RHEUMASEARCH

Synovial tissues concentrate APRIL.

Arthritis Res Ther 2009 Sep 29;11(5):R144.
 
INTRODUCTION: A proliferation-inducing ligand (APRIL) from the TNF family, owing to its role in the generation and survival of plasma cells (PCs), is currently targeted for rheumatoid arthritis (RA) treatment. However, little is known about APRIL expression in RA lesions, hampering our understanding of the way APRIL may modulate this autoimmune disease.
 
METHODS: We performed immunological staining of human normal, non-RA and RA synovial tissues with a pair of antibodies specifically recognizing APRIL-producing cells and secreted APRIL.
 
RESULTS: We detected significant amounts of secreted APRIL in normal synovium mostly concentrated around blood vessels and at the lining layer, but no cells producing APRIL. Meanwhile, we observed that blood neutrophils constitutively secrete APRIL, indicating that blood APRIL may diffuse into the synovium via its fenestrated vessels. Synovium from non-RA and RA patients retained similarly secreted APRIL, but in this case APRIL-producing cells, including neutrophils and macrophages, were present in the tissue. Notably, PCs--when present in RA synovium--accumulated in areas of APRIL retention, spreading from blood vessels towards the lining layer. CONCLUSIONS: PCs accumulate in synovial zones rich in secreted APRIL, consistent with a pro-survival role of APRIL for PCs in RA. The concentration of APRIL by normal synovium indicates that this tissue may constitute a proper environment for PCs even before RA onset.

Interleukin-33 is biologically active independently of caspase-1 cleavage.

J Biol Chem 2009; May 22.
 
The new interleukin (IL)-1 family cytokine IL-33 is synthesized as a 30-kDa precursor. Like pro-IL-1beta, human pro-IL-33 was reported to be cleaved by caspase-1 to generate an 18-kDa fragment, which is sufficient to activate signaling by the IL-33 receptor T1/ST2. However, the proposed caspase-1 cleavage site is poorly conserved between species. In addition, it is not clear whether caspase-1 cleavage of pro-IL-33 occurs in vivo and whether, as for IL-1beta, this cleavage is a prerequisite for IL-33 secretion and bioactivity. In this study, we further investigated caspase-1 cleavage of mouse and human pro-IL-33 and assessed the potential bioactivity of the IL-33 precursor. We observed the generation of a 20-kDa IL-33 fragment in cell lysates, which was enhanced by incubation with caspase-1. However, in vitro assays of mouse and human pro-IL-33 indicated that IL-33 is not a direct substrate for this enzyme. Consistently, caspase-1 activation in THP-1 cells induced cleavage of pro-IL-1beta but not of pro-IL-33, and activated THP-1 cells released full-length pro-IL-33 into culture supernatants. Finally, addition of full-length pro-IL-33 induced T1/ST2-dependent IL-6 secretion in mast cells. However, we observed in situ processing of pro-IL-33 in mast cell cultures, and it remains to be determined whether full-length pro-IL-33 itself indeed represents the bioactive species. In conclusion, our data indicate that pro-IL-33 is not a direct substrate for caspase-1. In addition, our results clearly show that caspase-1 cleavage is not required for pro-IL-33 secretion and bioactivity, highlighting major differences between IL-1beta and IL-33.
 

Magnetically retainable microparticles for drug delivery to the joint: efficacy studies in an antigen-induced arthritis model in mice.

Arthritis Res Ther 2009; 11: R72
 
INTRODUCTION: Conventional corticosteroid suspensions for the intra-articular treatment of arthritis suffer from limitations such as crystal formation or rapid clearance from the joint. The purpose of this study was to investigate an innovative alternative consisting of corticosteroid encapsulation into magnetically retainable microparticles.
 
METHODS: Microparticles (1 or 10 microm) containing both superparamagnetic iron oxide nanoparticles (SPIONs) and dexamethasone 21-acetate (DXM) were prepared. In a preliminary study, we compared the persistence of microparticles of both sizes in the joint. A second study evaluated the influence of a subcutaneously implanted magnet near the knee on the retention of magnetic microparticles in the joint by in vivo imaging. Finally, the efficacy of 10-microm microparticles was investigated using a model of antigen-induced arthritis (AIA) in mice. Phosphate-buffered saline, DXM suspension, SPION suspension, blank microparticles and microparticles containing only SPIONs were used as controls. Arthritis severity was assessed using 99mTc accumulation and histological scoring.
 
RESULTS: Due to their capacity of encapsulating more corticosteroid and their increased joint retention, the 10-microm microparticles were more suitable vectors than the 1-microm microparticles for corticosteroid delivery to the joint. The presence of a magnet resulted in higher magnetic retention in the joint, as demonstrated by a higher fluorescence signal. The therapeutic efficacy in AIA of 10-microm microparticles containing DXM and SPIONs was similar to that of the DXM suspension, proving that the bioactive agent is released. Moreover, the anti-inflammatory effect of DXM-containing microparticles was more important than that of blank microparticles or microparticles containing only SPIONs. The presence of a magnet did not induce a greater inflammatory reaction.
 
CONCLUSIONS: This study confirms the effectiveness of an innovative approach of using magnetically retainable microparticles as intra-articular drug delivery systems. A major advantage comes from a versatile polymer matrix, which allows the encapsulation of many classes of therapeutic agents (for example, p38 mitogen-activated protein kinase inhibitors), which may reduce systemic side effects.
 

Which Subgroup of Rheumatoid Arthritis Patients Benefits From Switching to Rituximab Versus Alternative Anti-TNF Agents After Previous Failure to Anti-TNF Agent?

Ann Rheum Dis 2009; May 4
 
BACKGROUND: Patients with rheumatoid arthritis (RA) with an inadequate response to TNF antagonists (aTNFs) may switch to an alternative aTNF or start treatment from a different class of drugs, such as rituximab (RTX). It remains unclear in which clinical settings these therapeutic strategies offer most benefit.
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OBJECTIVE: To analyse the effectiveness of RTX versus alternative aTNFs on RA disease activity in different subgroups of patients.
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METHODS: A prospective cohort study of patients with RA who discontinued at least one aTNF and subsequently received either RTX or an alternative aTNF, nested within the Swiss RA registry (SCQM-RA) was carried out. The primary outcome, longitudinal improvement in 28-joint count Disease Activity Score (DAS28), was analysed using multivariate regression models for longitudinal data and adjusted for potential confounders.
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RESULTS: Of the 318 patients with RA included; 155 received RTX and 163 received an alternative aTNF. The relative benefit of RTX varied with the type of prior aTNF failure: when the motive for switching was ineffectiveness to previous aTNFs, the longitudinal improvement in DAS28 was significantly better with RTX than with an alternative aTNF (p = 0.03; at 6 months, -1.34 (95% CI -1.54 to -1.15) vs -0.93 (95% CI -1.28 to -0.59), respectively). When the motive for switching was other causes, the longitudinal improvement in DAS28 was similar for RTX and alternative aTNFs (p = 0.40). These results were not significantly modified by the number of previous aTNF failures, the type of aTNF switches, or the presence of co-treatment with a disease-modifying antirheumatic drug.
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CONCLUSION: This observational study suggests that in patients with RA who have stopped a previous aTNF treatment because of inffectiveness changing to RTX is more effective than switching to an alternative aTNF.
 

Comparison of Drug Retention Rates and Causes of Drug Discontinuation Between Anti-TNF Agents in Rheumatoid Arthritis.

Arthritis Care Res 2009; 61: 560-568
 
OBJECTIVE: Tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of severe rheumatoid arthritis (RA), yet drug discontinuation is common. The aim of this study was to compare treatment retention rates and specific causes of anti-TNF discontinuation in a population-based RA cohort.
 
METHODS: All patients treated with etanercept, infliximab, or adalimumab within the Swiss Clinical Quality Management RA cohort between 1997 and 2006 were included in the study. Causes of treatment discontinuation were broadly categorized as adverse events (AEs) or nontoxic causes, and further subdivided into specific categories. Specific causes of treatment interruption were analyzed using a Cox proportional hazards model and adjusted for potential confounders.
 
RESULTS: A total of 2,364 anti-TNF treatment courses met the inclusion criteria. Treatment discontinuation was reported 803 times: 309 with etanercept, 249 with infliximab, and 245 with adalimumab. Drug inefficacy represented the largest single cause of treatment discontinuation (55.8% of cases). The median time of receiving anti-TNF therapy was 37 months, but discontinuation rates differed between the 3 anti-TNF agents (P < 0.001), with shorter retention rates for infliximab (hazard ratio [HR] 1.24, 99% confidence interval [99% CI] 1.01-1.51). The specific causes of treatment discontinuation revealed an increased risk of AEs with infliximab (HR 1.4, 99% CI 1.003-1.96), mostly due to an increased risk of infusion or allergic reactions (HR 2.11, 99% CI 1.23-3.62). Other discontinuation causes were equally distributed between the anti-TNF agents.
 
CONCLUSION: In this population, infliximab was associated with higher overall discontinuation rates compared with etanercept and adalimumab, which is mainly due to an increased risk of infusion or allergic reactions.
 

Anakinra is a Possible Alternative in the Treatment and Prevention of Acute Attacks of Pseudogout in End-Stage Renal Failure.

Joint Bone Spine 2009; 76: 424-6
 
We describe the case of a 71-year-old man with recurrent pseudogout attacks affecting multiple joints. He had end-stage renal failure that contra-indicated the use of non-steroidal anti-inflammatory drugs and was resistant to therapy with glucocorticoids. Based on the recent findings that interleukin (IL)-1beta is involved in crystal-induced inflammation, the patient received anakinra, a specific IL-1 inhibitor, in order to treat an acute attack of pseudogout. In addition, anakinra was administered as preventive therapy 3days per week after each hemodialysis session. Under this treatment, he did not present any severe episode of arthritis after a follow-up of 8 months. This observation suggests that anakinra is efficacious and safe for the prevention of crystal-induced arthritis in patients with severe renal failure.
 

Adaptive immune response in JAM-C deficient mice: Normal initiation but reduced IgG memory.

J Immunol 2009; 182: 4728-4736
 
We have recently shown that junctional adhesion molecule (JAM)-C-deficient mice have leukocytic pulmonary infiltrates, disturbed neutrophil homeostasis, and increased postnatal mortality. This phenotype was partially rescued when mice were housed in ventilated isolators, suggesting an inability to cope with opportunistic infections. In the present study, we further examined the adaptive immune responses in JAM-C(-/-) mice. We found that murine conventional dendritic cells express in addition to Mac-1 and CD11c also JAM-B as ligand for JAM-C. By in vitro adhesion assay, we show that murine DCs can interact with recombinant JAM-C via Mac-1. However, this interaction does not seem to be necessary for dendritic cell migration and function in vivo, even though JAM-C is highly expressed by lymphatic sinuses of lymph nodes. Nevertheless, upon immunization and boosting with a protein Ag, JAM-C-deficient mice showed decreased persistence of specific circulating Abs although the initial response was normal. Such a phenotype has also been observed in a model of Ag-induced arthritis, showing that specific IgG2a Ab titers are reduced in the serum of JAM-C(-/-) compared with wild-type mice. Taken together, these data suggest that JAM-C deficiency affects the adaptive humoral immune response against pathogens, in addition to the innate immune system.
 

Non infectious lupus pericarditis: a retrospective hospital-based observation in Yaounde – Cameroun.

Clin Rheumatol 2009; 28: 465-468
 
To determine the frequency of non-infectious lupus pericarditis in patients with systemic lupus erythematosus (SLE) seen in the Yaoundé Central and General Hospitals. A descriptive retrospective study was carried out in Rheumatology Units of Yaoundé Central and General Hospitals, from January 2001 to January 2004. Inclusion criteria: patients fulfilling the American College of Rheumatology criteria for SLE and presenting with pericarditis. The study consisted of 22 female and one male SLE patients with a mean age of 26 years (range=13-65). Ten out of 23 patients (43%) presented pericarditis with a mean duration of illness before the diagnosis of pericarditis of 2 years. Pericardial rub was the commonest sign (seven cases), followed by dyspnea (six cases) and chest pain (six cases). The diagnosis of pericarditis was proven by echocardiography in all cases. Typical serological findings included anti-nuclear antibodies, anti-double-stranded DNA, and anti-Sm antibodies. Chest X-ray revealed cardiomegaly in all the patients. Electrocardiogram showed abnormal repolarization (seven patients) and low voltage QRS complexes (three cases). Treatment consisted of steroids administration. Four patients had relapse of pericarditis during subsequent lupus flares. This short series shows that non-infectious pericarditis is common in SLE patients in Africa.
 

Clinical Experience with Mycophenolate Mofetil in Systemic Autoimmune Conditions Refractory to Common Immunosuppressive Therapies.

Swiss Med Wkly 2009; 139: 41-46
 
OBJECTIVES: Standard therapies against inflammatory rheumatic diseases consist of immunosuppressive drugs with high toxicities and many side effects. Except in the treatment of systemic lupus erythematosus with renal involvement, controlled studies with mycophenolate mofetil (MMF) are lacking in other autoimmune and inflammatory systemic diseases. Here we describe our clinical experience with MMF in several unusual indications.
 
METHODS: We collected data including serological findings, adverse events and response to treatment in eleven patients with autoimmune diseases including systemic lupus erythematosus (SLE), mixed connective tissue disease MCTD), polymyositis (PM), diffuse systemic sclerosis that were treated in our rheumatology unit.
 
RESULTS: Our results show remission in ten patients with minimal side effects and reduced prednisone dosage. The median dose of MMF was 2 g per day. Adverse events were limited, with one case of leucopenia, one tachycardia and one colitis. One patient definitively stopped the treatment because of side effects.
 
CONCLUSIONS: MMF seems to be a very powerful and attractive alternative medication in the treatment of immune-mediated inflammatory diseases. The good tolerance and safety profile makes it an excellent therapeutic option permitting a global reduction of corticosteroids doses.
 

Inhibition of IL-33 signaling attenuates the severity of experimental arthritis.

Arthritis Rheum 2009 ; 60 : 738-749
 
OBJECTIVES: Interleukin-33 (IL-33; or, IL-1F11) was recently identified as the ligand of the IL-1 family receptor T1/ST2. The aim of this study was to examine IL-33 production in human and mouse joints and to investigate the role of IL-33 and T1/ST2 in experimental arthritis.
 
METHODS: IL-33 expression was examined in human synovial tissue, rheumatoid arthritis (RA) synovial fibroblasts, and arthritic mouse joints. Mice with collagen-induced arthritis (CIA) were treated with blocking anti-ST2 antibody or control antibody beginning at the onset of disease. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (LN) cell responses were examined ex vivo, and joint messenger RNA (mRNA) was used for expression profiling.
 
RESULTS: IL-33 was highly expressed in human RA synovium. In cultured synovial fibroblasts, IL-33 expression was strongly induced by IL-1beta and/or tumor necrosis factor alpha. Furthermore, IL-33 mRNA was detected in the joints of mice with CIA and increased during the early phase of the disease. Administration of a blocking anti-ST2 antibody at the onset of disease attenuated the severity of CIA and reduced joint destruction. Anti-ST2 antibody treatment was associated with a marked decrease in interferon-gamma production as well as with a more limited reduction in IL-17 production by ex vivo-stimulated draining LN cells. Finally, RANKL mRNA levels in the joint were reduced by anti-ST2 treatment.
 
CONCLUSIONS: IL-33 is produced locally in inflamed joints, and neutralization of IL-33 signaling has a therapeutic effect on the course of arthritis. These observations suggest that locally produced IL-33 may contribute to the pathogenesis of joint inflammation and destruction.
 

The Effectiveness of Leflunomide as Co-Therapy of TNF inhibitors in Rheumatoid Arthritis. A Population Based Study.

Arthritis Rheum 2009 ; 60 : 738-749
 
BACKGROUND: Randomised trials have demonstrated that the efficacy of anti-tumour necrosis factor (TNF) agents is significantly increased by concomitant methotrexate (MTX) in rheumatoid arthritis (RA). In clinical routine, anti-TNF agents are commonly prescribed with other disease-modifying antirheumatic drugs (DMARDs) than MTX, however their effectiveness in combination with anti-TNF agents is not well established.
 
OBJECTIVES: To compare the effectiveness of leflunomide (LEF) and other conventional DMARDs with MTX as co-therapy to anti-TNF agents in RA.
 
METHODS: All patients on anti-TNF agents and conventional DMARDs within the Swiss Clinical Quality Management SCQM)-RA database were included (n = 1218) and categorised according to the type of co-therapy into anti-TNF+MTX (n = 842), anti-TNF+LEF (n = 260) and anti-TNF+other DMARDs (n = 116). Drug discontinuation rates and incidence of toxic side effects were analysed using Cox proportional hazard models. Progression of radiographic damage, the evolution of functional disability and the improvement of RA disease activity were analysed using longitudinal regression models, adjusting for potential confounders.
 
RESULTS: The overall discontinuation rates of anti-TNF and conventional DMARD combination therapies were relatively high with a median survival of only 16 months (interquartile range (IQR): 10-37), but they did not differ between the three regimens (p = 0.69). The progression of radiographic damage (p = 0.77), functional disability (p = 0.09) and RA disease activity (p = 0.33) were also similar between the different regimen. In addition, no significant difference in the frequency of adverse events emerged.
 
CONCLUSIONS: Overall these results suggest that LEF and potentially other conventional DMARDs offer an effective and safe alternative to MTX as co-therapy in combination with anti-TNF agents.
 

Mutations in the IL-1RN locus leads to autoinflammation.

Nat Reviews Rheumatology 2009; 5: 480-2
 

 

The biological and clinical importance of the 'new generation' cytokines in rheumatic diseases.

Arthritis Res Ther. 2009 May 19; 11: 230
 
A better understanding of cytokine biology over the last two decades has allowed the successful development of cytokine inhibitors against tumour necrosis factor and interleukin (IL)-1 and IL-6. The introduction of these therapies should be considered a breakthrough in the management of several rheumatic diseases. However, many patients will exhibit no or only partial response to these therapies, thus emphasising the importance of exploring other therapeutic strategies. In this article, we review the most recent information on novel cytokines that are often members of previously described cytokine families such as the IL-1 superfamily (IL-18 and IL-33), the IL-12 superfamily (IL-27 and IL-35), the IL-2 superfamily (IL-15 and IL-21), and IL-17. Several data derived from experimental models and clinical samples indicate that some of these cytokines contribute to the pathophysiology of arthritis and other inflammatory diseases. Targeting of some of these cytokines has already been tested in clinical trials with interesting results.
 

Relationship between gamma-interferon and interleukin-17 in Chlamydia trachomatis reactive arthritis.

Clin Exp Rheumatol 2009; 27: 885-886