Immunogenicity of subcutaneous TNF inhibitors and its clinical significance in real-life setting in patients with spondyloarthritis.

KEY MESSAGES: Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1-2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.

Impact of physicians' adherence to treat-to-target strategy on outcomes in early rheumatoid arthritis in the NEO-RACo trial.

OBJECTIVES: It is well recognized that medication adherence of rheumatoid arthritis (RA) patients is often poor. As less attention has been paid to physicians' adherence to targeted treatment, we aimed to investigate how it affects outcomes in aggressively treated early RA patients. METHOD: In the new Finnish RA Combination Therapy (NEO-RACo) trial, 99 patients with early active RA were treated, targeting remission, with a combination of methotrexate, sulfasalazine, hydroxychloroquine, and low-dose prednisolone for 2 years, and randomized to receive infliximab or placebo for the initial 6 months. After 2 years, therapy was unrestricted while remission was still targeted. Patients were divided into tertiles by physicians' adherence to treat-to-target, which was evaluated with a scoring system during the initial 2 years. After 5 years of follow-up, the between-tertile differences in remission rates, 28-joint Disease Activity Score (DAS28) levels, radiological changes, cumulative days off work, and the use of anti-rheumatic medication were assessed. RESULTS: Follow-up data were available for 93 patients. Physicians' good adherence was associated with improved remission rates at 2-4 years and lower DAS28 levels throughout the follow-up. In a multivariable model, physicians' adherence was the most important predictor of remission at 3 months and 2 years (p < 0.001 for both). Between 2 and 5 years, biologics were used more often in the tertile of low adherence compared with the other two groups (p = 0.024). No significant differences were observed in radiological progression and cumulative days off work. CONCLUSIONS: Physicians' good adherence is associated with improved remission rates and lesser use of biologics in early RA.

A nationwide cross-sectional overview of patients with rheumatoid arthritis followed in outpatient specialty clinics in Finland.

OBJECTIVES: We aimed to conduct a cross-sectional overview of patients with rheumatoid arthritis (RA) in outpatient specialized clinics in Finland. METHOD: Consecutive patients were enrolled in the study. The data collected comprised demographic, disease- and treatment-related variables. RESULTS: Between November 2011 and May 2012, 890 patients with RA (77% female) were enrolled from 14 sites. The median age was 59.8 years and the time from diagnosis 7.2 years. Values for the Disease Activity Score using 28 joint counts (DAS28) ranged from 0.28 to 6.61 (median 2.55) with 52% and 70% of patients reaching remission and low disease activity, respectively. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies were evident in 70% and 63% of patients, respectively. Median Health Assessment Questionnaire (HAQ) scores with and without aids and devices were 0.75 [interquartile range (IQR) 0.13-1.38] and 0.63 (IQR 0.13-1.13), respectively. Conventional disease-modifying anti-rheumatic drugs (DMARDs) were used by 91% of patients. A triple therapy of methotrexate (MTX), hydroxychloroquine (HCQ), and sulfasalazine (SSZ) was used by 15%, other MTX-based combination by 30%, MTX alone by 20%, and other DMARDs alone or in combination by 26% of patients. In addition, glucocorticoids and biologics were taken by 58% and 21% of patients, respectively. Of the 184 biologics users, 18% were not using DMARDs concomitantly. CONCLUSIONS: Our cross-sectional review of patients with RA revealed that > 50% of patients were in remission according to DAS28. Comparison with previous studies revealed a reduction in disease activity of prevalent RA cases, possibly resulting from increased use of aggressive anti-rheumatic treatments.

Once-monthly oral ibandronate provides significant improvement in bone mineral density in postmenopausal women treated with glucocorticoids for inflammatory rheumatic diseases: a 12-month, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To study the efficacy and safety of once-monthly oral ibandronate in the prevention of glucocorticoid (GC)-induced osteoporosis (GIOP) in postmenopausal women with inflammatory rheumatic diseases. METHOD: A randomized, double-blind, placebo-controlled, parallel-group study of 140 postmenopausal women was conducted. At baseline, the mean lumbar spine (LS) (L1-L4) bone mineral density (BMD) was normal or osteopaenic (T-score ≥ -2.0) and the patients were receiving treatment with 5-15 mg/day of prednisone equivalent. Patients were randomized 1:1 to receive either monthly oral ibandronate 150 mg or placebo for 12 months. All patients received vitamin D and calcium supplements. The primary endpoint was the relative change in mean LS BMD from baseline to 12 months. RESULTS: Mean LS BMD increased significantly by 2.6% and 3.2% from baseline to 6 and 12 months with ibandronate compared to 0.3% and -0.1% with placebo, respectively (p < 0.001). Comparable significant mean increases were also found in trochanter, femoral neck and total hip BMDs at 12 months. Reductions in the serum levels of bone turnover markers C-terminal telopeptide of type I collagen (sCTX), N-terminal propeptide of type I procollagen (P1NP), and tartrate-resistant acid phosphatase (TRACP) were significantly more marked in the ibandronate group than in the placebo group at 1, 6, and 12 months. Adverse events (AEs) were reported at a similar frequency in both groups. A higher proportion of serious AEs (SAEs) were reported in the ibandronate group without emergence of any single SAE. CONCLUSIONS: Once-monthly oral ibandronate provides a significant increase in LS and total hip BMD with an acceptable safety profile in postmenopausal women treated with low-dose GCs for inflammatory rheumatic diseases.

Effect of oral clodronate on structural damage and bone turnover in rheumatoid arthritis.

OBJECTIVES: To study the effect of oral clodronate on structural damage and bone metabolism in rheumatoid arthritis (RA). METHODS: In this 2-year proof-of-concept study, sixty patients with at least moderately active RA were randomised to receive anti-rheumatic therapy alone or together with oral clodronate 1600 mg daily. Radiographs of hands and feet and serum samples for bone biomarkers were studied at baseline and at 24 months. RESULTS: At 24 months, progression of radiographic joint damage was similar in the 2 groups. Clodronate suppressed carboxyterminal cross-linked peptide of type I collagen (p=0.03) and aminoterminal propeptide of type I procollagen (p=0.01). Eight patients (27%) withdrew from clodronate therapy due to adverse drug reactions. CONCLUSIONS: Oral clodronate did not retard the focal bone damage in RA despite its beneficial effect on overall bone metabolism, as judged by the decrease in the reference bone biomarkers.

Rituximab therapy in patients with rheumatoid arthritis refractory or with contraindication to anti-tumour necrosis factor drugs: real-life experience in Finnish patients.

OBJECTIVES: To describe the effects of rituximab therapy in patients with rheumatoid arthritis (RA) in routine clinical practice in Finland. METHODS: Data were collected retrospectively from patient records in five rheumatology clinics in Finland. All RA patients treated during 2005-2008 (n = 81) were included. Information on disease-modifying anti-rheumatic drugs (DMARDs), DMARD combinations, and biologics prior to rituximab use was collected as well as treatment responses after initiating rituximab therapy. The Disease Activity Score using 28 joint counts (DAS28) was used to determine disease activity and European League Against Rheumatism (EULAR) responses. RESULTS: Mean disease duration was 14 (range 0-47) years and the median number of prior DMARDs and biologics used were 7 (1-12) and 2 (0-4), respectively. Efficacy analysis was performed on 57 patients with available DAS28 data at treatment onset and follow-up visits. Median DAS28 declined from 6.07 (3.19-7.70) to 3.99 (1.53-6.55) by the first rituximab treatment course. Altogether 77% of the patients achieved a EULAR response, 26% with a good response including 18% with remission. Furthermore, the patients treated concomitantly with DMARDs other than methotrexate (MTX) achieved a EULAR response slightly more often than the patients on MTX (85% vs. 70%) only. A second course of rituximab was given to 48% of the patients on an average of 9 months after initial therapy, with the median DAS28 score declining further to 3.49 (0.1-5.74). Safety and tolerability assessment of the 81 patients indicates rituximab to be well tolerated. CONCLUSIONS: Rituximab can effectively control disease activity in patients with active disease and poor response to previous therapies, in combination with MTX but also with other DMARDs.

Regulation of MMP-9 (gelatinase B) in activated human monocyte/macrophages by two different types of bisphosphonates.

Metalloproteinases (MMP), particularly MMP-9 produced by the intratumor monocyte/macrophages, play an important role in tumor invasion and metastases. Recent clinical trials in patients with primary breast cancer suggest that bisphosphonates (BP), above all clodronate, may reduce bone metastases. The aim of the present study was to evaluate whether the effects of BPs on cancer dissemination include inhibition of MMP-9 production in human monocyte/macrophages. The effects of clodronate and pamidronate on the MMP-9 expression in and secretion from stimulated human monocyte/macrophages were measured using quantitative reverse transcriptase - polymerase chain reaction (RT-PCR) and enzyme-linked immunoadsorbent assay (ELISA), respectively. The MMP-9 mRNA levels remained relatively stable in the presence of clodronate. In contrast, pamidronate at 30 microM-300 microM increased the mRNA levels 5- to 10-fold. MMP-9 secretion was dose-dependently down-regulated by clodronate whereas pamidronate at 30 microM induced a 50% increase on MMP-9 secretion (p < 0.05), followed by a down-regulation at higher concentrations. The results suggest that MMP-9 is differentially regulated at mRNA and enzyme protein level by BPs, which affect ATP-dependent intracellular enzymes (clodronate) or post-translational modification of GTPases (pamidronate). These findings may have implications for the therapeutic use of these compounds.

Clinical and biochemical response to single infusion of clodronate in active rheumatoid arthritis--a double blind placebo controlled study.

OBJECTIVE: To investigate the efficacy and tolerability of intravenous clodronate in patients with rheumatoid arthritis (RA). TREATMENT AND METHODS: Twenty-six patients with active RA were randomly allocated to receive either a single iv. infusion of placebo or 600 mg clodronate. Efficacy and safety were assessed weekly during the following three weeks by clinical and laboratory evaluations. RESULTS: Serum osteocalcin and carboxyterminal propeptide of type I procollagen (markers of bone metabolism) were significantly decreased in the clodronate group at the end of the study, whereas the indices of disease activity including number of swollen joints, number of tender joints, patient's and doctor's estimation of condition (visual analogue scale), erythrocyte sedimentation rate and serum C-reactive protein level were not affected by clodronate treatment. No serious adverse effects were observed. CONCLUSIONS: A single infusion of clodronate in patients with RA was safe and caused a decline in the markers of bone metabolism, but this short-term treatment did not suppress disease activity. Results from recent clinical and preclinical studies, however, suggest that the anti-inflammatory efficacy of clodronate requires liposome encapsulation.

Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate.

The hypothesis of the present work was that the pannus tissue overlying the articular hard tissues has an aggressive phenotype and contains the newly discovered collagenase-3 and its endogenous inducers and activators. We therefore analyzed the eventual presence of collagenase-3 and its regulation at the pannus-cartilage junction. Collagenase-3 mRNA (in situ hybridization) and enzyme protein (ABC and immunofluorescence staining) were found in the pannocytes in the pannus-hard tissue junction. Inflammatory round cells associated with the critical interface contained TNF-alpha and IL-1beta. These cytokines induced collagenase-3 secretion in cultured rheumatoid synovial fibroblasts. Procollagenase-3 activators, stromelysin-1, 72 kDa type IV collagenase/gelatinase and membrane-type 1-MMP, were also found in the pannus-hard tissue junction. Active collagenase-3 was inhibited with alendronate (IC50 = 500-750 microM). Collagenase-3, due to its substrate profile and local synthesis in a milieu favoring its activation, might play a major role in the degradation of cartilage type II and bone type I collagens. Alendronate, at concentrations attainable in vivo, is able to inhibit collagenase-3. This might offer an option to control collagenase-3-mediated tissue destruction in rheumatoid arthritis.

Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis.

OBJECTIVE: To define the pattern of mRNA expression of all human matrix metalloproteinases (MMPs) described to date in rheumatoid arthritis (RA) and traumatic synovial membrane, in order to differentiate between a physiological tissue remodelling pattern and that associated with inflammatory tissue destruction. METHODS: Analysis of SwissProt protein and EMBL/GenBank nucleotide sequence banks, protein sequence alignment, reverse transcriptase-polymerase chain reaction and nucleotide sequencing were used. RESULTS: MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-11 (stromelysin-3) and MMP-19 were constitutively expressed. MMP-1 (fibroblast type collagenase), MMP-9 (gelatinase B) and MMP-14 (MT1-MMP) were expressed in all RA, but only in 55-80% of trauma samples. MMP-13 (collagenase-3) and MMP-15 (MT2-MMP) were expressed exclusively in RA (80-90% of the samples). MMP-20 (enamelysin) was absent and MMP-8 (collagenase-2) was rarely found in RA or trauma. All other MMPs (-7, -10, -12, -16, -17) had an intermediate pattern of expression. CONCLUSIONS: Some MMPs without interstitial collagenase activity seem to have a constitutive pattern of expression and probably participate in physiological synovial tissue remodelling. Some MMPs are exclusively associated to RA synovitis, for example, MMP-13, which preferentially degrades type II collagen and aggrecan, and MMP-15, which activates proMMP-2 and proMMP-13 and is involved in tumour necrosis factor alpha processing. This clear cut rheumatoid/inflammatory MMP profile, more complex than has been previously appreciated, may facilitate inflammatory tissue destruction in RA.

Inhibition of matrix metalloproteinase-1 by dichloromethylene bisphosphonate (clodronate).

Interstitial collagenase present in human jaw cyst extract and purified human fibroblast-type collagenase (MMP-1) were both efficiently inhibited in vitro by clodronate, an osteoactive, antiresorptive bisphosphonate. The IC50 of clodronate to inhibit MMP-1 is 150 microM. These findings suggest an extended and hitherto undescribed properties for clodronate/biphosphonates in prevention and treatment of tissue degradation in both bone and soft tissue destructive diseases.