[Polymyalgia rheumatica: new developments and challenges]. / Polymyalgia rheumatica.

- Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disorder in which inflammation markers, both erythrocyte sedimentation rate (ESR) and CRP values, are often elevated. However, a non-abnormal ESR or CRP value does not preclude the diagnosis.- PMR is an arbitrary diagnosis and presents both diagnostic and therapeutic challenges.- Imaging diagnostics, such as echography, MRI or FDG-PET/CT, may potentially be applied more frequently as a second-line investigation when there is doubt concerning the diagnosis. Currently these additional imaging techniques are not applied in first line diagnostics.- Glucocorticoids remain the cornerstone treatment for polymyalgia rheumatica. Often patients react swiftly to this, but in 29-45% of cases an effect is only observed 3-4 weeks later. The treatment course typically lasts 1-3 years.- More research has been conducted into potential glucocorticoid-sparing treatments. Most of the scientific evidence concerns the effectiveness of methotrexate; there is some evidence regarding the effectiveness of azathioprine and leflunomide. Tocilizumab, an IL-6 receptor inhibitor, has shown promise as a treatment, but further evidence is required.

Prediction of successful dose reduction or discontinuation of adalimumab, etanercept, or infliximab in rheumatoid arthritis patients using serum drug levels and antidrug antibody measurement.

BACKGROUND: To evaluate if TNF inhibitor serum drug levels (DL) or anti-drug antibodies (ADAb) can predict successful dose reduction (in patients with high DL) or discontinuation (in patients with no/low DL or ADAb) in rheumatoid arthritis (RA) patients. RESEARCH DESIGN AND METHODS: RA patients that were using adalimumab (n = 42), etanercept (n = 76) or infliximab (n = 51) and were doing well, were tapered until discontinuation or flare (1-1.5 year follow up). Random timed DL for adalimumab and etanercept and trough DL for infliximab were measured before dose reduction: Receiver-Operator-Curves (ROC) analyses with optimal cut-off DL were determined. RESULTS: No predictive value of adalimumab and infliximab DL for all outcomes were found, except for an inverse association of lower etanercept DL and higher chance for successful dose reduction (Area Under the Curve (AUC) 0.36, 95% CI 0.23-0.49; cut-off <2.6 mg/l). In sub analyses, higher adalimumab trough DL predicted successful dose reduction (AUC 0.86, 0.58-1.00; cut-off >7.8). ADAb were infrequent and not predictive of successful discontinuation. CONCLUSIONS: No predictive value of baseline adalimumab, etanercept and infliximab DL or ADAb for successful dose reduction or discontinuation in RA was found in this context, with the possible exception of high adalimumab trough levels for successful dose reduction.

Dose reduction of tocilizumab in rheumatoid arthritis patients with low disease activity.

OBJECTIVES: Tocilizumab is effective in the treatment of rheumatoid arthritis (RA). A proportion of patients achieve low disease activity using a lower than registered starting dose. We investigated the feasibility of dose reduction to 4 mg/kg in patients who reached low disease activity at the registered dose of 8 mg/kg. METHODS: In this retrospective study, data were collected of 22 patients successfully treated with tocilizumab 8 mg/kg for about 6 months and tapered to 4 mg/kg because of low disease activity. In case of loss of disease control, the dose could be increased again to 8 mg/kg. The percentage of patients with successful dose reduction and difference in DAS28 was described. RESULTS: Mean DAS28 at time of dose reduction was 2.3 (SD 0.9). After 3 and 6 months follow-up, 77% (95% CI 54-91) and 55% (95% CI 32-76) of patients had successfully reduced the dose without losing disease control, respectively. DAS28 at 3 and 6 months was somewhat higher than baseline, 2.7 (SD 1.2) and 2.5 (SD 1.0) respectively. All patients who experienced worsening of disease activity after dose reduction regained low disease activity after dose escalation. CONCLUSIONS: Dose reduction of tocilizumab seems feasible in a substantial proportion of patients. Dose escalation after flare was effective in all patients.

Improving compliance to meal-replacement food regimens. Forming implementation intentions (conscious IF-THEN plans) increases compliance.

Creating and changing habits around dieting behaviour can be a way to help consumers to consume more healthy products and to control their weight. Previous studies suggested that implementation intentions - deliberate plans on when, where and how - increase the likelihood that consumers perform the intended behaviour (Armitage, 2004; Gollwitzer & Sheeran, 2006; Jackson et al., 2005). This study investigated the effect of forming implementation intentions on compliance to a regimen based on a range of meal-replacement food products and snacks. Participants (n = 57) were allocated to one of two groups, either: (1) an implementation-intention group, who formed deliberate plans (implementation intentions) to consume the products - these implementation intentions were formed only once at the beginning of the study -, or (2) a control group who formed no implementation intentions. Participants were then instructed to follow a daily regimen, which included the consumption of foods from a range of meal-replacement products and snacks provided gratis for four weeks. Results showed that the implementation-intention group consumed significantly more meal-replacement food products per week (p < 0.05) and decreased their BMI score more than did the control group (p < 0.05). The effect of forming the implementation intentions was apparent for 18 days. These findings indicate that forming implementation intentions may assist individuals in their compliance to a meal-replacement product regimen.

The use of different methods for rapid determination of the ESR induces DAS28 misclassification in clinical practice.

OBJECTIVES: Monitoring of disease activity using DAS28 is more effective than routine RA care, but the ESR measurement is time consuming. Alternative rapid ESR determination methods can be used but effects on DAS28 classification are unknown. METHODS: Alternative rapid ESR methods, including the Starrsed 30-minute mode and Alifax Roller Test-1TH, were compared to the Westergren method. Mean difference, limits of agreement (LoA) and intraclass correlation coefficients (ICC) were calculated. Based on these results, using a longitudinal design the percentage of DAS28 misclassification for the Alifax Roller Test-1TH was measured. RESULTS: The Alifax showed acceptable ICCs, but LoA were large. ICC was 0.67 (0.56-0.76), LoA -43;34. The longitudinal study on the Alifax (n=125) showed an ICC of 0.93, a kappa of 0.61, but disease activity was misclassified in 26% of the patients. Use of the ESR from the previous visit resulted in comparable levels of misclassification. CONCLUSIONS: ESR measured by automated analysers like Alifax show acceptable ICC but LoA are large compared to the Westergren ESR. The Alifax Roller Test-1TH is very rapid but DAS28 misclassification is considerable and even as large as when using the ESR of the previous visit.

Drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha antibody compared with methotrexate in long-standing rheumatoid arthritis.

OBJECTIVES: To compare the 48-week drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha (TNF-alpha) monoclonal antibody (moAb) and methotrexate (MTX) in patients with active long-standing rheumatoid arthritis (RA). Secondary aims were to identify potential predictors for clinical response. METHODS: Patients with RA, enrolled in phase I trials with a human anti-TNF-alpha moAb and followed for at least 48 weeks at our centre, were compared with patients receiving MTX monotherapy without folate supplementation. The first 6 weeks of anti-TNF therapy were placebo-controlled and followed by an open-label study. Patients treated with MTX participated in a 48-week, double-blind, phase III study of MTX alone vs MTX with folate supplementation, which was co-ordinated by our department. The studies with anti-TNF-alpha and MTX were performed in the same period and had very similar inclusion, exclusion, response and stop criteria. RESULTS: Sixty-one patients treated with anti-TNF-alpha moAb were compared with 137 receiving MTX monotherapy. At baseline, patients in the anti-TNF-alpha group had a longer disease duration (median 108 vs 50 months, P=0.0001) and a more protracted history of second-line anti-rheumatic drugs than those treated with MTX (median 4 vs 1, P=0.0001). The 48-week dropout rate was lower among patients treated with anti-TNF (23 vs 45% in the MTX group, P<0.005). Proportional hazard analysis showed a significantly lower dropout risk among anti-TNF-treated patients [relative risk (95% confidence interval): 0.28 (0.12-0.6) uncorrected and 0.17 (0.06-0.45) corrected for confounders). The 48-week area under the curve for the disease activity score (DAS) was smaller in the anti-TNF-alpha group than in the MTX group (P=0.005). The percentage of responders was higher in the anti-TNF-alpha group over the whole study period. The median percentage of visits in which a patient fulfilled the European League Against Rheumatism (EULAR) response criteria was 83% in the anti-TNF-alpha group vs 40% in the MTX group (P=0.0001). Clinical and demographic characteristics were, in general, poor predictors for response to therapy at week 48. The clinical response after the first anti-TNF-alpha dose tended to increase the chance of prolonged efficacy of this approach [relative risk (95% confidence interval): 2 (0.75-6.0)]. The previous number of second-line drugs was the only predictive variable for response to MTX to which it was inversely related [relative risk (95% confidence interval): -0.71 (-0.57 to -0.88)]. CONCLUSIONS: In patients with active, long-standing RA, blocking TNF-alpha is more effective and better tolerated than MTX monotherapy. An early response increases the chance of a sustained effect of anti-TNF-alpha. In contrast to MTX, the response to anti-TNF-alpha is not affected by previous disease-modifying anti-rheumatic drug history.

Pain clinic EPR: requirements determination & configuration.

UNLABELLED: The focus of this study was to determine requirements for a general pain EPR (electronic patient record), design this EPR and develop a prototype for demo purposes in pain clinics in The Netherlands. The specifications for this EPR were derived from the 'Nijmegen Classification of Pain', analysis of patient paper records and in-depth interviews with six anaesthesiologists, three physiotherapists and two psychologists. For development a generic configuration tool was used. The actual EPR consisted of five components (two for the anaesthesiologists, one for the physiotherapist, one for the psychologist and one for the whole team). The five components comprised of numerous dialogues. The medical care process directed these dialogues. CONCLUSIONS: The different organisational settings and the variability in provided patient care compromised the development of an EPR for all pain clinics. Defining the granularity of the dialogues was influenced mainly by the factors mentioned previously. However, most respondents agreed on the importance of the following functional demands: registration speed, security, flexibility and supporting of communication between the care providers.

A formal framework of knowledge to support rational psychoactive drug selection.

Rational psychoactive drug selection is a data and knowledge intensive task which requires true expertise from clinical, pathophysiological and pharmacotherapeutic knowledge. This paper presents a framework of knowledge, which relates concepts from several disciplines required for psychoactive drug selection in a formal way. A framework, when based on formal semantics, avoids ambiguity and gives conceptual clarity and supports precise use of terminology which is required when many domain experts (clinicians, pharmacologists and basic science researchers) are involved. A formal framework permits linking of existing classification systems. It furthermore can serve as a knowledge base for drug selection decision support systems.

Towards a more rational use of psychoactive substances in clinical practice.

Complex knowledge and data intensive nature of the psychoactive drug selection and prescription process often makes for irrational and inconsistent use of psychoactive drugs in clinical practice. After describing the state of the art with respect to psychoactive drug prescription practices and selection processes, our aim is to analyze the advantages of computer support systems in assisting the clinician in his clinical decisions. Finally, we will review the neuropsychiatric expert systems developed for the neuropsychiatric domain. Suboptimal psychoactive drug therapy is common practice, which leads to hospital admissions, extended length of hospital stay, ineffective therapy and increased costs. Furthermore, the psychoactive drug selection process is a complex decision process, using up-to-date integrative knowledge of drugs from basic sciences to the clinical level. Due to the information load, the lack of appropriate up-to-date information at the point of clinical care and the problem of integrating and weighing all information relatively equally, it is questionable whether any clinician can manage such a complex situation with optimal effectiveness. As has been shown in a number of experiments, clinicians can benefit from computer-based systems that provide access to accurate, up-to-date information. We maintain that more rational use of psychoactive drugs in clinical practice is needed, and conclude that rational psychoactive drug prescription is a knowledge and data-intensive task requiring true expertise derived from clinical, pathophysiological and pharmacotherapeutic knowledge. We will be developing a Multidisciplinary Psychoactive Drug Selection advisor system, M-PADS, to support the integration of various types of biomedical information and deliver that integrated information supportive to evidence-based rational drug prescription in the practice of medicine for the drug treatment of individual patients.

Progress with formalization in medical informatics?

The prevailing view of medical informatics as a primarily subservient discipline in health care is challenged. Developments in both general informatics and medical informatics are described to identify desirable properties of modeling languages and tools needed to solve key problems in the application field. For progress in medical informatics, it is considered essential to develop far more formal modeling languages, modeling techniques, and tools. A major aim of this development should be to expel ambiguity from concepts essential to medicine, positioning medical informatics "at the heart of health care."

Requirements for medical modeling languages.

OBJECTIVE: The development of tailor-made domain-specific modeling languages is sometimes desirable in medical informatics. Naturally, the development of such languages should be guided. The purpose of this article is to introduce a set of requirements for such languages and show their application in analyzing and comparing existing modeling languages. DESIGN: The requirements arise from the practical experience of the authors and others in the development of modeling languages in both general informatics and medical informatics. The requirements initially emerged from the analysis of information modeling techniques. The requirements are designed to be orthogonal, i.e., one requirement can be violated without violation of the others. RESULTS: The proposed requirements for any modeling language are that it be "formal" with regard to syntax and semantics, "conceptual," "expressive," "comprehensible," "suitable," and "executable." The requirements are illustrated using both the medical logic modules of the Arden Syntax as a running example and selected examples from other modeling languages. CONCLUSION: Activity diagrams of the Unified Modeling Language, task structures for work flows, and Petri nets are discussed with regard to the list of requirements, and various tradeoffs are thus made explicit. It is concluded that this set of requirements has the potential to play a vital role in both the evaluation of existing domain-specific languages and the development of new ones.

Computerized charting of case reports.

Follow-up schemas are used in the planning of care delivery for patients who had a larynx tumour resection. Because of the diversity of this population, the idea has arisen that control schemas should be tuned to individual patient histories in order to optimize care delivery. To arrive at refined guidelines, detailed analysis of 300 case reports is planned. In this context a patient case report tool PCRT has been developed to support the analysis of computerized case reports. PCRT is based on an existing patient case report language and can generate case report charts using a newly developed charting method implemented with internet-based technology. This paper presents the charting method and explains the charting algorithm.

Formal description of disease courses.

Patient case analysis is an elementary and crucial process clinicians are confronted with daily. The importance and complexity is reflected in the need to discuss individual patient cases in clinicopathological conferences and the documentation of more than 70,000 patient cases in MEDLINE. This paper introduces DCGL, a technique to model disease course descriptions as present in medical literature. DCGL enables advanced computerised matching of generic disease course descriptions with individual patient case descriptions, a basic function in computerised patient case analysis.

Formal description of temporal knowledge in case reports.

Patient case analysis is an elementary and crucial process which clinicians are daily confronted with. The importance and complexity is reflected in the need to discuss cases in clinicopathological conferences and the documentation of more than 70,000 patient cases in MEDLINE. This paper introduces a generic patient case report language (PCRL) based on general medical temporal concepts to formalise temporal knowledge as present in case descriptions. The lack of such a generic technique is reflected by the fact that computers are very restrictive in accepting patient specific temporal information. Acceptance is almost always controlled and guided by specific predefined disease or treatment models. We strive for a case library consisting of unambiguous patient case descriptions formulated independent from future use.

An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia.

Essential thrombocythaemia (ET) is a chronic myeloproliferative syndrome due to sustained proliferation of megakaryocytes, which results in elevated numbers of circulating platelets, thrombotic or haemorrhagic episodes and occasional leukaemic transformation. The cause of ET is unknown. Hereditary thrombocythaemia (HT) with autosomal-dominant transmission has been described with manifestations similar to those of sporadic ET. As the thrombopoietin gene (THPO) encodes a lineage-restricted growth factor with profound stimulatory effects on megakaryopoiesis and platelet production, we tested the hypothesis that HT results from a mutation in the human THPO gene. In a Dutch family with eleven affected individuals, the thrombopoietin protein (TPO) concentrations in serum were consistently elevated in individuals with HT. We derived an intragenic CA marker for the human THPO gene and performed linkage analysis in fourteen informative meioses in this family. This resulted in a lod score of 3.5 at theta=0. A G-->C transversion was found in the splice donor site of intron 3 of the THPO gene in all affected family members. This mutation leads to THPO mRNAs with shortened 5'-untranslated regions (UTR) that are more efficiently translated than the normal THPO transcripts. We conclude that a splice donor mutation in THPO leads to systemic overproduction of TPO and causes thrombocythaemia.

H reflexes as a measure for uremic polyneuropathy. A longitudinal study in patients treated with dialysis or renal transplantation.

Assessment of peripheral nerve function in end stage uremia by clinical and conventional nerve conduction velocity studies was compared to that using H reflex measurements. The latter proved to be the most sensitive technique. The results of the test correlated well with clinical and with other neuro-physiological measures. Nerve function as evaluated by H reflexes remained stable during the first 2 years of dialysis, but deteriorated later on. H reflex latencies shortened after renal transplantation. The results of H reflex measurements did not correlate with biochemical parameters, which makes the test a less attractive overall measure for the efficiency of therapy in uremia. In the follow-up of patients under treatment for uremic polyneuropathy, however, recording of H reflexes provides an important measure.

Familial essential thrombocythemia: clinical characteristics of 11 cases in one family.

Reports on familial occurrence of essential thrombocythemia (ET) are scanty. Many clinical and hematological aspects of familial ET have not been clarified yet. We studied 16 family members in four successive generations. By laboratory tests and bone marrow examination they were divided into a non-thrombocythemia group (n = 5) and into ET patients (n = 11). Five ET patients were asymptomatic, three patients had both vaso-occlusive and hemorrhagic symptoms, and three patients only vaso-occlusive symptoms. The platelet count ranged from 500 to 1700 x 10(9)/l. Symptoms correlated with age but not with platelet count. ADP-induced platelet aggregation distinguished best between patients and non-ET subjects. Four patients and four non-ET subjects had factor VIII:C or von Willebrand factor antigen abnormalities; all but one had blood group O. These abnormalities were not due to inherited von Willebrand's disease according to haplotype analysis. Two patients and three non-ET subjects had a bleeding diathesis. One of these two patients and all three non-ET subjects had a decreased factor VIII:C or vWF:Ag. No chromosome abnormalities were found. In conclusion, familial ET has a relatively benign course with clinical manifestations similar to nonfamilial cases, and it is probably transmitted by an autosomal dominant mode of inheritance.

Encephalopathy in patients on continuous ambulatory peritoneal dialysis and patients on chronic haemodialysis.

A group of 121 patients, 22 with a preterminal chronic renal insufficiency (PCRI), 74 on chronic haemodialysis (CHD), and 25 on continuous ambulatory peritoneal dialysis (CAPD), was evaluated by means of neurophysiological and neuropsychological studies to detect signs of central nervous system dysfunction. CHD patients were studied the day before dialysis treatment. In each patient the neurophysiological and neuropsychological studies were performed on the same day. The same overall result emerged from the neurophysiological and neuropsychological studies: all three patient groups showed significant deviations from the values obtained from a healthy reference group, whereas no differences were found between the three patient groups. Biochemical variables (a.o. PTH, Al, PO4) showed inconsistent or only minor correlations with the encephalopathic parameters. Apparently traditional biochemical variables are not a reliable measure to safeguard renal patients from neurotoxic damage. With respect to central nervous system dysfunction CAPD appears to be as 'safe' as CHD.

The amount of plasminogen, tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in human thrombi and the relation to ex-vivo lysibility.

Thrombolytic therapy successfully reopens obstructed blood vessels in the majority of cases. However, it is not known why a substantial amount of thrombi are resistant to lysis by a fibrinolytic agent. In vitro studies have demonstrated that tissue-type plasminogen activator (t-PA) and plasminogen incorporated in the clot (during formation) increase lysibility. To test whether lysibility of in vivo formed human thrombi is related to their composition, we studied 25 venous thrombi obtained at autopsy and 21 arterial thrombi obtained during embolectomy. Plasminogen activator inhibitor-1 (PAI-1) antigen was measured in a phosphate-buffered saline (PBS) extract of each thrombus; t-PA antigen and plasminogen antigen were determined in a 6 M urea extract of the thrombus, representing bound proteins. Lysibility was measured as weight reduction during 8 h of incubation in PBS containing streptokinase (SK) 100 U/ml, corrected for spontaneous lysis, reflected by weight loss in PBS without SK. In addition, lysibility in SK was compared with lysibility in urokinase (UK) 100 U/ml and in t-PA 200 U/ml. Spontaneous lysis amounted to 29 +/- 5% (mean +/- SEM) and 33 +/- 5% in venous and arterial thrombi, respectively, and inversely correlated with the PAI-1 content of thrombi (r = -0.43, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)