Matrix Metalloproteinases-3 Baseline Serum Levels in Early Rheumatoid Arthritis Patients without Initial Radiographic Changes: A Two-Year Ultrasonographic Study.

OBJECTIVE: To investigate the association of high baseline serum levels of metalloproteinases-3 (MMP-3) with structural damage to hand and feet joints, assessed by ultrasonography (US), in patients with early, treatment-naïve rheumatoid arthritis (RA), without initial X-ray-visible erosions, during 24 months follow-up. METHODS: Sixty-three early RA (European League Against Rheumatism/American College of Rheumatology 2010), disease-modifying anti-rheumatic drugs/glucocorticoid naïve patients (mean age 53.4 ± 14.1) with symptom duration ≤12 months, had baseline serum levels of MMP-3 tested. OMERACT US group definition was used to detect the presence, as well as longitudinal diameter of erosions by US at study entry and after 24 months, at the level of wrists, metacarpophalangeal (MCP2/MCP5) joints of both hands, and fifth metatarsophalangeal joints. RESULTS: Complete data were collected from 52 out of 63 patients. High baseline serum levels of MMP-3 (MMP-3-positive) were found in 46/63 patients. 122 bone erosions in total (1.9 bone erosions/patients) were detected by US at baseline visit and 213 erosions (4.3/patients) after 24 months. MMP-3 positive patients had significantly higher total number of erosions than MMP-3-negative (p = 0.039) and higher increase in size of bone erosions in the feet but not in the hand joints after follow-up (OR 4.82 [1.23-18.9], p = 0.024; OR 1.17 [0.320-4.26], p = 0.816 respectively). CONCLUSION: After 2 years of follow-up, US assessment showed a higher number of new bone erosions in MMP-3-positive compared to MMP-3-negative patients with early RA and no visible initial radiographic changes. High baseline levels of MMP-3 predict significantly higher structural damage progression at the level of feet, but not at the level of hand joints.

Activity and expression of dipeptidyl peptidase IV on peripheral blood mononuclear cells in patients with early steroid and disease modifying antirheumatic drugs naïve rheumatoid arthritis.

BACKGROUND: Dipeptidyl peptidase IV (DPPIV/CD26) plays an important role in T cell activation and immune regulation, however the role of this enzyme in early rheumatoid arthritis (eRA) has not been clearly defined. The aim of this study was to determine the serum activity of DPPIV, its expression on peripheral blood mononuclear cells (PBMC) and to examine possible correlations with disease activity (DAS28) in untreated patients with eRA. METHODS: The study included 50 patients newly diagnosed with RA, who had not received any corticosteroid or disease modifying antirheumatic drugs (DMARD) therapy and whose conventional radiographs of hands and feet showed no structural damage. The control group consisted of 40 healthy volunteers. Also, 30 patients with chronic RA (cRA) were examined. The serum activity of DPPIV was determined by the direct photometric method, while expression of CD26 on PBMC was determined using flow cytometry. RESULTS: Decreased DPPIV serum activity was detected in patients with eRA and cRA compared to the control group (p=0.024, p<0.0001, respectively). Although, the percentage of overall CD26+ white blood cells (WBC) was significantly decreased in eRA patients (p<0.001), the percentage of CD26+ lymphocytes and monocytes and mean fluorescence intensity of CD26 on these cells in eRA patients showed no significant difference compared to healthy volunteers. DAS28 showed no significant correlation with CD26 expression or DPPIV serum activity, but a significant inverse correlation between the duration of symptoms and DPPIV serum activity was observed. CONCLUSIONS: Our results show that a decrease in DPPIV serum activity, but not CD26 expression, is present in an early stage of rheumatoid arthritis.

Inter & intra-observer reliability of grading ultrasound videoclips with hand pathology in rheumatoid arthritis by using non- sophisticated internet tools (LUMINA study).

AIM: To evaluate the inter- and intraobserver agreement of a group of European rheumatologist ultrasonographers in grading musculoskeletal ultrasound videoclips posted on the Internet by using a non-sophisticated electronic environment. METHODS: Forty short movie clips (less than 30 secs) were made available over the Internet to all participants. Normal and pathological RA hand joints and tendons were included in the movie clips. In the first phase 30 investigators from European countries were invited to evaluate the clips and to interpret/grade them. No instruction session was held prior to the initiation of the study. For synovitis the requested scoring system included 0 to3 grades and for tenosynovitis a binary variable 0/1; separate evaluations were performed for gray scale (GS) and Power Doppler (PD) examinations. In the second phase the responders were asked to grade the same clips in a different order without having access to their first grading scale. Light's k and Cohen's k were used to analyse inter- and intraobserver reliability. RESULTS: Twenty two European rheumatologists agreed to finalise both study phases. Mean Cohen's κ for intraobserver reliability was 0.614/0.689 for tenosynovitis GS/PD and 0.523/0.621 for synovitis GS/PD. Light's k for interobserver reliability was 0.503 for tenosynovitis evaluation and 0.455 for global (synovitis and tenosynovitis) evaluation. Mean global overall agreement was 84.95% (90.2% for global synovitis). CONCLUSIONS: An over-the-net US evaluation and grading has shown moderate to good reliability. The results could be improved if a training session is added at the beginning of the study.

Ultrasonographic measures of synovitis in an early phase clinical trial: a double-blind, randomised, placebo and comparator controlled phase IIa trial of GW274150 (a selective inducible nitric oxide synthase inhibitor) in rheumatoid arthritis.

OBJECTIVES: To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA). METHODS: A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area. RESULTS: At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). CONCLUSIONS: This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.

Construct validity and reliability of ultrasound disease activity score in assessing joint inflammation in RA: comparison with DAS-28.

OBJECTIVE: To investigate the construct validity and reliability of US DAS compared with 28-joint DAS (DAS-28) in assessing joint inflammation and in prediction of structural damage in patients with RA. METHODS: Ninety patients with active RA were prospectively recruited and followed up during the 6 months of treatment. The patients underwent clinical, laboratory and X-ray assessment, along with blinded power Doppler US (PDUS) and grey-scale (GS) US (GSUS) examination at baseline and 6 months. A subgroup of 25/90 randomly assigned patients underwent MRI examination of their hands at baseline. A PDUS examination of 22 joints and GSUS examination for effusion/hypertrophy (E/H) of 28 joints were performed by two independent examiners, blinded to clinical findings. E/H was qualitatively assessed as absent or present, and PD signal was semi-quantitatively graded from 0 to 3. PDUS score for synovitis in 22 joints and GS score for E/H in 28 joints were included in US DAS calculation. Clinical scoring, PDUS and GSUS inter-observer reliability were evaluated. RESULTS: Strong correlation was found between US DAS and standard assessment of disease activity such as the DAS-28, ESR and CRP levels. Correlation between US DAS and patients' and physicians' visual analogue scale of activity was moderate, whereas correlations of US DAS with Health Assessment Questionnaire - Disability Index (HAQ-DI) and Short Form 36 Health Survey (SF-36) were weak to moderate. US DAS correlated with X-ray, MRI and US parameters and rates of joint damage. CONCLUSION: US DAS better anticipated future joint damage than standard DAS-28.

[Therapy of lupus nephritis with standard therapeutic protocols and cyclosporine]. / Terapija lupusnog nefritisa standardnim protokolima lecenja i ciklosporinom.

The study carried out was at the Department of Nephrology, Military Medical Academy, over the period from 1996 to 2001. Different types of lupus nephritis were documented in 42 patients and were treated with standard therapeutic protocols (corticosteroids, the pulse dose of cyclophosphamide + corticosteroids) and cyclosporine in the target serum concentration of 100-120 ng/ml along with pronisone of 15-20 mg per day. The different degree of damaged renal function was observed. Renal biopsy was performed in 13 patients and in one patient rebiopsy was done. Twenty one patients were treated only with corticosteroids (remission in 23.8% of cases), with cyclophosphamide + corticosteroids 33 patients (remission in 42.4% of cases) and cyclosporine + corticosteroids 12 patients (remission in 91.7% of cases). The pulse therapy with cyclophosphamide in combination with corticosteroids, and cyclosporine in combination with lower doses of corticosteroids was statistically more successful in comparison with corticosteroids monotherapy (p < 0.01). Remission was found in 73.8% of patients, terminal renal weakness was observed in 7 patients, and fatal outcome in 4 patients. We recommend the pulse therapy of cyclophosphamide in combination with corticosteroids in the treatment of severe clinical forms of lupus nephritis, and in refractive forms cyclosporine in combination with low doses of corticosteroids.

[Comparison of various cyclophosphamide treatment regimens on the course and outcome of lupus nephritis ]. / Poredjenje dejstva razlicitih rezima lecenja ciklofosfamidom na tok i ishod lupusnog nefritisa.

INTRODUCTION: Immunosuppressive drugs, particularly cyclophosphamide, are widely accepted as the treatment of choice for severe, proliferative lupus nephritis. However, there is no consensus with regard to: 1) the dose required for achieving control of disease activity; 2) duration of cyclophosphamide therapy after the achievement of treatment response; 3) treatment of lupus nephritis relapses [1-5]. In the Institute of Rheumatology, Belgrade, two regimens of intravenous cyclophosphamide have been introduced in the treatment of lupus nephritis patients years ago. The first has comprised the so called "small pulses" that have been used since 1985, and the second has been standard protocol with high doses of cyclophosphamide, accepted in 1990. Results of these follow-up studies were published previously [6-8]. AIM: The aim of this study was to compare the efficacy of two regimens of intravenous pulse cyclophosphamide in the treatment of patients with severe lupus nephritis. METHODS: We analyzed the results of two follow-up studies comprising patients with lupus nephritis, treated with cyclophosphamide: 1) 41 females treated with "small pulses", consisting of 400 mg of cyclophosphamide weekly at treatment onset, followed by the same dose fortnightly for the next three months, and finally on monthly basis for several months or years; 2) 33 patients (29 females and 4 males) treated with standard protocol consisting of "induction phase" with 6 monthly pulses of high doses (0.5-0.75 g/m2 body surface), followed by "maintenance phase" with quarterly pulses for additional 1-2 years. The evaluation of long-term treatment effects was based on remission/response rate [9], number of patients with renal failure, end-stage renal disease and death outcome. RESULTS: Groups of patients were quite comparable with respect to their demographic and clinical data (Table 1). The only difference was much higher frequency of renal biopsy in "high dose" cyclophosphamide pulse (85% versus 32%), confirming the presence of proliferative lupus nephritis. Cummulative dose of cyclophosphamide and treatment duration were not significantly different between treatment groups. At the end of the follow-up, distributions of favorable (remission/response) and unfavorable outcome was similar (p = 0.831; Mann-Whitney U test), as well as dynamics of remission achieving (p = 0.068; Log-rank test), cummulative renal survival (p = 0.129; Log-rank test) and patient survival (p = 0.577; Log-rank test). DISCUSSION: Similar efficacy of two different cyclophosphamide regimens in our patients with lupus nephritis was not surprising considering that cummulative cyclophosphamide doses and treatment duration were similar obtaining similar control of disease. During induction phase of treatment, patients on small pulses have received even higher cummulative dose of cyclophosphamide. Aggressive immunosuppressive treatment with cyclophosphamide has significantly ameliorated the outcome of lupus nephritis. In different studies, rate of assessed clinical response is 60-80 [13-17]. Significant proportion (42%) of patients who achieved partial remission, as well as complete remission, developed flare of renal disease several months after the end of the treatment, necessitating restarting of pulse cyclophosphamide therapy. The results of our study were in accordance with those results, especially with results of Mosca et al. [18] who have applied the duration of treatment similar to ours in high pulse regimen. CONCLUSION: Treatment response did not differ between two different cyclophosphamide regimens (small pulses and standard high doses protocol), but standard protocol seemed to be more comfortable for patients. We recommend standard protocol for patients with biopsy proved proliferative lupus nephritis as a gold treatment standard. However, sustained remission of proliferative lupus nephritis is a goal that still remains to be achieved.