RADAI-5 and electronic monitoring tools.

Tighter monitoring of patients is regarded one of the key approaches to improve management of rheumatoid arthritis (RA). It could be demonstrated that the patient relevant disease course is not simply the linear link between two observation points, but fluctuates significantly in up to 80% of patients surveyed three times over two months, which understandably compromises quality of life. Patient self-report questionnaires such as the Rheumatoid Arthritis Disease Activity Index-Five (RADAI-5) have been shown to provide reliable information about disease activity, functionality, and other important aspects of daily life. The internal consistency of such questionnaires was shown to be significantly higher than the one of the DAS28 or the CDAI. Innovative electronic tools can be easily foreseen to constitute the media to enhance the dialogue between healthcare professionals and patients to improve disease care. These tools collect patient-recorded outcomes (PROs) data, through which physicians can monitor the course of the individual disease. Electronic versions can enable patients to receive additional medical attention between visits and provide a more detailed record of disease course over time. Applying the RADAI-5 or other questionnaires in electronic assessment tools will allow for the individual assessment of health levels, well-being, joint pain and the quality of life. Such tools will enable more frequent patient monitoring, with the potential to improve the patient's situation as well as to enhance physicians' time management, and to prioritise patients who may need further attention.

A combination of cellular biomarkers predicts failure to respond to rituximab in rheumatoid arthritis: a 24-week observational study.

BACKGROUND: Although B cell depletion with rituximab (RTX) is an effective treatment strategy in rheumatoid arthritis (RA), one third of patients do not achieve remission or low disease activity (LDA). Thus, identifying patients who will benefit from RTX is highly desirable. In the present study we investigated whether lymphocyte subsets other than B cells are predictors of a clinical response to RTX treatment. METHODS: Patients with RA who were receiving RTX for the first time were included in an observatory registry. Clinical assessments, complete blood count and flow cytometry of lymphocyte subsets were obtained at baseline and at week 24 after RTX. Complete data were available for 44 patients. Logistic regression and receiver operating characteristic curve analyses were computed to analyze the predictive value of lymphocyte subsets for European League Against Rheumatism (EULAR) response and LDA (defined as disease activity score in 28 joints (DAS28) ≤3.2) at week 24. RESULTS: EULAR responders had lower total lymphocyte counts (LC), T cells and CD4 + T cells at baseline. Although these parameters were independent predictors of EULAR response they failed in determining who would reach LDA. In contrast, LC >2910/µl or plasmablast frequency >2.85 % at baseline predicted a significantly higher DAS28 at week 24 after RTX and identified patients not achieving LDA at week 24 with sensitivity of 93.3 % and specificity of 44.8 %. CONCLUSIONS: A combination of LC and plasmablast frequency identifies patients with RA who will not benefit from RTX with high probability.

Is the state of health of rheumatoid arthritis patients receiving adequate treatment, predictable? - Results of a survey.

BACKGROUND: A survey was conducted to evaluate whether a steady improvement in the quality of life of Rheumatoid Arthritis (RA) patients as frequently reported in clinical studies, does actually occur. The focus of this study laid on the personal perception of RA patients. How do patients who have been treated along accepted guidelines see the state of their health and their joint pain at different points in time? METHODS: RA patients were asked to complete a questionnaire and return it to an opinion research centre. The questionnaire, which was developed by the authors, was divided into the areas: demography, symptom description and medical care, as well as the illness in a personal context. Three telephone interviews followed in monthly intervals when the patients' feelings about their illness, their every-day coping mechanisms and their social lives were rated. Intra-subject correlation and the level of agreement among patients when assessed at three different points within a two month period, was determined. RESULTS: 127 patients replied to the questionnaire. RA exerts a significant impact on a patient's daily life. Average ratings of current state of health and joint pain (answered on a 5-part scale extending from 1 (very good) to 5 (very bad)) range between 2.6 and 2.9 all three times. However, intra-subject correlation between the different assessment times, is in general quite modest. Concerning the question: "How is your join pain today?" only 14 of 127 participants express identical ratings all three times , while in one third of the participants, a difference of two digits on the 5-part scale, at least twice had to be noticed. Intra-class correlation coefficients between answers at different points are often much smaller than 0.5. Results were similar in all subgroups analysed (men vs. women; patients receiving biologics vs. those not receiving biologics; disease duration ≤3 years vs. 4 to 10 years vs. ≥11 years). CONCLUSION: On an individual level personal assessments of health, well-being and joint pain are nevertheless unsteady even within the timeframe of two months. This is why, even now, RA patients still cannot plan their lives as non-affected people can.

Patient-centered psoriatic arthritis (PsA) activity assessment by Stockerau Activity Score for Psoriatic Arthritis (SASPA).

BACKGROUND: To investigate whether a modified Rheumatoid Arthritis Disease Activity Index-5 could be applied as a routine assessment tool for psoriatic arthritis (PsA) patients. METHODS: Ninety-seven PsA outpatients (mean age 49.78 years; age range 23-80 years; 49 male, 48 female), completed a prototype questionnaire. Tender and swollen joint counts, including enthesiopathy, physician's assessment of disease activity on a visual analog scale (MDglob), erythrocyte sedimentation rate, and patient satisfaction with disease status (PatSat: 1 = excellent to 5 = unsatisfactory) were recorded. Factorial analysis was performed and alpha, as a measure of reliability, and tau were calculated. The ultimate five-item questionnaire, calculated by (Q1 + Q2 + Q3 + Q4 + Q5)/5, was then handed over to 152 PsA outpatients (mean age 54.02 years; age range 26-80 years; 82 male, 70 female), and analyzed accordingly. RESULTS: Analyzing the internal consistency of the prototype questionnaire revealed the highest alpha value of 0.849, on deleting the question targeting disease course. Alpha for the final Stockerau Activity Score for Psoriatic Arthritis (SASPA) was 0.875, with all items contributing to the final result (item loading from 0.573 to 0.910). Kendall's tau for the relationship between SASPA scores and swollen joint count, tender joint count, and MDglob was 0.34, 0.416, and 0.392, respectively. The sensitivity of the questionnaire to change was demonstrated in patients starting treatment with a tumor necrosis factor blocker (standardized mean difference: 2.1). CONCLUSION: The SASPA questionnaire constitutes a fully patient-administered tool to monitor PsA activity. Its reliability, convergent validity, and sensitivity to change were demonstrated.

Quality of care of rural rheumatoid arthritis patients in Austria.

OBJECTIVES: To determine how fast rheumatoid arthritis (RA) was diagnosed in a group of patients in a rural area and whether medical care and patient satisfaction were adequate in a predominantly non-urban settlement. METHODS: When visiting their rheumatologist, patients with RA were asked to complete a questionnaire at home after the consultation and then return it to an independent opinion research centre, where the data were collected and analysed. The form comprised various areas, namely demography, aspects of the diagnosis, medical care, therapeutic measures and the illness in a personal context. RESULTS: Of 150 patients, 127 answered the questionnaire. A total of 63 % of the patients lived in settlements of less than 5,000 inhabitants, and a further 18 % in settlements of more than 5,000-50,000 inhabitants. The rheumatologist attended could be reached within 1 h for 90 % of the patients. In slightly fewer than 30 % of the respondents, the diagnosis of RA was made within 3 months, and in 44%, within 6 months. In 75 %, the diagnosis was made by a rheumatologist. After experiencing the first symptoms, 80 % of the respondents contacted their general practitioner. A high degree of satisfaction appears to originate from the information supplied by the rheumatologist attended. Most patients believed they were involved in decision making regarding their therapy. CONCLUSION: The majority of the respondents came from rural areas. RA was diagnosed within 6 months for almost half of the patients questioned. Most patients believed they were well informed and involved in therapeutic decision making.

Remission in rheumatoid arthritis: a comparison of the 2 newly proposed ACR/EULAR remission criteria with the rheumatoid arthritis disease activity index-5, a patient self-report disease activity index.

OBJECTIVE: We analyzed whether a patient self-report remission criterion, such as that according to the Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), meets the criteria of the 2011 proposed American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) definition of remission. METHODS: The 2 approaches of the ACR/EULAR proposal [Boolean- and Simplified Disease Activity Index (SDAI)-based] as well as the RADAI-5 were used to assess whether patients with RA are in remission. Sensitivity, specificity, positive and negative predictive values (PPV, NPV), and kappa analyses were performed to illustrate the relationship among the different approaches defining remission at a group level. RESULTS: In total, 705 patients' assessments were included. Eighty-nine patients were classified as being in remission according to the Boolean-based and 169 according to the SDAI-based definition of the ACR/EULAR proposals, and 154 according to the RADAI-5. Sixty-eight assessments were classified as being in remission according to all 3 definitions. In the case of RADAI-5 remission, sensitivity was 78%, specificity 86%, PPV 45%, and NPV 96%, indicating remission according to the Boolean-based definition; and 60%, 92%, 66%, and 90%, respectively, indicating remission according to the SDAI-based definition. In the case of remission according to the SDAI-based ACR/EULAR definition, sensitivity was 52%, specificity 100%, PPV 98%, and NPV 87%, also indicating remission according to the Boolean definition; while according to the Boolean definition the values were 98%, 87%, 52%, and 100%, respectively. Kappa statistics showed fair to good agreement for all 3 definitions. CONCLUSION: Nearly twice as many assessments were classified as being in remission using the SDAI-based or the RADAI-5 definitions when compared to the Boolean-based definition. Remission according to the RADAI-5 also was highly specific for both ACR/EULAR criteria. Sensitivity for the RADAI-5 criterion was even better for the Boolean-based definition than that for the SDAI-based definition.

B lymphocyte-typing for prediction of clinical response to rituximab.

INTRODUCTION: The 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. METHODS: Fifty-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. RESULTS: At 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. CONCLUSIONS: The 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 use of tumour necrosis factor alpha-blockers in daily routine. An Austrian consensus project.

To define relevant disease parameters and their respective limits indicating the initiation of TNF-alpha-blockers in individual patients. Subsequently, to analyze retrospectively patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), who started TNF-alpha inhibition in 2006. Points to consider, regarded relevant for individual treatment decisions as well as their assessment methods, were ascertained by experts' consensus applying the Delphi technique. Subsequently, these parameters' thresholds with respect to the initiation of a TNF-alpha-blocker were identified. Thereafter, the rheumatologists representing 12 centres all over Austria agreed to retrospectively analyze their patients started on a TNF-alpha-blocker in 2006. Experts' opinion regarding disease parameters relevant to initiate TNF-alpha-blockers in RA patients only slightly differed from those applied in clinical trials, but the parameters' threshold values were considerably lower. For PsA patients, some differences and for AS patients, considerable differences between experts' opinion and clinical studies appeared, which held also true for decisive parameters' means and thresholds. Six hundred and fifty patients, started on TNF-blockers in 2006, could be analyzed retrospectively, 408 RA patients (53.3 years mean, 340 females), 93 PsA patients (48.9 years mean, 59 males) and 149 AS patients AS (42.2 years mean, 108 males), representing approximately 25% of all Austrian patients initiated on a TNF-blocker in this respective year. Far more individualized, patient-oriented treatment approaches, at least in part, are applied in daily routine compared with those derived from clinical trials or recommendations from investigative rheumatologists.

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.

Immunization of patients with rheumatoid arthritis with antitumor necrosis factor alpha therapy and methotrexate.

PURPOSE OF REVIEW: The aim of this study is to highlight the recent findings on the use of methotrexate and/or TNFalpha-blockers in adult patients with rheumatoid arthritis and their effects on the immune response to various vaccines. RECENT FINDINGS: Regarding influenza vaccination, methotrexate monotherapy is not associated with a decreased response, whereas the use of etanercept and infliximab in combination with methotrexate may cause lower titers and lower response rates. Concerning pneumococcal vaccination, methotrexate seems to impair responsiveness. The concomitant use of adalimumab and methotrexate is also associated with decreased response, whereas the concomitant use of etanercept or infliximab seems not to have an effect on response rates. As immunological pathways seem to play a major role, T-cell-dependent pneumococcal vaccines are designed to achieve higher response rates and protective titers. SUMMARY: Patients with rheumatic disorders are more likely to develop preventable infectious diseases, which underlines the importance of adequate immunoprotective titers. Several studies have shown that the combination of methotrexate and certain TNFalpha-blockers are affecting the responsiveness to vaccines. Further findings indicate that the response also depends on what type of vaccine is used.

Immunopathologic role of B lymphocytes in rheumatoid arthritis: rationale of B cell-directed therapy.

Although the immunopathogenesis of rheumatoid arthritis (RA) remains unclear, recent advances have paved the way for new therapies, such as anti-cytokine and cell-directed therapies. Here, B cells have re-gained interest concerning the pathogenesis of a number of autoimmune diseases after observing that patients with RA and non-Hodgkin lymphoma, who received anti-CD20 therapy leading to B cell depletion, demonstrated remarkable improvements. The underlying modes of action appear to be related to B cell functions, such as deletion of memory B cells, interruption of immune activation, antigen-presentation and production of inflammatory cytokines. In many RA patients, synovial extrafollicular germinal centers develop, where B cells play an intimate role in local inflammation and the generation of memory B cells and plasma cells. These local processes lead to activation of the immune system and ultimately to joint destruction in RA. Recent data demonstrating the clinical value of B cell depletion in refractory RA patients substantiate the notion that B cells are important players in the pathogenesis of the disease. Future studies should clarify which functions are affected by B cell depletion, providing the promise of new avenues to patient-tailored therapies.

The MHC2TA -168A>G gene polymorphism is not associated with rheumatoid arthritis in Austrian patients.

An association between susceptibility to rheumatoid arthritis (RA) and a common -168A>G polymorphism in the MHC2TA gene with differential major histocompatibility complex (MHC) II molecule expression was recently reported in a Swedish population. The objective of the present study was to replicate this finding by examining the -168A>G polymorphism in an Austrian case-control study. Three hundred and sixty-two unrelated RA cases and 351 sex-matched and age-matched controls as well as 1,709 Austrian healthy individuals were genotyped. All participants were from the same ethnic background. Genotyping was performed using 5' allelic discrimination assays. The association between susceptibility to RA and the -168A>G single nucleotide polymorphism was examined by chi-square test. Comparison was made assuming a dominant effect (AG + GG genotypes versus AA genotype). In contrast to the primary report, the frequency of MHC2TA -168G allele carriers was not significantly different between patients and controls in the Austrian cohort. The homozygous MHC2TA -168 GG genotype was more frequent in matched controls than in Austrian RA patients. There was no association between the presence of RA-specific autoantibodies and the MHC2TA -168 GG genotype. In this cohort of Austrian patients, no association between the MHC2TA polymorphism and RA was found.

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

Rheumatoid 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.

Receptor revision and atypical mutational characteristics in clonally expanded B cells from the cerebrospinal fluid of recently diagnosed multiple sclerosis patients.

PURPOSE: To determine whether cerebrospinal fluid (CSF) B cells exhibit clonal expansion in patients recently diagnosed with multiple sclerosis (MS). CSF B cell clonal expansion was detected early in the disease process. Evidence of receptor revision was present in at least one MS patient who had been recently diagnosed with MS. Targeting of mutations to RGYW/WRCY motifs within CDRs was nominally observed in the CSF B cell clones despite the high mutational frequencies (MF). These observations are consistent with the presence of intense specific B cell stimulation and expansion in the CNS of MS patients early in the disease process.