatoide Arthritis (RA) ist eine chronisch entzündliche Erkrankung, die durch Inflammation des Synovialgewebes gekennzeichnet ist. Obwohl das auslösende Ereignis immer noch unbekannt ist, konnte in letzter Zeit gezeigt werden, dass die vermehrte Produktion von Tumor-Nekrose-Faktor (TNF) alpha für die Aufrechterhaltung des entzündlichen Prozesses wichtig ist. Durch lösliche Rezeptoren wie Etanercept oder Antikörper wie Infliximab oder Adalimumab, die an TNF alpha binden und es dadurch neutralisieren, konnte eine neue Klasse von hocheffektiven anti-rheumatischen Medikamenten entwickelt werden. Es gibt aber leider Patienten, die nur ungenügend ansprechen oder bei denen die Wirkung nachlässt. Bei diesen Patienten kann eine gegen B-Lymphozyten gerichtete Therapie neue Möglichkeiten bieten. Es konnte nämlich gezeigt werden, dass diese Zellgruppe eine wichtige Rolle in der RA spielt. B-Lymphozyten produzieren nicht nur eine Vielzahl von Autoantikörpern, sondern stimulieren direkt autoaggressive T-Lymphozyten im Synovium. Weiters sezernieren B-Lymphozyten verschiedene proinflammatorische Zytokine, die auch Monozyten und Synoviozyten aktivieren. In mehreren Plazebo-kontrollierten Studien konnte die Effektivität der gegen B-Lymphozyten gerichteten Therapie bei Patienten mit ungenügendem Ansprechen auf klassische Basistherapeutika oder TNF-Blockade gezeigt werden. Die verschiedensten B-Lymphozyten-Antigene werden derzeit auf ihr therapeutisches Potential untersucht.

Response to: ‘Paying attention to carpal tunnel contents lesions: ultrasound for evaluation of carpal tunnel syndrome’ by zhu and Liu

Our and several previous studies demonstrated a high diagnostic value of ultrasound for carpal tunnel syndrome (CTS).1 ,2 Among the various abnormalities within the carpal tunnel reported, the increase of the cross-sectional area (CSA) of the median nerve is the most commonly studied ultrasound abnormality.3 Additionally, ultrasound allows the identification of secondary causes of CTS, such as synovitis, tenosynovitis, calcified masses or tophaceous gout, as pointed out by zhu et al. 4 We acknowledge that the diagnostic value of ultrasound is not perfect, as some patients may suffer from CTS despite a normal ultrasound result and, …

The Glu228Ala polymorphism in the ligand-binding domain of death receptor 4 is not associated with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease resulting in inflammation of the synovial lining and destruction of the adjacent bone and cartilage. Although the initiating event of RA is still unknown, recent research has demonstrated the importance of the increased production of tumour necrosis factor (TNF) α in the perpetuation of the inflammatory process of this disease. Targeting this molecule with soluble receptors—that is, etanercept, or antibodies, like infliximab or adalimumab, a new class of highly effective antirheumatic drugs has been developed. Unfortunately, not all patients respond sufficiently to TNF blockade or become unresponsive, and therefore …

A7.10 A combination of cellular biomarkers predicts clinical response to rituximab in rheumatoid arthritis

Background and objectives Although B cell depletion with rituximab (RTX) is an effective treatment strategy in rheumatoid arthritis (RA) one third of patients does not achieve low disease activity after rituximab. We have previously reported that the frequency of circulating plasmablasts is a negative predictor of RTX response; however, additional biomarkers could be helpful to better tailor treatment strategies to RA patients. In the present study we investigated, whether other lymphocyte subsets or combinations thereof are useful predictors of a clinical response to RTX treatment. Material and methods RA patients receiving RTX for the first time were included in the Austrian rituximab registry. Clinical assessments, complete blood count and flow cytometry of lymphocyte subsets were obtained at baseline as well as at weeks 2 and 24 after RTX. Complete data was available for 48 patients. Logistic regression and receiving operating characteristic curve analyses were computed to analyse the predictive value of lymphocyte subsets for EULAR response and DAS ≤3.2 at week 24. Results Seventy-five percent of patients had a moderate or good EULAR response at week 24. Responders had lower total lymphocyte counts (TLC), T cells and CD4+ T cells at baseline. Both, baseline TLC and baseline CD4+T cell independently predicted EULAR response. Furthermore, a combination of TLC and plasmablast frequency independently predicted achievement of low disease activity. Less than 7% of patients with high TLC or plasmablast frequency reached low disease activity. Conclusions In RA, patients with increased TLC or high plasmablast frequency are at high risk of failing therapy with RTX.

AB1036 Ultrasound in Carpal Tunnel Syndrome: Predictive Value of Baseline B-Mode and Power Doppler Assessment for Long-Term Functional Outcome

Background The diagnostic value of ultrasound imaging in Carpal Tunnel Syndrome (CTS) by means of measurement of the Cross-sectional Area (CSA) of the median nerve has been established. However, reports on its prognostic value regarding the long term outcome is rare and contradictory. Objectives To investigate the prognostic value of baseline B-mode and Power Doppler (PD) ultrasound assessment of the median nerve in CTS patients regarding their long-term functional outcome. Methods Out of 36 patients with suspected CTS we conducted a prospective study on 27 patients with confirmed CTS, who underwent baseline visit and two follow-up visits: short-term after 2,8 months, long-term after 26,8 months (mean). Clinical, neurophysiological (NCS) and sonographic evaluation was performed at each visit. Ultrasound was performed using a Logiq E9 ultrasound device with multifrequence linear transducer, measuring the CSA of the median nerve at the following anatomic levels: (1) proximal border of the Pronator quadratus muscle (CsP), (2) area of the proximal Third of the pronator quadratus muscle (CsT) and (3) in the carpal canal, level of the Scaphoid tubercle and pisiform bone (CsS). PD-signals were graded from 0-3. Clinical outcome was evaluated regarding patients clinical improvement, based on: (1) the DASH questionnaire, (2) the visual analogue scale for grading pain symptoms (painVAS), (3) the VAS for grading severity of the clinical condition, completed by the examiner (physVAS). We conducted multivariate inclusive logistic regression models (including age, gender, BMI, vascularisation and symptom duration as independent variables) to determine the predictive value of CSA and PD for the binary dependent variable of outcome: improvement/no improvement of both at least 20% and 70%. Results 42,2% and 33,3% of the CTS patients showed improvement regarding painVAS, 53,3% and 42,2% presented improvement of their physVAS and 37,8% and 15,6% showed improvement of DASH outcome measure of at least 20% and 70% from baseline to long-term follow-up, respectively. CsS, CsS/CsP and CsS/CsT were higher in patients without improvement compared to those with at least 20% or 70% improvement. CsS/CsP presented the most relevant predictive value for clinical improvement, being significant in all logistic regression models predicting an improvement of at least 20% (exp(B): 0,000 – 0,012, p<0,05). In models predicting an improvement of at least 70%, CsS/CsP showed to be significant for painVAS and almost reached significance for physVAS and DASH (p=0,069 and p=0,076 respectively). We found similar results for CsS/CsT (being significant in all regression models predicting an improvement of at least 20%) and CsS (being significant in models predicting an improvement of at least 20% of painVAS and DASH and predicting an improvement of at least 70% of painVAS). Since surgery can not be considered to be an independent variable, models including this factor resulted to be insignificant. Conclusions A higher CsA at baseline predicts a worse clinical outcome of CTS patients as determined by VAS and DASH. PD examination has no predictive value regarding CTS outcome. Disclosure of Interest None declared