Publication of the Month Revised APS criteria in AI patients. Prediction of Rheumatoid Arthritis. Diagnostic Algorithm for Coeliac Disease

Transcription

1 Publication of the Month 2007 Issue 12/2007 Issue 11/2007 Issue 10/2007 Issue 09/2007 Issue 08/2007 Issue 07/2007 Issue 06/2007 Issue 05/2007 Issue 04/2007 Issue 03/2007 Issue 02/2007 Issue 01/2007 Revised APS criteria in AI patients Detection of DNA antibodies ELISA vs. CLIFT Detection of Celiac Disease Comparison of Anti-CP Assays New Predictors of Disease Prediction of Rheumatoid Arthritis ANA detection with ELISA? Diagnostic Algorithm for Coeliac Disease Cigarette Smoking, SLE, and RA EULAR recommendations for early arthritis Recent advances in coeliac diseases Detection of DNA antibodies

2 December 12/07: Revised APS criteria in AI patients The antiphospholipid syndrome (APS), first described by Hughes in 1985, is a disease branching into all aspects of medicine, and linking thrombosis and autoimmunity. Since 1984 the International Congress on Antiphospholipid Antibodies has taken place every second year. Classification criteria for the antiphospholipid syndrome (APS) were formulated during the Eighth International Symposium on Antiphospholipid Antibodies in 1998 in Sapporo, Japan, and were updated in a workshop, preceding the eleventh congress in Sydney in The updated criteria were published in 2006 by Miyakis et al (see Publication of the Month March 2006). The major differences to the Sapporo-criteria are the adding of anti-ß2gpi antibodies of both the IgG and IgM isotype to the laboratory criteria and the introduction of a clear statement on threshold for positive (>40 GPL or MPL units, or >99th percentile). The interval between two serological measurements was increased from at least 6 weeks (Sapporo) to 12 weeks (Sydney). In the following study the authors evaluated the new APS criteria with 336 samples from autoimmune patients: Swadzba J, Iwaniec T, Szczeklik A, Musial J Revised classification criteria for antiphospholipid syndrome and the thrombotic risk in patients with autoimmune diseases J Thromb Haemost 2007, 5: patients with autoimmune diseases were included in the study: 235 with systemic lupus erythematosus (SLE, according to ACR criteria), 44 with SLE-like disease (where three ACR criteria are met), 32 patients with primary APS, 12 with MCTD, 6 with systemic sclerosis, 5 with poly-/dermatomyositis, 1 with ulcerative colitis and 1 with autoimmune thrombocytopenia. Clinical signs of APS were identified retrospectively in 180 patients (53.6%). Lupus anticoagulants (LA) were found in 95, anti-cardiolipin antibodies (acl) in 120, and anti-ß2gpi in 101 patients (using >99 th percentile). At least one antibody was found in 165 patients. Simultaneous occurrence of both clinical and laboratory criteria for APS was present in 112 patients, including 32 with primary APS, 67 SLE patients, 11 with SLE-like syndrome and 2 with systemic sclerosis. All antibodies examined were associated with a statistically significant risk of thrombosis. The highest risk was associated with the presence of anti-ß2gpi IgG, acl IgG and LA (particularly strong LA). The authors conclude that the updated APS classification criteria represent a step forward. However, many problems still remain and further modifications seem necessary. Currently, the main problem is the need for better identification methods of anti-phospholipid antibodies (apl) with major clinical significance. This month the fully automated acl test EliA Cardiolipin will be launched maybe one little step in the required improvement of APS diagnostics.

3 November 11/07: Detection of DNA antibodies ELISA vs CLIFT Antibodies to double-stranded DNA (dsdna) are one of the 11 diagnostic criteria for the classification of SLE, which were established by the American Rheumatism Association (ARA) in In addition, dsdna antibodies reflect disease activity, serve as a predictor of disease exacerbation and are suitable to monitor the response to therapy. Sensitivity and specificity of dsdna antibodies in SLE are highly dependent on the method used. The most frequently used methods in routine clinical laboratories are Farr assay (RIA), CLIFT (Crithidia luciliae immunofluorescence test), and ELISA. The Farr was the first quantitative anti-dsdna assay used and remains the standard reference method. However, it is time-consuming, technically more difficult, and involves the use of radioactive dsdna. CLIFT is highly specific though its sensitivity is recognised as being low. It also becomes cumbersome when large numbers of samples are involved, and is not quantitative unless the titre is determined by assaying serial sample dilutions. On the other hand, ELISA systems for anti-dsdna are straightforward, rapid, quantitative, and reproducible but require highly purified antigens. Moreover, commercial anti-dsdna ELISA kits are inconsistent in terms of performance which may relate to the antigens selected. To overcome these issues, many laboratories use a combination of methods for dsdna antibody measurement e.g. screen with ELISA and confirm with CLIFT. The problem then becomes what to do when there are discrepancies in the different method results. In the following study the authors evaluate the clinical significance of ELISA positive but CLIFT negative results: Kim KH, Han JY, Kim JM, Lee SW, Chung WT Clinical significance of ELISA positive and immunofluorescence negative anti-dsdna antibody Clin Chim Acta 2007, 380: patients were tested with ELISA (Scimedx, USA) and CLIFT (MBL, Japan) according to the manufacturers instructions. 93 blood donors were found negative by both assays. Of 131 ELISA positive samples, 60 were negative with the CLIFT. Of the 60 discrepant samples, 44 were available in sufficient amounts for further analysis. These samples, as well as the 93 blood donors found negative in both the ELISA and the CLIFT, were further tested using Farr and another 3 commercial dsdna ELISA tests. Full clinical review was performed on these patients to determine the clinical relevance of the results. 35 (79.5%) of the 44 discrepant samples had 3 or more SLE criteria, excluding the anti-dsdna criterion. The performance of the kits and methods was as follows: Kit Antigen Sens Spec Efficiency QuantaLite Calf thymus Euroimmun Salmon testis MesaCUP Bacteriophage Scimedx Plasmid CLIFT (0.00) FARR Recombinant Table: Diagnostic efficiency of different anti-dsdna tests with respect to the number of SLE criteria present for the 44 anti-dsdna ELISA positive and CLIFT negative patients and for 93 healthy blood donors. Although the study is limited by the fact that not all samples were tested by all methods, it still gives a likely indication as to the usefulness of the different methods in a clinical setting. The results of the study showed that some anti-dsdna ELISA kits have diagnostic efficiencies that are similar to that of the Farr assay. The study identifies a group of patients that are ELISA positive but CLIFT negative for anti-dsdna, and indicates that the majority of these patients have clinically relevant SLE.

4 October 10/07: Detection of Celiac Disease Celiac disease (CD) is one of the most common lifelong disorders with possible significant morbidity consequences in untreated patients. However, most cases remain undiagnosed due to poor awareness by primary care physicians. General population screening is not yet considered justifiable ethically or financially but in the following study, a North American clinical research group created an active casefinding strategy in order to increase the frequency of CD diagnosis and to determine the most common clinical presentations of the condition. Catassi C, Kryszak D, Louis-Jacques O, Duerksen DR, Hill I, Crowe SE, Brown AR, Procaccini NJ, Wonderly BA, Hartley P, Moreci J, Bennett N, Horvath K, Burk M, Fasano A Detection of Celiac Disease in Primary Care: A Multicenter Case-Finding Study in North America Am J Gastroenterol 2007; 102: In this multicenter, prospective study, any individual over the age of 18 yrs seeking care from their physician was informed of the study by the practice reception staff. Those willing to participate completed a questionnaire. 976 individuals were considered at risk for CD and therefore eligible for the study because they indicated the presence of one or more of the 11 CD-suggestive conditions listed in the questionnaire such as family history of CD, chronic fatigue, infertility, bloating and others. All participants were tested for IgA anti-ttg antibodies and those with elevated anti-ttg were subsequently tested for serum IgA antiendomysial antibodies. All subjects who were positive for EMA were advised to undergo an intestinal biopsy and HLA typing for definitive diagnosis of CD. In individuals (103 patients) with very low values of IgA anti-ttg (<0.5 arbitrary units) total serum IgA level was determined, but was found to be normal in all 103 cases. In 976 patients ttg-iga was performed. 30 had elevated titres (3.07%), 8 of those were EMA negative, all 22 EMA positive were diagnosed with CD. The most frequent conditions relevant to CD screening in these 22 cases were bloating (n=12), thyroid disease (11), irritable bowel syndrome (7), unexplained chronic diarrhoea (6), chronic fatigue (5), and constipation (4). The prevalence of CD was 2.25%. During the 12 months preceding this study, only 15 patients had been diagnosed with CD out of 54,988 individuals seen by the participating practices. During the study period, the diagnostic rate significantly increased from 0.27 to 8.6 cases per 1,000 visits. These data indicate that CD is still largely under-diagnosed in North America at the primary care level. By applying simple and well-established criteria for CD case finding, a 32-fold increase in the diagnostic rate was able to be achieved. Many newly diagnosed cases of CD reported a long-standing history of symptoms (usually for years) that should have raised the suspicion of CD well before. The authors recommend that all individuals with one or more of the large variety of clinical manifestations and conditions associated with CD should have serological testing and, if positive, should be referred for definitive diagnosis by means of an intestinal biopsy.

5 September 09/07: Comparison of Anti-CP Assays Antibodies to citrullinated proteins / peptides (anti-cp) are among the most important discoveries of recent years in the field of immunologic diagnostics. Anti-CP are markers for rheumatoid arthritis, especially for early diagnosis of the disease. Their presence at disease onset has a high positive predictive value for the development of erosive joint lesions. With its high clinical specificity, the test is particularly useful in differential diagnosis between RA and other arthritides. Numerous assays against citrullinated peptides or proteins are now on the market, but only a few comparative studies have been conducted on them. In the following study, the diagnostic accuracy of the 11 most commonly used commercial EIA methods for the detection of anti-cp was evaluated: Bizzaro N, Tonutti E, Tozzoli R, Villalta D Analytical and Diagnostic Characteristics of 11 2 nd - and 3 rd -Generation Immunoenzymatic Methods for the Detection of Antibodies to Citrullinated Proteins Clin Chem 53, The sera used in this study were from 100 consecutive patients with rheumatoid arthritis, 74 healthy individuals, and 128 patients with other diseases. The 11 assays were Aeskulisa RA CP-Detect (Aesku Diagnostika), VCP IgG (Astra srl), Diastat anti-ccp (Axis-Shield), Immunoscan RA Mark2 (Eurodiagnostica), CCP IgG (Euroimmun), CPA (Genesis Diagnostics), Quanta Lite CCP IgG, Quanta Lite CCP 3.0 IgG, and Quanta Lite CCP 3.1 IgG-IgA (Inova Diagnostics), Anti-MCV (Orgentec Diagnostika) and EliA CCP (Phadia). The authors evaluated within-run and between-run CVs, sensitivity and specificity when using the cutoff recommended by the manufacturer, as well as the sensitivity at a defined specificity. Because the most clinically significant characteristic of the test is its very high specificity, the authors took a specificity value of 98.5% as reference, and compared the sensitivity value of each method with that preset specificity value. The data thus compared demonstrated that the best performances were obtained with the 4 methods that use the original mixture of synthetic peptides: the assays from Eurodiagnostica, Axis-Shield, Phadia and Euroimmun. At a predefined specificity of 98.5%, these four assays still achieved sensitivities of 70% (Axis-Shield) up to 74% (Phadia). Of the 3 methods produced by Inova, the CCP-3 formulation gave only slightly different results from the method that uses the CCP-2 antigen (67% vs 64% sensitivity). In view of the results of this study, the combination of IgA with IgG antibodies (CCP-3.1 vs. CCP-3.0) does not improve the performance of the test and therefore does not seem to be useful. The authors conclude that not all commercially available methods for the detection of anti-cp antibodies have the same degree of diagnostic accuracy, and that careful selection is needed to obtain reliable results.

6 August 08/07: New Predictors of Disease Working in the field of autoimmunity it quite often occurs that you are asked to explain autoimmunity, autoantibodies or the diagnostic use of autoantibodies and it becomes rapidly apparent that it is not easy to explain these complex issues. Scientific American is a popular-science magazine, which brings articles about new and innovative research to the amateur and lay audience. It is a well-respected publication despite not being a peer-reviewed scientific journal. In the March issue of 2007, Abner Louis Notkins from the National Institutes of Health (NIH) wrote an easy to understand, but not simplistic, article about autoantibodies as predictors of disease: Notkins AL New Predictors of Disease Scientific American March 2007, The idea that autoantibodies might serve as early warning signs of later disease came from research into how type 1 diabetes arises. The discovery that autoantibodies frequently herald the onset of type 1 diabetes prompted scientists to examine whether the same might be true in other autoimmune diseases. One that has been the focus of especially intense research is rheumatoid arthritis. Antibodies against citrulline often appear in the bloodstream before the first symptoms turn up, in some cases more than 10 years earlier. The knowledge that the anticitrulline autoantibody might serve as a predictive marker is particularly exciting because, in contrast to the situation in type 1 diabetes, doctors already have medicines that might be delivered to prevent or slow the onset of arthritis. For certain other autoimmune disorders, the detection of predictive autoantibodies could potentially enable people to shut down autoimmune activity by avoiding certain triggers in their environment. A case in point is celiac disease. Autoantibodies against tissue transglutaminase emerge up to seven years before symptoms do, suggesting that high-risk individuals might forestall the disease entirely by eliminating gluten from their diet. This idea has not yet been tested, however. Forecasts of the future have always intrigued and frightened people. Handled properly, though, such knowledge could benefit the millions of patients and doctors destined to battle autoimmune diseases.

7 July 07/07: Prediction of Rheumatoid Arthritis Making individualized decisions regarding treatment is one of the most important challenges in medicine. In rheumatology practices, the majority of patients who present with recent-onset arthritis have undifferentiated arthritis, which is a form of arthritis that does not fulfil the classification criteria for a more definitive diagnosis. About 40 to 50 % of patients with undifferentiated arthritis experience spontaneous remission, whereas one third of patients will go on to be classified as having rheumatoid arthritis (RA). New treatment protocols have put greater importance on the need for early diagnosis and therapy of RA patients but their costs and side-effects means that they must be restricted to those where RA diagnosis and probable progression can be confirmed. In the following publication a group from Leiden University, The Netherlands, introduce a prediction model for patients with undifferentiated arthritis: Van der Helm-van Mil AHM, le Cessi S, van Dongen H, Breedveld FC, Toes REM, Huizinga TWJ A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis Arthritis Rheum 2007; 56: In this study 570 patients with undifferentiated arthritis were tested. 177 of them developed RA. A prediction score was calculated for every patient with undifferentiated arthritis based on 9 variables that are commonly assessed during the first visit: age, sex, distribution of involved joints, morning stiffness, number of tender or swollen joints, CRP level, and the presence of RF and anti-ccp antibodies. The range of possible scores is 0 14, with higher scores indicating a greater risk of developing RA. None of the patients who had a prediction score below 3 progressed to RA during the 1-year follow-up period, and all of the patients who had a score above 11 did experience progression to RA. Among the patients with a score between 3 and 11, the frequency of a progression to RA increased with rising scores. Thus, with this easy-to-use tool, the risk of developing RA can be predicted, thereby allowing individualized decisions regarding the initiation of treatment with disease-modifying antirheumatic drugs. Previously, in 2002, a related group from Leiden University introduced a clinical model for the prediction of 3 forms of arthritis outcome: self-limiting, persistent nonerosive, and persistent erosive arthritis. (Visser H et al: How to Diagnose Rheumatoid Arthritis Early. Arthritis Rheum 2002; 6: ). This prediction model consists of 7 variables: symptom duration at first visit, morning stiffness for more than one hour, arthritis in more than 3 joints, bilateral compression pain in the MTP joints, RF positivity and anti-ccp positivity and the presence of erosions. In both models shared epitope testing is not considered. Recently, a Belgian group investigated the predictive value of the human leucocyte antigen-shared epitope: Vander Cruyssen B, Hoffman IEA, Peene I, Union A, Mielants H, Meheus L, De Keyser F Prediction models for rheumatoid arthritis during diagnostic investigation: evaluation of combinations of rheumatoid factor, anti-citrullinated protein / peptide antibodies and the human leucocyte antigen-shared epitope Ann Rheum Dis 2007; 66: The authors conclude that the potential additional value of shared epitope testing disappears when anti-citrullinated protein/peptide antibody (ACPA) testing is available. Combined RF and ACPA testing is useful, especially when RF is considered as a continuous parameter reflecting an increasing probability for RA at higher RF titres. This study discusses a LIA ACPA assay which has a comparatively low sensitivity for RA (see Ref.4). It would be interesting to see how the model performs using an established, semi-quantitative high sensitivity, high specificity anti-ccp assay.

8 June 06/07: ANA detection with ELISA? The frequency of antinuclear antibodies (ANA) is especially high in a number of systemic rheumatic diseases. As well, these autoantibodies can be found in many other diseases, autoimmune or not. ANA detection is part of the diagnostic criteria of rheumatic diseases such as SLE. ANA screening assays are often performed by indirect immunofluorescence (IIF), either on rodent tissue or HEp-2 or Hep-2000 cells. The frequency of ANA testing has increased rapidly in clinical routine and, subsequently, the number of positive tests has also increased. This means that autoimmunity laboratories now perform many follow-up assays which are more expensive and, in the majority of cases, give a negative result. To avoid such expensive and time-consuming procedures, it would be efficient to have a screening method that could detect those sera which are positive by IIF for autoantibodies relevant for the diagnosis of rheumatic diseases. The following study evaluated a commercially available ELISA assay for anti-nuclear antibodies (ANA) screening in a large routine laboratory setting: Sinclair D, Saas M et al Can an ELISA replace immunofluorescence for the detection of anti-nuclear antibodies? The routine use of ANA screening ELISAs Clinical Laboratory 2007, 53 (3-4): In this study, in a routine serology laboratory setting, 2000 consecutive sera with requests for an ANA screen were tested by ELISA and results compared to those obtained by immunofluorescence. From these results an ANA ratio cut-off protocol was established to guide further action. A second series of 7000 samples was studied to assess the efficacy of this. The antigens included in the ELISA used are Ro (52 and 60), La, Sm, RNP, Scl-70, Jo-1, PM- Scl, histones, centromere nucleosomes and double stranded DNA. Among 2000 routine samples 162 showed a positive result with the ELISA. This agreed reasonably well with the IIF screening experience which yielded 216 positives. 54 patients had an ANA that was visible by immunofluorescence but who had no ANA by ELISA. Further study of these 54 patients showed them to have the following ANA patterns: nuclear matrix, tubulin, peroxisomes, nuclear mitotic apparatus, vimentin and lysosomal patterns. Although well described, the antibodies giving rise to these patterns are not known to have significant clinical correlations. None of these patients showed clinical signs or symptoms that led to a referral for consultant rheumatologist opinion in the intervening time. According to the authors experience, the change from IIF to ELISA has not compromised the clinical outcome for their patients. Results show that the ANA ELISA can successfully replace IIF for the detection of clinically significant antibodies.

9 May 05/07: Diagnostic Algorithm for Coeliac Disease It is estimated that the ratio of known to undiagnosed cases of coeliac disease is 1:7. This suggests a failure in case finding for this disease. The median delay in diagnosis ranges from 5 to 11 years. Serological markers are a cheap and non-invasive method for clinicians to identify celiac patients. However, the internationally accepted gold standard diagnostic test is the demonstration of villous atrophy on a duodenal biopsy. Because of the limitations of endoscopy, antibody negative coeliac disease, and delays in diagnosis, many centres around the world suggest or recommend routine duodenal biopsy. The reported prevalence of coeliac disease when taking a routine duodenal biopsy ranges from 1.0% to 5.2%. The authors of the following article devised and evaluated a clinical decision that used a combination of pre-endoscopy serological testing (for tissue transglutaminase antibodies, anti-ttg) and assessment of symptoms to identify patients with coeliac disease: Hopper AD, Cross SS, Hurlstone DP et al (2007) Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool Br Med J, online first, doi: /bmj BE (published 23 March 2007) 2000 patients were recruited, of whom 739 were categorised into the high risk group and 1261 into the low risk group according to their referral indications. In total, 77 patients were newly diagnosed with coeliac disease. The prevalence of coeliac disease in all patients attending for gastroscopy was 3.9% and in the high risk group it was 9.6%. The prevalence of tissue transglutaminase antibody negative coeliac disease was 0.4% (7 of 2000 patients). All cases of antibody negative coeliac disease occurred in the high risk group. Only one of these seven patients had selective IgA deficiency. Antibody negative coeliac disease accounted for 9.1% (7/77) of cases within this cohort. Anti-tTG alone Combining biopsy of the high risk group and pos anti-ttg Sensitivity 90.9% 100% Specificity 90.9% 60.8% Positive predictive value 28.6% 9.3% Negative predictive value 99.6% 100% Thus, the strategy of pre-endoscopy serological testing for coeliac disease combined with biopsy of high risk cases had a sensitivity of 100% in this cohort of patients and no cases of coeliac disease were missed. By using this decision tool instead of routine duodenal biopsy, 58.5% of patients would have avoided a duodenal biopsy yet the same number of cases of coeliac disease would have been detected. These data support the need for duodenal biopsy in high risk patients even if they are antibody negative. Unfortunately, the authors do not state which anti-ttg test was used. The sensitivity and particularly the specificity of this assay are surprisingly low and result in a very low PPV. All studies with Celikey showed a much higher specificity for coeliac disease (e.g. Bürgin Wolff et al, Scand J Gastroenterol 2002, 37: : sensitivity 96% and specificity 99%). However, even though a relatively low performing assay was used, the algorithm proposed by the authors still avoids many unnecessary biopsies. Using a more specific assay would reduce the number even further.

10 April 04/07: Cigarette Smoking, SLE, and RA While the rights of non-smokers is a hot topic for lawmakers right now, especially in Europe, the influence of smoking on the development of autoimmune diseases is a growing topic in the group of immunologists and rheumatologists. Exposure to tobacco has consistently been associated with rheumatoid arthritis (RA) and other autoimmune diseases. The following studies were also published in 2006: Freemer MM, King Jr TE, Criswell LA (2006) Association of smoking with dsdna autoantibody production in systemic lupus erythematosus Ann Rheum Dis 65, Majka DS, Holers VM (2006) Cigarette smoking and the risk of systemic lupus erythematosus and rheumatoid arthritis Ann Rheum Dis 65, Freemer et al. showed in their study that smoking is associated with dsdna seropositivity in white patients with systemic lupus erythematosus (SLE). More specifically, patients with SLE who smoked at the time of their serological evaluation for dsdna were more likely to be seropositive than patients with SLE who were former or never smokers at the time of serological evaluation. These results provide a potential mechanism that may underlie dsdna autoantibody formation. In RA, cigarette smoking has been associated with rheumatoid factor positivity. In affected subjects, exposure to tabacco has also been associated with several measures of disease severity such as the presence of radiographic erosions etc. (see Majka et al) On the 5th International Congress on Autoimmunity in Sorrento at the end of last year a Brazilian study was presented about HLA-DRB1 SE genes may trigger specific immune reactions to citrullinated proteins in RA smoking patients (Oliveira RD et al). The authors concluded that environmental factors contribute to the raising of anti-ccp in individuals with HLA background to RA, being the smoking a strong candidate. Thus, the risk for relatives of RA patients to get also RA is much higher for smokers than for nonsmokers. Using the results of Freemer et al as well as results of other studies on the association of smoking and RA and SLE, Majka et al. discuss in their article the possible mechanisms underlying this association. The concept of a gene-environment interaction is suggested and should be pursued. Smoking is a common habit that is potentially modifiable. Because autoantibodies to dsdna and CCP may affect disease course in SLE and RA, respectively, smokers with these diseases should be counselled to stop smoking. This is perhaps the most clnically relevant point to be gained from these studies.

11 March 03/07: EULAR recommendations for early arthritis The definition of rheumatoid arthritis is sometimes imprecise and in practice, early inflammatory arthritis is often undifferentiated. An early diagnosis is complicated by the absence of specific tests and diagnostic criteria. In the past few years the development of effective new treatments and the validation of new concepts have highlighted the need to develop guidelines for the management of early arthritis. The objective of the the European League Against Rheumatism (EULAR) was to formulate, and obtain consensus on a set of recommendations aiming at improving the management of early arthritis: Combe B, Landewe R, Lukas C, et al (2007) EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT) Ann Rheum Dis 66, Recommendation 1: Arthritis is characterised by the presence of joint swelling, associated with pain or stiffness. Patients presenting with arthritis of more than one joint should be referred to and seen by a rheumatologist, ideally within six weeks after the onset of symptoms. Recommendation 2: Clinical examination is the method of choice for detecting arthritis. In doubtful cases, ultrasound, power Doppler, and MRI may be helpful in detecting synovitis. Recommendation 3: Exclution of other diseases than rheumatoid arthritis requires careful history taking and clinical examination, and ought to include at least the following laboratory tests: complete blood cell count, urinary analysis, transaminases, and antinuclear antibodies. Recommendation 4: In every patient presenting with early arthritis to the rheumatologist, the following factors predicting persistent and erosive disease should be measured: number of swollen and tender joints, ESR or CRP, level of rheumatoid factor and anti-ccp antibodies, and radiographic erosions. Recommendation 5: Patients of risk of developing persistent and/or erosive arthritis should be started with DMARDs as early as possible even if they do not yet fulfil established classification criteria for inflammatory rheumatological diseases. Recommendation 6: Patient information concerning the disease and its treatment and outcome is important. Education programmes aimed at coping with pain disability and the maintenance of work ability may be employed as adjunct interventions. Recommendation 7: NSAIDs have to be considered in symptomatic patients after evaluation of gastrointestinal, renal, and cardiovascular status. Recommendation 8: Systemic glucocorticoids reduce pain and swelling and should be considered as a (mainly temporary) adjunct to the DMARD strategy. Intra-articular glucocorticoid injections should be considered for the relief of local symptoms of inflammation. Recommendation 9: Among the DMARDs, methotrexate is considered the anchor drug and should be used first in patients at risk of developing persistent disease. Recommendation 10: The main goal of DMARD treatment is to achieve remission. Regular monitoring of disease activity and adverse events should guide decisions on choice and changes in treatment strategies (DMARDs including biological agents) Recommendation 11: Non-pharmaceutical interventions such as dynamic exercises, occupational therapy, and hydrotherapy can be applied as treatment adjunct to pharmaceutical interventions in patients with early arthritis. Recommendation 12: Monitoring of disease activity should include tender and swollen joint count, patient s and physician s global assessments, ESR, and CRP. Arthritis activity should be assessed at one to three month intervals, for as long as remission is not achieved. Structural damage should be assessed by x rays every 6 to 12 months during the first few years. Functional assessment (for example, HAQ) can be used to complement the disease activity and structural damage monitoring.

12 February 02/07: Recent advances in coeliac diseases Several screening studies worldwide have shown that approximately 1% of the population may have undetected coeliac disease. The prevalence is even higher in first and second degree relatives of people with coeliac disease. This high prevalence combined with increasing population and primary care awareness is leading to more and more referrals. Consequently many more patients with no or only mild clinical symptoms are identified. These changes in clinical practice have been paralleled by a dramatic increase in our knowledge of disease pathogenesis, making coeliac disease the best understood human autoimmune disorder. In the following review article, the authors present selected major recent advances in both clinical and basic science aspects of coeliac disease: Van Heel DA, West J (2006) Recent Advances in Coeliac Disease Gut 55, Starting with a review of all recent epidemiological studies, this paper covers clinical manifestations, impact of undetected coeliac disease, impact of clinically diagnosed coeliac disease, clinical implications of basic science advances, and finally ends with diagnostics and therapeutics. With the appreciation of the high prevalence of coeliac disease, there is increasing use of serology in screening asymptomatic people and testing those with suggestive features. Another review, also published in 2006, focuses on serodiagnosis and its growing role: Lewis NR, Scott BB (2006) Systematic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests) Aliment Pharmacol Ther 24, studies fulfilled the reviewers criteria of being a peer reviewed published study, the study included untreated patients and controls, both EMA and ttg antibody were tested, all patients had had a biopsy with clear diagnostic criteria, and it was clear which controls were biopsy negative and which had not been biopsied. In table 1 all studies are listed, including number of patients and sensitivity and specificity for EMA and anti-ttg. From the results of this review the authors recommend the use of recombinant human ttg antibody test to exclude coeliac disease if the pretest probability is low. If it is positive they recommend small bowel biopsy to confirm the diagnosis. If for any reason biopsy is precluded then the EMA test could be used to confirm the diagnosis. On the theme of coeliac disease, we came across a prospective study on pathogenesis which might be of interest: Steene LC, Honeyman MC, Hoffenberg EJ et al. (2006) Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study Am J Gastroenterol 101, ,931 children, who carried HLA risk alleles for coeliac disease were followed from infancy. Anti-tTG and rotavirus antibodies were assayed in serial serum samples from each child and 2 matched controls. 54 children developed coeliac disease. This study provides the first indication that a high frequency of rotavirus infection may increase the risk of coeliac disease in childhood in genetically predisposed individuals.

13 January 01/07: Detection of DNA antibodies Antibodies to double-stranded DNA (dsdna) can be found in patients with systemic lupus erythematosus (SLE) and, much less frequent, in patients with other rheumatic diseases (using more sensitive methods). Thus, pathological concentrations of dsdna antibodies are one of the 11 diagnostic criteria for the classification of SLE, which where established by the American Rheumatism Association (ARA) in In addition, dsdna antibodies reflect the disease activity, serve as a predictor of disease exacerbation and are suitable to monitor the response to therapy. Sensitivity and specificity of dsdna antibodies in SLE are highly dependent on the method used. In the following study the authors give a brief review on the different methods, how they work and their advantages and disadvantages: Rouquette AM, Desgruelles C (2006) Detection of antibodies to dsdna: an overview of laboratory assays Lupus 15, The most frequently used methods in routine clinical laboratories are the CLIF test (immunofluoresence on Crithidia luciliae), the Farr assay (RIA), the ELISA (enzyme linked immunosorbent assay) and some newer methods such as EliA dsdna from Phadia or the Liaison dsdna assay from Diasorin. When comparing different methods for the detection of anti-dna antibodies it has to be considered that anti-dna antibodies are a very heterogeneous group, reacting with different epitopes and with different degrees of avidity. Obviously, each method detects a slightly different subgroup of anti-dna antibodies and although there is an international standard for anti-dsdna (WHO 80) it will never be possible to compare results which are obtained by different methods. While the Farr RIA finds the diagnostically most relevant high avidity antibodies, the ELISA may detect also antibodies with lower avidity, what leads to a higher sensitivity but a lower specificity compared to RIA. EliA on the ImmunoCAP instruments tries to be a compromise between these methods, measuring mainly high avidity antibodies for anti-dsdna. The specificity and sensitivity is found to be in between the values of a typical ELISA and the RIA. The authors conclude that discrepancies of anti dsdna results exist between laboratories in spite of increasing quality insurance procedures from both manufacturers and users. Therefore, results must be interpreted by a physician who is aware of the technique used in the laboratory and experienced in evaluating a complex disease such as SLE.