Benefits of pre-referral preparation for rheumatology clinics.

Appropriate allocation of rheumatology clinic appointments depends on the information contained in referral letters. Such letters were analysed for the presence of pertinent information and a scoring system was devised to assess the quality of enclosed data. In a smaller cohort, relevant basic tests were carried out prior to the appointment. 122 referral letters were received over a 1 month period. Symptom duration was documented in (39) 32%, while (64) 52.5% listed medications. Only (23) 17.2% indicated the urgency of the problem. Approximately (31) 25% of referrers performed relevant routine investigations. Mean score out of 10 was 5.1 (range 1.5-9). Of the 40 (33%) patients with pre-appointment investigations, the clinic attendance rate and subsequent discharge rate were significantly higher than those without these tests. This study shows that comprehensive referral letters and basic investigations significantly help to prioritize appointments and facilitate earlier diagnosis and treatment for patients with rheumatic disease.

Influenza and pneumococcal vaccination and varicella status in inflammatory arthritis patients.

Patients with inflammatory arthritis are at increased risk of vaccine preventable infections. This risk is increased by immunomodulatory therapies. Vaccination for influenza and pneumococcal disease reduces the risk. Severe cases of varicella infection have occurred in patients on biologic therapies. We sought to identify vaccination rates for commonly acquired infections and to ascertain varicella immune status in patients with inflammatory arthritis. 100 patients with inflammatory arthritis were administered a standardised questionnaire. Data collected included age, diagnosis, vaccination history, history of varicella, treatment and the presence of other indications for vaccination. 58 patients (58%) had not received the influenza vaccine in the past year. Only 19 patients (19%) had ever received pneumococcal vaccine. Anti TNF use did not predict vaccination (p = .46). An increasing number of co morbid conditions predicted both pneumococcal (p < 0.003) and influenza vaccine (p < 0.03) administration. Nineteen patients (19%) gave no history of varicella infection, none having had varicella titres checked pre treatment. Immunisation rates in patients with inflammatory arthritis on immunosuppressive therapies are low. Immunisation schedules should be available for each patient during rheumatology and general practice consultations.

Importance of full evaluation in patients who complain of neck pain.

INTRODUCTION: Although neck pain is common in patients with chronic rheumatic disorders, any change in the quality or severity of pain should be further investigated. MATERIALS AND METHODS: We report two patients who recently presented with increasing neck pain on a background of chronic inflammatory arthritis. RESULTS: Both patients were found to have suffered fractures of the cervical spine. In each case, the bones appeared osteopenic and reduced bone density is likely to have made the patients susceptible to fracture. CONCLUSION: This report highlights the need to comprehensively evaluate patients with chronic rheumatic disorders who note a significant change in their neck symptoms.

The value of synovial cytokine expression in predicting the clinical response to TNF antagonist therapy (infliximab).

OBJECTIVES: Clinical response to TNF-alpha blockade in the treatment of RA is heterogeneous. The study aims were to determine whether pre-treatment synovial cytokine expression predicted infliximab response and whether synovial changes after therapy correlated with response. METHODS: Fifty-one patients had arthroscopic biopsies of the knee joint prior to infliximab (3 mg/kg) treatment. Synovial tissue cell numbers (CD68 and CD3 positive) and cytokine expression (TNF-alpha, lymphotoxin-alpha, IL-1alpha, -beta and receptor antagonist, and IL-6) pre-treatment was assessed using semi-quantitative immunohistochemistry. Changes in these parameters were assessed 16 weeks after infliximab in 32 patients who underwent repeat arthroscopic biopsy. RESULTS: Of the total patients, 47% (n = 24) achieved an ACR20 response; 53% (n = 27) did not. Baseline synovial TNF-alpha, IL-1alpha and -beta expression did not differ between the two groups. No differences in baseline TNF-alpha levels were observed with ACR levels of response (ACR20 and ACR50/70 groups). Post-treatment biopsies (17 ACR responders, 15 ACR non-responders) revealed significant reductions in sub-lining layer TNF-alpha expression in both response and non-response groups with significant reduction in vascularity and membrane proliferation scores. The worst ACR non-responders (<20% CRP suppression) demonstrated no reduction in any of the parameters. CONCLUSION: Pre-treatment synovial TNF-alpha or IL-1 expression does not predict TNF blockade response. Both ACR response and non-response was associated with reduction in synovial TNF-alpha-level expression. Suppression in TNF-alpha levels was not observed in the worst non-responders. The improvements (including in vascularity), independent of ACR clinical response, are compatible with the reduced structural damage documented in all groups of patients independent of response.

Early joint erosions and serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 in rheumatoid arthritis.

OBJECTIVE: To further evaluate the roles of matrix metalloproteinase 1 (MMP-1), MMP-3, and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the pathogenesis of joint inflammation and articular erosions in early inflammatory arthritis. METHODS: Untreated patients with joint symptoms for <2 years were evaluated at presentation and followed up prospectively for 18 months. Swollen joint count and serum levels of C-reactive protein (CRP) were determined every 6 months. Serum levels of MMP-1, MMP-3, and TIMP-1 were measured by double-antibody sandwich enzyme-linked immunosorbent assay at the same time intervals. The number of joint erosions in serial radiographs of the hands and feet was also recorded. Analysis of synovial fluid levels of MMPs and TIMP-1 at presentation was completed in some patients. RESULTS: Of 175 patients evaluated at baseline, 85 had rheumatoid arthritis (RA), 39 had seronegative spondylarthropathy, 38 had undifferentiated arthritis, and 13 had self-limiting arthritis. Of 164 patients with available radiographs of the hands and feet at presentation, 33 (20.1%) had joint erosions. Baseline levels of MMP-1, MMP-3, and TIMP-1 were significantly higher (P = 0.0001, P = 0.013, and P = 0.0001, respectively) and ratios of TIMP-1:MMP-1 and TIMP-1:MMP-3 were significantly lower (P = 0.0001 and P = 0.013, respectively) in RA versus non-RA patients. In RA patients, serum levels of CRP correlated with MMP-3 and TIMP-1 levels, but not with MMP-1 levels. The number of erosions at presentation correlated with baseline levels of both MMP-1 and MMP-3, but not with levels of TIMP-1. One hundred one patients were followed up for the next 18 months. The number of patients with erosions and the number of erosions per patient increased significantly during this period. Area under the curve (AUC) measurements of MMP-1 and TIMP-1 levels, but not of MMP-3 levels, yielded significantly higher values in RA than in non-RA patients. In RA patients, only the AUC level of MMP-3 correlated with the AUC CRP level (r = 0.67, P = 0.0001), while only the AUC level of MMP-1 correlated with the number of new joint erosions (r = 0.28, P = 0.034). CONCLUSION: These data suggest an uncoupling of the pathophysiologic mechanisms associated with joint inflammation and articular erosion. Treatments that inhibit the production and activity of MMP-1 may preferentially limit the formation of new joint erosions and improve the long-term functional outcome of some patients with inflammatory arthritis.

Synovial tissue protease gene expression and joint erosions in early rheumatoid arthritis.

OBJECTIVE: To relate the expression of proteases in the lining and sublining layers of the synovial membrane to the rate of joint damage during 1 year in patients with early inflammatory arthritis. METHODS: Samples of synovial membrane were obtained by closed-needle biopsy or needle arthroscopy from inflamed knees of 20 patients with early inflammatory polyarthritis (mean disease duration 9.6 months, range 2 weeks to 18 months). Expression of matrix metalloproteinase 1 (MMP-1), cathepsin B (CB), and cathepsin L (CL) was examined using in situ hybridization. Immunohistochemistry was used to identify infiltrating mononuclear cell populations. Radiographs of the hands and feet, performed at presentation and after 1 year, were evaluated for the development of new erosions. RESULTS: Twelve patients had rheumatoid arthritis (RA), 6 had psoriatic arthritis (PsA), 1 had gout, and 1 had an undifferentiated arthritis. Six patients had erosions at presentation. Eleven patients (10 with RA, 1 with PsA) demonstrated at least 1 new erosion after 1 year of followup. MMP-1, CB, and CL messenger RNA (mRNA) were expressed in the synovial membrane of all patients and were present throughout the lining layer, as well as in perivascular cellular infiltrates and endothelial cells in the sublining layer. In the lining layer, the mean percentages of protease mRNA-positive cells per high-power field were higher in those patients who developed new joint erosions than in those without evidence of joint damage. A similar pattern was observed in the sublining layer, where mean numbers of protease mRNA-positive cells were also greater in patients with new joint erosions. There were significant differences between the two groups in MMP-1 mRNA expression in both the lining and sublining layers (P = 0.0007 and P = 0.0027, respectively), as well as in sublining layer CL mRNA expression (P = 0.017), but not in CB mRNA expression. Numbers of lining layer CD68+ cells correlated positively with lining layer MMP-1 mRNA expression (P = 0.043) and with the development of new joint erosions (P = 0.002). CONCLUSION: The detection of MMP-1, CB, and CL in the synovium soon after the onset of symptoms highlights the potential for early joint destruction in patients with RA. High levels of MMP-1 mRNA expression in the lining layer distinguished patients with more rapidly progressive erosive disease. This is the first study to demonstrate features of early synovial pathophysiology that may identify patients at increased risk of developing new joint erosions.

The effects of treatment with interleukin-1 receptor antagonist on the inflamed synovial membrane in rheumatoid arthritis.

OBJECTIVE: To evaluate the effects of treatment with interleukin-1 receptor antagonist (IL-1Ra) on synovial tissue in rheumatoid arthritis (RA). METHODS: Twelve patients with RA entering a randomized clinical trial of human recombinant IL-1Ra underwent synovial biopsies before and after treatment. Cellular infiltration and adhesion molecule expression were evaluated after immunohistochemical staining. RESULTS: There was a notable reduction in intimal layer macrophages and subintimal macrophages and lymphocytes after treatment with IL-1Ra at 150 mg/day (n=3). Increased cellular infiltration was observed in all patients receiving placebo (n=3); variable changes were observed after IL-1Ra 30 mg/day (n=6). In a limited study of adhesion molecule expression, down-regulation of E-selectin and vascular cell adhesion molecule-1 was observed after treatment with IL-1Ra 150 mg/day, but not after IL-1Ra 30 mg/day or placebo. The apparent arrest of progressive joint damage seen in four patients after treatment with IL-1Ra was associated with reduced intimal layer macrophage accumulation in all patients. CONCLUSION: Treatment of RA with IL-1Ra resulted in reduced mononuclear cell infiltration of synovial membrane, which may represent the in vivo inhibition of biologically relevant IL-1ss-mediated pathogenic effects.

Amyloid precursors and amyloidosis in inflammatory arthritis.

Recent data demonstrating the multifunctional role of serum amyloid A (SAA) in the pathogenesis of amyloidosis have yielded important insights into this potentially fatal consequence of chronic inflammation. SAA has been shown to participate in chemotaxis, cellular adhesion, cytokine production, and metalloproteinase secretion and is thus integrally involved in the disease process. In addition to its production by the liver as part of the acute phase response, SAA is also expressed by several pathologic tissues such atherosclerotic plaques, rheumatoid synovitis and in the brains of patients with Alzheimer disease. Its constitutive production in normal tissue suggests a role for SAA in host defense and tissue turnover. Many pathways are involved in the regulation of SAA, and as more becomes known about these, potential therapeutic targets may be identified. However, the prevention of secondary amyloidosis is best achieved by early and adequate treatment of patients with chronic inflammatory disorders. Suppression of the acute phase response and normalization of SAA levels are likely to significantly impact on the incidence of amyloidosis in inflammatory arthritis.

Steroid-induced osteoporosis in systemic lupus erythematosus.

The patient with SLE is at considerable risk of osteoporosis, because of the inflammatory disease itself, its consequences, and its treatments. Because of their extensive use, glucocorticoids are thought to be the most frequent cause of drug-related osteoporosis and may be responsible for much of the bone loss in lupus. This article focuses on the mechanisms of steroid-induced osteoporosis in SLE and outlines strategies for prevention and treatment.

Serum amyloid A in the assessment of early inflammatory arthritis.

OBJECTIVE: Acute phase serum amyloid A (A-SAA) has been reported to be more sensitive than C-reactive protein (CRP) as a marker of disease activity. It may function in immune regulation and is linked to the development of secondary amyloidosis. We investigated the profile of A-SAA in early inflammatory arthritis and compared A-SAA with CRP and erythrocyte sedimentation rate (ESR) in relation to diagnosis and disease activity. METHODS: Using a sensitive and specific ELISA, A-SAA was measured in the serum of 140 patients with early arthritis (disease duration 2 weeks to 24 mo, mean 6 mo). CRP was determined using a standard ELISA; ESR and clinical disease activity variables were also recorded. RESULTS: Sixty-four patients had rheumatoid arthritis (RA), 19 psoriatic arthritis (PsA), 28 undifferentiated arthritis (UA), and 29 other forms of arthritis. A-SAA levels correlated with both CRP (r = 0.73, p = 0.0001) and ESR (r = 0.6, p = 0.0001). The magnitude of the A-SAA response was greater than either the CRP or ESR, and very high A-SAA levels were observed in disease as early as 2 weeks. Highest A-SAA concentrations occurred in RA (median 70.3 mg/l, maximum 1542) compared with the other groups (medians, PsA: 33 mg/l; UA: 12.3 mg/l; other arthritis: 11.2 mg/l), with values > 520 mg/l observed exclusively in RA. A-SAA, unlike CRP or ESR, could distinguish patients with a final diagnosis of RA from those who had persistent UA. In RA, A-SAA provided the strongest correlations with clinical measurements of disease activity. Clinical improvement was also best represented by A-SAA, while disease deterioration was associated with a significant increase in A-SAA values, but not CRP or ESR. CONCLUSION: Compared with ESR or CRP, A-SAA correlates best with markers of disease activity, and in patients with recent onset arthritis, very high levels of SAA occur exclusively in RA. As A-SAA is sensitive to change and accurately reflects alterations in disease status, it is the best marker available for the assessment of inflammatory joint disease.

Quantitative analysis of synovial membrane inflammation: a comparison between automated and conventional microscopic measurements.

OBJECTIVE: The objective of this study was to quantify selected features of chronic synovial tissue inflammation by computerised image analysis and to validate the results by comparison with conventional microscopic measurements. METHODS: Synovial biopsy samples were obtained from the knee joints of patients with chronic arthritis and prepared for immunohistochemical analysis using standard techniques. Following the development of special software, four parameters of chronic synovial inflammation were evaluated: intimal layer thickness, CD3+ cell infiltration, CD8+ cell infiltration and vascularity. Intimal layer thickness was expressed in microns. The intensity of CD3+ and CD8+ cell infiltration was expressed as the percentage area of the tissue section occupied by positively stained cells. Vascularity was expressed as the percentage area occupied by blood vessels. Conventional quantitative microscopic analysis was also undertaken and the results from both methods compared. RESULTS: Seventy eight tissue sections were selected for study. Measurements of intimal layer thickness by both techniques correlated strongly: r = 0.85, p = 0.0006. Measurements of CD8+ cell infiltration, usually widely dispersed, also correlated well: r = 0.64, p = 0.005. Measurements of CD3+ cell infiltration, often densely aggregated, correlated less well: r = 0.55, p = 0.02. Measurements of vascularity demonstrated no statistically significant correlation: r = 0.41, p = 0.07. Proficiency in the use of computerised image analysis was readily acquired. CONCLUSION: Computerised image analysis was successfully applied to the measurement of some features of synovial tissue inflammation. Further software development is required to validate measurement of blood vessels of variable size.

Collagenase, cathepsin B and cathepsin L gene expression in the synovial membrane of patients with early inflammatory arthritis.

OBJECTIVE: To examine the expression of the matrix metalloproteinase, MMP-1, and the cysteine proteases, cathepsin B (CB) and cathepsin L (CL), in the synovial membrane (SM) of patients with early inflammatory arthritis. METHODS: Samples of SM were obtained by blind needle biopsy or needle arthroscopy from inflamed knees of 28 patients with early inflammatory arthritis (mean disease duration 10.2 months, range 2 weeks-18 months). Sixteen patients had rheumatoid arthritis (RA), nine psoriatic arthritis and there was one each with ankylosing spondylitis, gout and an undifferentiated arthritis. Comparison was made with tissue from two patients with established erosive RA and three normal synovial tissue samples. In situ hybridization was performed using digoxigenin-labelled RNA probes. RESULTS: MMP-1, CB and CL were expressed in all patients with early arthritis and in established erosive RA, whereas normal synovium showed only scanty expression. The three proteases were prominent in perivascular infiltrates and endothelial cells of early arthritis tissue. MMP-1 was observed primarily in the lining layer, but was also evident in the sublining area. CB and CL were expressed to a lesser extent in the lining layer, and were present mainly in the subintima. The three proteases were not found in lymphoid aggregrates. No differences were observed between the disease categories. CONCLUSIONS: The detection of MMP-1, CB and CL in the synovium shortly after symptom onset implies that the potential for joint destruction exists at a very early stage in the disease. In addition, the perivascular and endothelial cell expression suggests a role for these proteases in mononuclear cell influx to the inflamed synovium and in angiogenesis.

Amyloid precursors and amyloidosis in rheumatoid arthritis.

Amyloidosis refers to the extracellular accumulation of amyloid fibrils, derived from a circulating precursor, in various tissue and organs. The most common form of amyloidosis worldwide is that which occurs secondary to chronic inflammatory disease, particularly rheumatoid arthritis. The precursor molecule is serum amyloid A (SAA), an acute phase reactant, which can be used as a surrogate marker of inflammation in many diseases. SAA has a number of immunomodulatory roles, can induce chemotaxis and adhesion molecule expression, has cytokine-like properties and can promote the upregulation of metalloproteinases. It enhances the binding of high density lipoprotein to macrophages and thus helps in the delivery of lipids to sites of injury for use in tissue repair. It is thus thought to be an integral part of the disease process. Moreover, elevated levels of SAA over time predispose to secondary amyloidosis. Pathogenic factors underlying this disease are outlined along with guidelines for diagnosis and management.

Microscopic measurement of cellular infiltration in the rheumatoid arthritis synovial membrane: a comparison of semiquantitative and quantitative analysis.

Microscopic measurement of inflammation in synovial tissue may be important in studies of clinical status, prognosis and response to treatment. The aim of this study was to compare quantitative microscopic analysis of inflammation with a semiquantitative grading system in rheumatoid arthritis (RA) synovial membrane. Knee synovial membrane samples from 16 patients with RA, including paired samples taken before and after treatment in nine patients, were immunostained with anti-CD68 and anti-CD3 monoclonal antibodies using standard techniques. The intensity of macrophage and T-lymphocyte infiltration was measured both by quantitative and semiquantitative techniques, and the results were compared. In a cross-sectional comparison, both methods correlated significantly for lining layer macrophage infiltration, as well as sublining layer macrophage and T-cell infiltration. However, in some patients demonstrating a clinical response to treatment, semiquantitative analysis lacked sensitivity to biologically relevant changes in mononuclear cell infiltration. These observations have important implications for future studies of therapeutic modalities.

Interleukin-1 receptor antagonist.

There are three members of the IL-1 gene family: IL-1 alpha, IL-1 beta, and IL-1ra, IL-1 alpha, and IL-1 beta are both antagonist molecules with many proinflammatory effects. IL-1ra is an antagonist molecule that can inhibit the effect of IL-1 alpha and IL-1 beta by specifically blocking the IL-1 receptor on target effector cells. IL-1 alpha and IL-1 beta are considered to be pivotal cytokines in the pathogenesis of many inflammatory diseases. Anti-IL-1 treatment has been shown to cause amelioration of arthritis in animal models and in RA, suggesting that IL-1ra may be an important therapeutic option in the future management of RA.

Microscopic measurement of synovial membrane inflammation in rheumatoid arthritis: proposals for the evaluation of tissue samples by quantitative analysis.

Previous studies have used various techniques for microscopic analysis of rheumatoid synovium, ranging from rapid analysis of limited areas of tissue to detailed quantification of extensive areas. The sensitivity and reproducibility of these methods have not been tested. This study sought to determine the minimum area of rheumatoid synovium needed to allow accurate microscopic analysis of synovial inflammation. Multiple synovial tissue samples were obtained from patients with rheumatoid arthritis at knee arthroplasty (n = 10), knee arthroscopy (n = 10) and by blind needle biopsy (n = 23). Lining layer thickness, sublining T-cell infiltration and vascularity were measured in all high-power fields (hpf) throughout every sample obtained from each patient. These complete measured results were compared with estimated results from limited numbers of hpf from each patient. It was observed that lining layer thickness estimated from as few as five readings from 3 samples/patient correlated significantly with the measured results obtained from as many as 85 readings/patient [Tau (T) = 0.70-0.94 for the three groups, all P < or = 0.005). Estimated measures of T-cell infiltration and vascularity derived from only 17 randomly selected hpf from 3 samples/patient (equivalent to 1 mm2) correlated significantly with the measured results obtained from up to 150 hpf/patient (T = 0.65-0.94, all P < or = 0.002). Quantitative analysis of inflammation in synovial tissue samples is both accurate and practical when restricted to an evaluation of a limited number of microscopic fields. It is proposed that lining layer thickness may be confidently quantified from five randomly selected readings from three tissue samples, and that sublining T-cell infiltration and vascularity may be quantified from 17 randomly selected hpf from the same samples.

Quantitative microscopic analysis of inflammation in rheumatoid arthritis synovial membrane samples selected at arthroscopy compared with samples obtained blindly by needle biopsy.

OBJECTIVE: To evaluate microscopic measures of inflammation in rheumatoid arthritis synovial tissue samples selected at arthroscopy compared with those obtained blindly by needle biopsy from the suprapatellar pouch (SPP) of the same joint. METHODS: Samples were selected at knee arthroscopy from the SPP and the lateral and medial gutters. Immediately following arthroscopy, a biopsy needle was inserted through the same portal into the SPP by a second investigator, and 3 further samples were obtained blindly. Using standard immunohistologic methods, all samples were analyzed by a single investigator without knowledge of the original tissue location and biopsy technique. Following staining with anti-CD3 and anti-CD68 monoclonal antibodies, T lymphocyte and macrophage infiltration were measured by quantitative analysis. RESULTS: Synovial tissues from 14 patients were analyzed. In comparing microscopic measures of inflammation using the 2 procedures, mean scores of lining cell depth and the percentage of CD68+ cells in the lining layer correlated positively (tau = 0.59, P = 0.003 and tau = 0.73, P = 0.0003, respectively). In the sublining layer, CD3+ cell counts also correlated significantly (tau = 0.71, P = 0.0004). Sublining CD68+ cell counts did not correlate. This was explained by the observation that CD68+ cell infiltration in areas adjacent to articular cartilage was significantly greater than in the SPP (P = 0.01), suggesting preferential trafficking to this site by macrophages, but not by T lymphocytes. Macroscopic appearance at arthroscopy did not predict microscopic features. CONCLUSION: Most microscopic measures of inflammation in synovial tissue samples obtained blindly from the SPP were similar to those determined in samples selected at arthroscopy. However, measurements in samples from the SPP may underestimate the intensity of macrophage infiltration in areas more adjacent to cartilage. These observations have important implications for future study of macrophage function in synovial tissue.