Ernest Brahn

Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis.

Angiogenesis inhibition, long studied in the treatment of malignancies, has begun to emerge as a potential therapeutic approach in managing inflammatory arthritis, particularly rheumatoid arthritis. The growth of new vessels is required for the development of the rheumatoid pannus, which then leads to extensive synovial inflammation and joint destruction. Vascular endothelial growth factor is the best studied mediator of angiogenesis, and several therapies have been developed that specifically target this molecule. Several other angiogenesis mediators, such as the angiopoietin−TIE system, hypoxia inducible factor and integrin αVβ3, as well as naturally occurring inhibitors of angiogenesis, are also being investigated as potential therapeutic targets. Additionally, there are a number of drugs, including paclitaxel, 2-methoxyestradiol and fumagillin analogs, that might have a role in inhibiting angiogenesis and, thus, in treating proliferative synovitis.

A 24-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy of Oral SCIO-469, a p38 Mitogen-activated Protein Kinase Inhibitor, in Patients with Active Rheumatoid Arthritis

Objective. To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA). Methods. Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26. Results. Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469. Conclusion. In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation.

A novel angiogenesis inhibitor suppresses rat adjuvant arthritis.

Rat adjuvant arthritis (AA) is an animal model of rheumatoid arthritis in which pannus formation and destruction of joints occur after immunization with complete Freunds adjuvant. Neovascularization is present within the synovium and may be critical for pannus growth. In this study the effects of a novel angiogenesis inhibitor, AGM-1470, on AA were evaluated. Lewis rats were immunized with CFA to induce arthritis. AGM-1470 treatment was initiated prior to arthritis onset (preventative protocol) or administered to rats with established disease (suppressive protocol). The severity of synovitis and the immunologic status of all rats were then evaluated. Using clinical and radiographic criteria, AGM-1470 significantly reduced arthritis incidence (preventative protocol) (P < 0.01) and disease severity (both protocols, P < 0.001, compared to controls) without affecting T cell function in vitro or phenotype in vivo. Additionally, histologic sections from control rats revealed marked pannus formation, destruction of bone/cartilage, and neovascularization. These findings were absent in AGM-1470-treated rats. AGM-1470 may offer a new treatment option for rheumatoid arthritis and other angiogenesis-dependent diseases.

Periostitis and hypertrophic pulmonary osteoarthropathy: report of 2 cases and review of the literature.

OBJECTIVES To demonstrate the clinical spectrum of hypertrophic osteoarthropathy (HOA). METHODS We report 2 cases of HOA and performed a computer-assisted search of Medline/PubMed for the medical literature from 1960 to June 2008 using the keywords HOA, periostitis, and clubbing. These were also combined with the text words cancer, rheumatic disease, etiology, pathogenesis, hypothesis, transplant, and treatment. Only the English language literature, with pertinent information, was included. RESULTS Our 2 cases include 1 HOA case with clubbing, in a patient with a right to left shunt from cryptogenic cirrhosis and interstitial lung disease, and 1 HOA case without apparent clubbing, in a patient with chronic lung transplant rejection secondary to tobacco smoking and related emphysema. Review of the literature has shown that HOA is associated with a wide variety of disorders, approximately 80% are found with primary or metastatic pulmonary malignancies. Various rheumatic diseases, such as systemic vasculitis, can also be associated with HOA. With respect to the pathogenesis, vascular endothelial growth factor, platelet-derived growth factor, and platelets may play crucial roles. Therapeutically, bisphosphonates, such as pamidronade or octreotide, may be tried to relieve symptoms in refractory cases. CONCLUSIONS HOA, especially periostitis without clubbing, may go unrecognized. Involvement of vascular endothelial growth factor, platelet-derived growth factor, and platelets in the pathogenesis of HOA has been postulated and supported by recent data. HOA may present as a partial syndrome without clubbing and about 20% of cases have HOA without detectable malignancy. One of our cases represents the first report of the association of HOA with lung transplantation.

Treatment with an apolipoprotein A-1 mimetic peptide in combination with pravastatin inhibits collagen-induced arthritis

To evaluate the therapeutic potential of an apolipoprotein A-1 (apoA-1) mimetic peptide, D-4F, in combination with pravastatin in collagen-induced arthritis (CIA), syngeneic Louvain rats were immunized with type II collagen and randomized to vehicle control, D-4F monotherapy, pravastatin monotherapy, or D-4F + pravastatin combination therapy. Clinical arthritis activity was evaluated and radiographs, type II collagen antibody titers, cytokine/chemokine levels, and HDL function analysis were obtained. There was significant reduction in clinical severity scores in the high and medium dose D-4F + pravastatin groups compared to controls (p< or =0.0001). Reduction in erosive disease occurred in the medium/high dose combination groups compared to non-combination groups (p< or =0.01). Favorable changes in cytokines/chemokines were noted with treatment, and response to combination D-4F/pravastatin therapy was associated with improvement in HDLs anti-inflammatory properties. Combination D-4F/pravastatin significantly reduced clinical disease activity in CIA, and may have dual therapeutic potential in other autoimmune diseases with increased cardiovascular morbidity and mortality.

Environmental Modulation of Autoimmune Arthritis Involves the Spontaneous Microbial Induction of T Cell Responses to Regulatory Determinants Within Heat Shock Protein 65

Both genetic and environmental factors are believed to be involved in the induction of autoimmune diseases. Adjuvant arthritis (AA) is inducible in susceptible rat strains by injection of Mycobacterium tuberculosis, and arthritic rats raise T cell responses to the 65-kDa mycobacterial heat-shock protein (Bhsp65). We observed that Fischer 344 (F344) rats raised in a barrier facility (BF-F344) are susceptible to AA, whereas F344 rats maintained in a conventional facility (CV-F344) show significantly reduced incidence and severity of AA, despite responding well to the arthritogenic determinant within Bhsp65. The acquisition of protection from AA can be circumvented if rats are maintained on neomycin/acidified water. Strikingly, naive unimmunized CV-F344 rats but not BF-F344 rats raised T cell responses to Bhsp65 C-terminal determinants (BCTD) (we have previously shown that BCTD are involved in regulation of acute AA in the Lewis rat); however, T cells of naive CV-F344 and BF-F344 gave a comparable level of proliferative response to a mitogen, but no response at all to an irrelevant Ag. Furthermore, adoptive transfer into naive BF-F344 rats of splenic cells of naive CV-F344 rats (restimulated with BCTD in vitro) before induction of AA resulted in a considerably reduced severity of AA. These results suggest that spontaneous (inadvertent) priming of BCTD-reactive T cells, owing to determinant mimicry between Bhsp65 and its homologues in microbial agents in the conventional environment, is involved in modulating the severity of AA in CV-F344 rats. These results have important implications in broadening understanding of the host-microbe interaction in human autoimmune diseases.

An Angiogenesis Inhibitor, 2-Methoxyestradiol, Involutes Rat Collagen-Induced Arthritis and Suppresses Gene Expression of Synovial Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor

Objective Rheumatoid arthritis (RA) pannus may be dependent on angiogenesis and several critical growth factors including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). 2-Methoxyestradiol (2ME2), an endogenous metabolite with low estrogen receptor affinity, has both antiangiogenic and antiproliferative activity. 2ME2 was assessed in the rat collagen- induced arthritis (CIA) model to determine if it could prevent or involute established synovitis. Methods Rats were immunized on Day 0 with collagen and randomized to a vehicle control or two 2ME2 prevention arms. In additional studies, multiple parallel treatment arms were initiated at Day 10 after arthritis onset. Results 2ME2 in preventive protocols at 30 or 100 mg/kg significantly delayed the onset and reduced the severity of clinical and radiographic CIA. In established CIA, oral 2ME2 at 50 mg/kg/bid, 100 mg/kg/day, and 300 mg/kg/day reduced severity compared to vehicle controls. Efficacy of 2ME2 delivery by osmotic pumps at 60 mg/kg/day was equivalent to 300 mg/kg/day by daily gavage. The 3 oral treatment protocols all significantly reduced radiographic scores in a dose-dependent fashion, with the greatest benefit at 300 mg/kg. 2ME2 showed marked suppression of synovial gene expression of proangiogenic bFGF and VEGF, with parallel reduction of synovial blood vessels. Serum antibody levels to native type II collagen were not reduced, suggesting that 2ME2 did not influence humoral immunity. Conclusion Our results indicate that 2ME2 may represent a novel agent for the treatment of inflammatory autoimmune diseases such as RA.

Systemic Sclerosis: Bilateral Improvement of Raynaud's Phenomenon with Unilateral Digital Sympathectomy

OBJECTIVES To demonstrate that unilateral digital sympathectomy, in patients with Raynauds phenomenon (RP) and systemic sclerosis (SSc), may result in bilateral resolution of RP and digital ulcerations. METHODS We report a case of SSc and RP that had bilateral benefits from unilateral digital sympathectomy. A computer-assisted Medline/PubMed search of the medical literature was performed for 1960 through June 2009 using the keywords sympathectomy, Raynauds phenomenon, systemic sclerosis, CREST, and digital ulcers. These searches were also combined with text words unilateral, ipsilateral, bilateral, digital sympathectomy, selective sympathectomy, autonomic nervous system, hyperhidrosis, etiology, pathogenesis, hypothesis, and treatment. Only pertinent literature, primarily in the English language, was included. RESULTS The majority of patients with SSc have RP and many suffer from digital ulcerations. Medical and behavioral management may have limited benefit and surgical intervention can be considered in recalcitrant cases, although efficacy data are sparse. We describe a man with limited SSc who underwent unilateral digital sympathectomy but manifested bilateral benefit. To our knowledge, this is the first published report of contralateral response with this procedure. The patient ultimately demonstrated these digital benefits when stressed with extreme cold and hypoxia while mountaineering. Despite the onset of high-altitude sickness and cerebral edema, his fingers remained unaffected while other mountaineers sustained severe frostbite or died of hypothermia. CONCLUSIONS Selective unilateral sympathectomy in SSc, for RP with digital ulcerations, can result in bilateral benefits despite intense challenge with cold and hypoxia.

Rheumatoid arthritis therapy: Advances from bench to bedside

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with significant functional disability and morbidity. Treatment with conventional disease-modifying anti-rheumatic drugs has substantial limitations including partial efficacy and poor tolerability. Advances in our understanding of the pathogenesis of RA over the past decade have fostered development of targeted therapies and greatly expanded the available treatment options. Several of the therapeutic targets identified by recent studies have been translated into effective therapeutic agents, and many additional agents are currently under active development. In this article, we review the biologic agents that have made successful transitions from bench to bedside as well as the biologic and small molecule agents that are at various stages of development in human trials.

Modulation of p38 MAPK activity in regulatory T cells after tolerance with anti-DNA Ig peptide in (NZB x NZW)F1 lupus mice.

Treatment of (NZB × NZW)F1 (NZB/W) lupus-prone mice with the anti-DNA Ig-based peptide pConsensus prolongs the survival of treated animals and effectively delays the appearance of autoantibodies and glomerulonephritis. We have previously shown that part of these protective effects associated with the induction of CD4+CD25+Foxp3+ regulatory T cells (Tregs) that suppressed autoantibody responses. Because the effects of pConsensus appeared secondary to qualitative rather than quantitative changes in Tregs, we investigated the molecular events induced by tolerance in Tregs and found that signaling pathways including ZAP70, p27, STAT1, STAT3, STAT6, SAPK, ERK, and JNK were not significantly affected. However, peptide tolerization affected in Tregs the activity of the MAPK p38, whose phosphorylation was reduced by tolerance. The pharmacologic inhibition of p38 with the pyridinyl imidazole inhibitor SB203580 in naive NZB/W mice reproduced in vivo the effects of peptide-induced tolerance and protected mice from lupus-like disease. Transfer experiments confirmed the role of p38 in Tregs on disease activity in the NZB/W mice. These data indicate that the modulation of p38 activity in lupus Tregs can significantly influence the disease activity.