Long-standing Rheumatoid Arthritis Research Articles

Reproducibility of Joint Swelling Assessment by Sonography in Patients with Long-lasting Rheumatoid Arthritis (SEA-Repro Study Part II)

To evaluate the intraobserver and interobserver reproducibility of B-mode and power Doppler (PD) sonography in patients with active long-standing rheumatoid arthritis (RA) comparatively with clinical data. In each of 7 patients being considered for a change in their RA treatment regimen, 7 healthcare professionals examined the 28 joints used in the Disease Activity Score 28-joint count (DAS28). Then 7 sonographers examined each of the 7 patients twice, using previously published B-mode and PD grading systems. The clinical reference standard was presence of synovitis according to at least 4/7 examiners. The sonographic reference standard was at least grade 1 (ALG1) or 2 (ALG2) synovitis according to at least 4/7 sonographers. Interobserver reproducibility of sonography was assessed versus the sonographer having the best intraobserver reproducibility. Agreement was measured by Cohen's kappa statistic. Intraobserver and interobserver reproducibility of B-mode and PD used separately was fair to good. Agreement between clinicians and sonographers at all sites using B-mode, PD, and both was 0.46, 0.37, and 0.36, respectively, for grade 1 synovitis; and 0.58, 0.19, and 0.19 for grade 2 synovitis. The number of joints with synovitis was smaller by physical examination (36.7%) than by B-mode with ALG1 (58.6%; p < 0.001). The number of joints with synovitis was higher by physical examination than by PD with both ALG1 (17.8%; p < 0.0001) and ALG2 (6.6%; p < 0.0001). PD findings explain most of the difference between clinical and sonographic joint assessments for synovitis in patients with long-standing RA.

Successful treatment of severe nodular scleritis with adalimumab

Ocular features may occur in longstanding rheumatoid arthritis. Among them, scleritis represents the most frequent manifestation of ophthalmologic rheumatoid disease. There are three types of anterior scleritis: diffuse, nodular, and necrotizing with and without inflammation (scleromalacia perforans). Nodular scleritis is the second cause of anterior scleritis representing 20% of all types of scleritis. The conventional treatment of nodular scleritis consists in topical steroids and DMARDS. In severe cases, the therapy with immunosuppressive agents to avoid complications is necessary. We describe a 46-year-old woman presented right nodular scleritis with rheumatoid arthritis. She was treated initially with topical steroids and DMARDs but was unable to received systemic steroids due to left open angle glaucoma in the opposite eye. After an ocular exacerbation, we initiated adalimumab with complete resolution of nodular scleritis. This is the first report of adalimumab in the treatment of nodular scleritis. Adalimumab could be a good alternative in patients with severe nodular scleritis who fail to have conventional treatment with DMARDs and unable to receive systemic steroids.

Notfälle in der Rheumatologie – Die Sicht des internistischen und orthopädischen Rheumatologen

Medical emergencies due to rheumatoid arthritis (RA) and ankylosing spondylitis (AS) can occur as a result of vasculitis, spinal instability, increased risk of fracture, tenosynovialitis with subsequent tendon rupture and septic arthritis. Structural changes in the cervical spine in long-standing RA render the joint facets and ligaments unstable. These patients are at high risk to develop neurological damage including myelopathy due to a narrowing of the spinal canal. Once neurological deficits occur, surgical treatment is generally indicated. Even minor injuries can cause fractures, especially in the thoracic spinal column as the most susceptible part. Because conventional X-ray images may not reveal these fractures, CT scans or MRI may be indicated. Neurological deteoration requires immediate surgical treatment. Also in RA, inflammation and glucocorticoid--induced osteoporosis increase the risk of fractures, including periprosthetic fractures. Surgical options are often demanding due to the reduced bone structure. Tendon ruptures on exposed bone structures and regions of high mechanical wear in the hand and foot need reconstructive surgery in a timely manner. Septic arthritis is a disabling and potentially life-threatening condition that requires prompt diagnosis and treatment. Aspiration and culture of synovial fluid are crucial for the diagnosis. Immediate antibiotic treatment, initially intravenously and then orally for sometimes prolonged periods of time as well as either arthroscopic intervention or open synovectomy are necessary.

Can disease-modifying anti-rheumatic drugs be discontinued in long-standing rheumatoid arthritis? A 15-year follow-up

Objective: To investigate the 15-year outcome of patients with early rheumatoid arthritis (ERA) with respect to the continuity of treatment.Methods: We conducted a 15-year follow-up study of 87 patients with ERA treated since diagnosis with disease-modifying anti-rheumatic drugs (DMARDs) according to the ‘sawtooth’ strategy. The patients were divided into groups according to the continuity of treatment: (A) ‘continuous DMARDs’, (B) ‘discontinued and restarted DMARDs’, and (C) ‘permanently discontinued DMARDs’. The main outcome measurements included the Health Assessment Questionnaire (HAQ), the Larsen score, and clinical remission according to the American Rheumatism Association (ARA) criteria.Results: Seventy (80%) patients participated in the 15-year follow-up. DMARDs were discontinued in 20 (29%) patients due either to remission or to a symptom-free period of the disease. The disease flared up in nine (45%) of these patients, in some patients several years after the discontinuation. At the 15-year follow-up, 59 (84%) patients were on DMARDs; only three (4%) were using biologicals. Functional capacity remained good in all groups (mean HAQ score 0.52). The mean Larsen score was higher (54) in group A than in groups B (25) and C (12) (p =0.001). The remission rate was 64% in group C and considerably lower in groups A (6%) and B (0%) (p<0.001).Conclusions: Our results indicate that most of the patients with long-standing RA require continuous DMARD treatment. If the treatment is discontinued, patients should be followed-up closely and DMARDs readministered without delay if the disease flares up.

A Case of Scleromalacia Perforance That Developing after Surgery for Excision of the Pterygium in a Patient with Rheumatoid Arthritis

The ocular manifestations of rheumatoid arthritis (RA) are common and they can vary from patient to patient. However, necrotizing anterior scleritis without inflammation (scleromalacia perforans) is a rare and serious opthalmic complication, and it is typically associated with long-standing RA. Although the etiology and pathogenesis of scleromalacia perforans are diverse and they are not completely understood, ophthalmic surgery is one of the well known causes of scleromalacia perforans. Patients with systemic autoimmune disease such as RA have an especially higher risk of scleromalacia perforans after opthalmic surgery. Because scleromalacia perforans is a potential threat not just to eyesight, but to life as well, early diagnosis and prompt treatment are required for its successful management. We experienced a case of scleromalacia perforans that developed after scleral excision of pterygium in a 58 year old woman who had a 7 year history of RA, and this was well treated with an early screral graft. We report here on this case along with a review of the relevant literature.

‘Choosing shoes’: a preliminary study into the challenges facing clinicians in assessing footwear for rheumatoid patients

BackgroundFootwear has been accepted as a therapeutic intervention for the foot affected by rheumatoid arthritis (RA). Evidence relating to the objective assessment of footwear in patients with RA is limited. The aims of this study were to identify current footwear styles, footwear characteristics, and factors that influence footwear choice experienced by patients with RA.MethodsEighty patients with RA were recruited from rheumatology clinics during the summer months. Clinical characteristics, global function, and foot impairment and disability measures were recorded. Current footwear, footwear characteristics and the factors associated with choice of footwear were identified. Suitability of footwear was recorded using pre-determined criteria for assessing footwear type, based on a previous study of foot pain.ResultsThe patients had longstanding RA with moderate-to severe disability and impairment. The foot and ankle assessment demonstrated a low-arch profile with both forefoot and rearfoot structural deformities. Over 50% of shoes worn by patients were open-type footwear. More than 70% of patients' footwear was defined as being poor. Poor footwear characteristics such as heel rigidity and sole hardness were observed. Patients reported comfort (17%) and fit (14%) as important factors in choosing their own footwear. Only five percent (5%) of patients wore therapeutic footwear.ConclusionsThe majority of patients with RA wear footwear that has been previously described as poor. Future work needs to aim to define and justify the specific features of footwear that may be of benefit to foot health for people with RA.

Acquired Hemophilia in a Patient with Rheumatoid Arthritis

Acquired hemophilia is a rare disease caused by an autoimmune reaction to coagulation factor VIII, The mortality rate of this disease is very high (8∼22%). Clinical manifestations are different from congenital hemophilia. Various diseases are associated with acquired hemophilia, including autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis (RA), tumors, inflammatory bowel disease, psoriasis, asthma, diabetes, acute hepatitis B or C, and drug reactions. However, the underlying cause is unknown in approximately 50% of cases. A few cases of acquired hemophilia with RA have been published. However, no cases have been reported in Korea. We had a patient with longstanding RA and acquired hemophilia who was suffering from upper and lower extremity purpura with a deep intramuscular hematoma. The patient was successfully treated using cyclophosphamide combined with steroid.

Role of carotid ultrasonography in the evaluation of cardiovascular risk in patients with rheumatoid arthritis

We read with great interest the article by Sodergren and colleagues in a recent issue of Arthritis Research & Therapy ('Atherosclerosis in early rheumatoid arthritis: very early endothelial activation and rapid progression of intima media thickness') [1]. In the study reported in the article, the authors showed no differences of carotid artery intima-media thickness (IMT) in patients with very early rheumatoid arthritis (RA) compared with controls at baseline [1]. However, in the subgroup of individuals who were re-evaluated 18 months after the first ultrasound measurement, the carotid IMT had increased significantly among the patients with RA. However, this was not the case for the controls [1]. With respect to these interesting observations, we would like to further emphasize the importance of carotid ultrasonography in the evaluation of the cardiovascular risk of patients with RA and the importance of the duration of the disease as a predictor of severity, so it can influence the development of cardiovascular events in these patients. We previously reported that, in long-standing RA patients with no classic cardiovascular risk factors at the time of the carotid assessment, the duration of the disease was the best predictor of carotid plaques [2]. On the other hand, RA is a chronic inflammatory disease, and even in the apparently quiescent phases of the disease, the cumulative effect of the chronic inflammatory burden may account for the progression of the atherosclerosis disease. In this regard, we observed that the mean values of C-reactive protein (CRP) over an extended follow-up rather than a single determination of CRP at the time of the carotid ultrasonography evaluation were associated with the carotid IMT [3]. Moreover, we found that carotid artery IMT had a high predictive power for the development of cardiovascular events over a 5-year follow-up period in 47 patients with RA without clinically evident cardiovascular disease at the time of the carotid ultrasonography evaluation [4]. In our study, carotid IMT categorized in quartiles was strongly associated with the development of cardiovascular events [4]. When logistic regression models were performed, carotid IMT at the time of the ultrasonographic study yielded a high predictive power for the development of cardiovascular events over the 5-year follow-up period. On the other hand, the duration of the disease is also considered an important risk factor of future cardiovascular events [5]. Taking all of these considerations together, we propose that ultrasonographic assessment of the carotid artery be performed on all patients with RA in order to establish a subgroup of patients with a high risk of cardiovascular complications. This procedure should be carried out at the time of the disease diagnosis and periodically there-after, in particular in those patients with severe disease and persistent elevation of markers of inflammation.

Cardiovascular morbidity and mortality remain similar in two cohorts of patients with long-standing rheumatoid arthritis seen in 1978 and 1995 in Malmo, Sweden

Patients with RA have an increased risk of cardiovascular disease. Management of RA has changed substantially over time. Our aim was to evaluate changes in cardiovascular morbidity and mortality over the period of 1978-2002. Two cohorts of consecutive patients with RA seen at outpatient clinics in Malmö, Sweden, were started in 1978 (n = 148) and 1995 (n = 161) and compared with the corresponding background population. Patients were followed for 8 years, and fatal and non-fatal cardiovascular first events were identified using two national registers, hospital discharge and cause of death. Standardized morbidity ratio (SMoR) and standardized mortality ratio (SMR), adjusted for age and sex were calculated. Sex distribution, age at disease onset and disease duration were similar in both groups. The 1995 cohort was more extensively treated with DMARDs and had less disease activity and disability. Total cardiovascular morbidity was increased in the 1978 cohort (SMoR 158; 95% CI 111, 225) as well as in the 1995 cohort (SMoR 168; 95% CI 118, 232). This was mainly due to an increased risk of coronary artery disease. Overall mortality was elevated in the 1978 cohort but not in the 1995 cohort. There was no change in cardiovascular excess mortality (SMR 175; 95% CI 100, 284; and 172; 100, 276 for the two cohorts, respectively). There were similar elevations in the incidence of cardiovascular comorbidity in RA patients, identified two decades apart compared with the general population, in spite of more extensive treatment and reduced disease severity in the more recent cohort.

Arterial stiffness in a muscular artery in women with longstanding rheumatoid arthritis compared with healthy controls and patients with traditional cardiovascular risk factors

Pulse wave velocity (PWV), a marker of arterial stiffness, reflects vascular dysfunction and is associated with cardiovascular risk. Rheumatoid arthritis (RA) is associated with profound changes in vascular function and premature death, mainly caused by cardiovascular diseases. The aim of this study was to investigate arterial stiffness in the brachial artery (a muscular type of artery) as measured by PWV in women with longstanding RA and to compare the results with healthy controls and to patients with traditional cardiovascular risk factors without RA. A total of 80 female participants underwent non-invasive measurement of PWV. Participants were allocated to one of three groups: patients with longstanding RA (disease duration >5 years) without traditional cardiovascular risk factors (n = 30), patients with traditional cardiovascular risk factors (n = 20) and healthy controls (n = 30). Patients and controls were matched for age. PWV was significantly higher in RA patients (8.6 +/- 0.9 m/s) as compared with healthy controls (8.1 +/- 0.7 m/s; P = 0.02). PWV was virtually the same in RA patients and patients who had traditional cardiovascular risk factors (8.6 +/- 1.5 m/s; NS). PWV was also higher in this group as compared with healthy controls, but this difference did not reach statistical significance (NS). RA is associated with a higher PWV as compared with healthy controls and is comparable to patients with known traditional risk factors. This reflects vascular dysfunction in patients with RA.

Circadian pattern and the effect of standardized physical exercise on procollagen IIA N-peptide (PIIANP) in rheumatoid arthritis at different stages and in healthy individuals

Background: Variant collagen IIA is re-expressed in diseased cartilage. Low procollagen IIA N-peptide (PIIANP) levels in serum have recently been reported in rheumatoid arthritis (RA). We investigated circadian rhythmicity and effect of physical activity on PIIANP in early and longstanding RA and in healthy subjects.Methods: Patients with early and longstanding RA and controls were included. Fasting and serial blood samples were collected during 24 h. PIIANP response to physical activity was studied before and serially after standardized exercise.Results and conclusion: In RA at different stages and healthy individuals, PIIANP exhibited no circadian rhythmicity, and PIIANP in serum was not influenced by physical activity.

Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNF agents failed are associated with response to rituximab in rheumatoid arthritis

We explored clinical factors associated with a major response to rituximab (RTX) (e.g. ACR >/=50, and European League against Rheumatism (EULAR) moderate to good response) in patients with active long-standing RA and inadequate response to anti-TNF agents or traditional DMARDs. RTX was used in 110 RA patients in six different Italian centres. The mean disease activity score on 28 joints (DAS28) was 6.4 +/- 0.99 and the mean HAQ was 1.63 +/- 0.68 at baseline. Thirty-two patients (29.1%) underwent RTX after the failure of DMARD therapy, 37 (33.6%) had failed or were intolerant to at least two anti-TNF agents, and 41 (37.3%) had failed or were intolerant to one anti-TNF agent. Univariate and multivariate analyses were performed. The number of previous anti-TNF agents (P = 0.043), HAQ (P = 0.023), RF positivity (P < 0.0001) and anti-cyclic citrullinated peptide (anti-CCP) positivity (P = 0.003) were associated with ACR response >or=50 between month +4 and month +6 after starting RTX by univariate analysis. Multivariate analysis confirmed that a lower HAQ, a lower number of anti-TNF agents failed before RTX and RF positivity, but not anti-CCP positivity, were the selected variables associated with an ACR response >or=50, with an accuracy of 84% of the model. Only RF positivity correlated with EULAR moderate to good response both in the univariate and in the multivariate analysis, with an accuracy of 79% of the model. RF-positive rather than anti-CCP-positive RA patients with lower baseline disability and a lower number of previously failed TNF blockers may be the best candidates to RTX.

Schamberg disease: uncommon reaction to a common drug

A 75-year-old woman with long-standing rheumatoid arthritis presented with a mildly pruritic, symmetrical erythematous rash on her legs ([Figure 1][1]). She was not taking any specific therapy for her rheumatoid arthritis but had taken acetaminophen for 3 days because of knee pain. She noticed the

Rituximab for the treatment of rheumatoid arthritis

This paper presents a summary of the evidence review group's critical review of the evidence for the clinical effectiveness and cost-effectiveness of rituximab for the treatment of severe rheumatoid arthritis (RA) following failure of previous therapy, including one or more tumour necrosis factor-alpha inhibitors (TNFi), compared with current standards of care, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's clinical evidence came from one randomised, placebo-controlled, double-blind trial (REFLEX--Random Evaluation of Long-term Efficacy of Rituximab in Rheumatoid Arthritis) comparing rituximab plus methotrexate (MTX) with placebo plus MTX in 517 patients with long-standing refractory RA. Rituximab plus MTX was more effective than placebo plus MTX across a range of primary and secondary outcome measures, e.g. American College of Rheumatology (ACR) responses, Health Assessment Questionnaire (HAQ). However, this evidence cannot be used directly to address the manufacturer's analysis of the decision problem because, in the REFLEX trial, rituximab was not compared with a relevant comparator (e.g. leflunomide or second or third TNFi). Long-term efficacy data for retreatment with rituximab are favourable, with an estimated mean time to retreatment of 307 days (n = 164). Evidence from a further five trials is presented as the basis for indirect comparisons with other disease-modifying antirheumatic drugs (DMARDs); however, it is not clear that all relevant clinical studies have been included in the indirect comparison exercise, the rationale for the choice of indirect comparison method adopted is unclear and the indirect comparison method used to adjust the ACR responses only uses a single value for the reference placebo. The submitted microsimulation Markov model was based upon the REFLEX trial. For the 'NICE-recommended' scenario and the 'sequential TNFi' scenario, the original submission reports incremental cost-effectiveness ratios (ICERs) of 14,690 pounds and 11,601 pounds per quality-adjusted life-year (QALY) gained respectively. After model assumptions were adjusted to more realistic estimates by the ERG, the ICERs for the NICE-recommended scenario and the sequential use of TNFi range from 37,002 pounds to 80,198 pounds per QALY gained and from 28,553 pounds to 65,558 pounds per QALY gained respectively. The guidance issued by NICE in August 2007 states that rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or intolerance of other DMARDs including treatment with at least one TNFi therapy.

Rituximab for the treatment of rheumatoid arthritis

This paper presents a summary of the evidence review group’s critical review of the evidence for the clinical effectiveness and cost-effectiveness of rituximab for the treatment of severe rheumatoid arthritis (RA) following failure of previous therapy, including one or more tumour necrosis factor-α inhibitors (TNFi), compared with current standards of care, based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission’s clinical evidence came from one randomised, placebo-controlled, double-blind trial (REFLEX – Random Evaluation of Long-term Efficacy of Rituximab in Rheumatoid Arthritis) comparing rituximab plus methotrexate (MTX) with placebo plus MTX in 517 patients with long-standing refractory RA. Rituximab plus MTX was more effective than placebo plus MTX across a range of primary and secondary outcome measures, e.g. American College of Rheumatology (ACR) responses, Health Assessment Questionnaire (HAQ). However, this evidence cannot be used directly to address the manufacturer’s analysis of the decision problem because, in the REFLEX trial, rituximab was not compared with a relevant comparator (e.g. leflunomide or second or third TNFi). Long-term efficacy data for retreatment with rituximab are favourable, with an estimated mean time to retreatment of 307 days (n = 164). Evidence from a further five trials is presented as the basis for indirect comparisons with other disease-modifying antirheumatic drugs (DMARDs); however, it is not clear that all relevant clinical studies have been included in the indirect comparison exercise, the rationale for the choice of indirect comparison method adopted is unclear and the indirect comparison method used to adjust the ACR responses only uses a single value for the reference placebo. The submitted microsimulation Markov model was based upon the REFLEX trial. For the ‘NICE-recommended’ scenario and the ‘sequential TNFi’ scenario, the original submission reports incremental cost-effectiveness ratios (ICERs) of £14,690 and £11,601 per quality-adjusted life-year (QALY) gained respectively. After model assumptions were adjusted to more realistic estimates by the ERG, the ICERs for the NICE-recommended scenario and the sequential use of TNFi range from £37,002 to £80,198 per QALY gained and from £28,553 to £65,558 per QALY gained respectively. The guidance issued by NICE in August 2007 states that rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or intolerance of other DMARDs including treatment with at least one TNFi therapy.

A 65‐year‐old man with longstanding seropositive rheumatoid arthritis and lower extremity ulceration

A 65‐year‐old man with longstanding seropositive rheumatoid arthritis and lower extremity ulceration

Multiparameter Phospho-Flow Analysis of Lymphocytes in Early Rheumatoid Arthritis: Implications for Diagnosis and Monitoring Drug Therapy

BackgroundThe precise mechanisms involved in the initiation and progression of rheumatoid arthritis (RA) are not known. Early stages of RA often have non-specific symptoms, delaying diagnosis and therapy. Additionally, there are currently no established means to predict clinical responsiveness to therapy. Immune cell activation is a critical component therefore we examined the cellular activation of peripheral blood mononuclear cells (PBMCs) in the early stages of RA, in order to develop a novel diagnostic modality.Methods and FindingsPBMCs were isolated from individuals diagnosed with early RA (ERA) (n = 38), longstanding RA (n = 10), osteoarthritis (OA) (n = 19) and from healthy individuals (n = 10). PBMCs were examined for activation of 15 signaling effectors, using phosphorylation status as a measure of activation in immunophenotyped cells, by flow cytometry (phospho-flow). CD3+CD4+, CD3+CD8+ and CD20+ cells isolated from patients with ERA, RA and OA exhibited activation of multiple phospho-epitopes. ERA patient PBMCs showed a bias towards phosphorylation-activation in the CD4+ and CD20+ compartments compared to OA PBMCs, where phospho-activation was primarily observed in CD8+ cells. The ratio of phospho (p)-AKT/p-p38 was significantly elevated in patients with ERA and may have diagnostic potential. The mean fluorescent intensity (MFI) levels for p-AKT and p-H3 in CD4+, CD8+ and CD20+ T cells correlated directly with physician global assessment scores (MDGA) and DAS (disease activity score). Stratification by medications revealed that patients receiving leflunomide, systemic steroids or anti-TNF therapy had significant reductions in phospho-specific activation compared with patients not receiving these therapies. Correlative trends between medication-associated reductions in the levels of phosphorylation of specific signaling effectors and lower disease activity were observed.ConclusionsPhospho-flow analysis identified phosphorylation-activation of specific signaling effectors in the PB from patients with ERA. Notably, phosphorylation of these signaling effectors did not distinguish ERA from late RA, suggesting that the activation status of discrete cell populations is already established early in disease. However, when the ratio of MFI values for p-AKT and p-p38 is >1.5, there is a high likelihood of having a diagnosis of RA. Our results suggest that longitudinal sampling of patients undergoing therapy may result in phospho-signatures that are predictive of drug responsiveness.

Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-depth statistical analysis of the major outcome

To obtain the simplest definition of minimal disease activity (MDA) and to compare it with published proposed definitions of MDA in patients with RA. Two hundred and fourteen patients with long-standing RA (LSRA) were evaluated for clinical and laboratory parameters. Factor analysis was performed to remove redundant variables included in the core set measure for MDA definition stated by the OMERACT. Receiver operating characteristic (ROC) curves analysis allowed to obtain optimal cut-off predictors of a 28-joint disease activity score (DAS28) < or =2.85. These were tested in 112 LSRA and 95 early-onset RA (ERA) patients. Factor and ROC curve analysis showed that the best predictors of a DAS28 < or = 2.85 in LSRA cohort were: (i) ESR <20 mm/h (sensitivity: 80%, specificity: 54%); (ii) swollen joint count (out of 28) < or =2 (sensitivity: 95%, specificity: 74%); (iii) patient global assessment (0-100) < or =15 (sensitivity: 78%, specificity: 78%); and (iv) HAQ (0-3) < or =0.5 (sensitivity: 91%, specificity: 61%). To each of these four criteria we assigned a value of 1 when it was satisfied (score ranging: 0-4). The cut-off with the highest overall accuracy for identifying RA patients with DAS28 < or = 2.85 was a score > or =3. We adopted these four parameters in order to define the residual MDA (RMDA). Comparing RMDA criteria, in distinct 112 LSRA and 95 ERA patients, with OMERACT, Simplified Disease Activity Index and Clinical Disease Activity Index definitions of MDA, we found a good agreement in the LSRA cohort and moderate agreement in the ERA cohort. HAQ, PaGA, SJC28 and ESR allow identification of RA patients with an RMDA. The RMDA criteria behaves similarly to OMERACT definitions, but appears more simple and feasible.

Adiponectin and leptin serum concentrations in patients with rheumatoid arthritis

Adipose tissue is regarded as an active metabolic and endocrine organ producing adipokines. The purpose of the study was to evaluate adiponectin and leptin concentrations in rheumatoid arthritis (RA) patients (pts) in relation to disease duration and activity. The study group consisted of 80 RA pts. Serum adiponectin and leptin concentrations remained within normal ranges. Adiponectin concentration correlated positively both with the age and disease duration. Both adipokines levels correlated negatively with glomerular filtration rate. There were significant positive correlations between adipokines' concentrations and lipid profile components (between adiponectin and HDL-cholesterol, leptin and total cholesterol and LDL-cholesterol). In pts with long-standing RA, there was a negative correlation between adiponectin and numbers of tender, swollen joints and a positive relationship between leptin level and DAS28. The results confirm adipokines' involvement in the process of inflammation and atherosclerosis: protective and antiinflammatory adiponectin effect and proatherogenic and proinflammatory leptin function.

MS characterization of apheresis samples from rheumatoid arthritis patients for the improvement of immunoadsorption therapy – a pilot study

Identification of proteins from apheresis samples was performed by both SDS-PAGE and 2-D gel separation of eluted proteins from staphylococcal protein A-based immunoadsorption columns (Prosorba(®) ) followed by MS peptide mass fingerprinting and MS/MS peptide sequencing on a MALDI QIT TOF mass spectrometer. MS/MS peptide sequencing was performed in conjunction with a micro reversed phase HPLC configured with an online MALDI plate-spotting device. Apheresis treatment had been performed in three patients with longstanding therapy refractory rheumatoid arthritis. 2-D gels displayed ca. 500 spots representing proteins that were eluted from the Prosorba(®) columns. From 54 gels, a total of 1256 protein spots had been picked and yielded in the identification of 56 non-redundant proteins without counting isoforms. Proteins from the eluates belong to five major groups comprising (i) immunoglobulins (IgG, IgA, IgM heavy and light chains; about 40% of the spots), (ii) proteins involved in coagulation, (iii) HDL/LDL-associated proteins, (iv) proteins from the complement system, and (v) acute phase proteins. MS analysis showed that the full-length C3 complement protein had been cleaved upon complement activation, presumably on the column, such that the anaphylatoxin C3a was produced and released during therapy. Our results are consistent with clinical observations on both patient responses to therapy and reported adverse events. For the first time, direct molecular information has become available to support mechanistic reasoning for the principle of function of staphylococcal protein A-based immunoadsorption therapy and for the explanation of adverse events. According to our results, removal and/or modulation of immune complexes together with complement activation can be regarded as the major events that are taking place during Prosorba(®) therapy. In order to avoid complement activation and induction of an inflammatory cascade, we suggest the prevention of C3a anaphylatoxin-related reactions during immunoadsorption therapy.