Hypereosinophilic Syndrome with Endomyocarditis: Identification by Next-Generation Sequencing of the JAK2-V617F Mutation.

Hypereosinophilic syndrome requires a peripheral absolute eosinophil count of ≥1.5 × 109 /L with clinical manifestations attributable to peripheral or tissue hypereosinophilia. Clinical manifestations can vary greatly, with the majority of patients relatively asymptomatic and the eosinophilia detected incidentally. However, in a minority of hypereosinophilia cases, they may present with severe lifethreatening organ dysfunction affecting skin, lung, heart, gastrointestinal tract, and nervous system. A case of hypereosinophilia with potentially life-threatening cardiovascular involvement is discussed. Initial laboratory investigations showed an elevated white blood cell count with 60% eosinophils. An endomyocardial biopsy revealed eosinophilic endomyocarditis with granuloma, rare giant cells, and no vasculitis, microorganisms, or malignancy. Her presentation met the criteria for either hypereosinophilic syndrome or eosinophilic granulomatosis with polyangitis. Molecular genetic analysis was negative for myelodysplastic syndrome panel/ Platelet Derived Growth Factor Receptor Beta (PDGFRB) (5q32)/Fibroblast Growth Factor Receptor 1 (FGFR1) Fluorescence In Situ Hybridization (FISH), Feline McDonough Sarcoma-related Tyrosine Kinase 3 (FLT3) Internal Tandem Duplication (ITD) mutation, Calregulin (CALR) exon 9 mutation, and T-cell gene rearrangement/polymerase chain reaction. Bone marrow biopsy revealed a mildly hypocellular marrow with multilineage hematopoiesis,+ megakaryocyte dysplasia, and focal eosinophilia. No excess blasts, no monotypic B-cell population, and no discrete pan T-cell aberrancies were found. Bone marrow cytogenetic studies showed a normal signal pattern for myeloproliferative neoplasms panel/Sec1 Family Domain Containing 2 (SCFD2)-Ligand of Numb Protein-X (LNX)-Platelet-derived Growth Factor Receptor Alpha (PDGFRA) fluorescence in situ hybridization with a normal karyotype of 46 XX. Next-generation sequencing, however, was positive for the JAK2-V617F mutation, a rare molecular abnormality in hypereosinophilic syndrome. The prevalence ranges from approximately 0% to 4%. The JAK2 point mutation leads to aberrant tyrosine phosphorylation and increased cytokine activation. The case demonstrates the complexity and challenging nature of advanced diagnostic opportunities in hypereosinophilia and the potential use, in select subsets, of targeted treatments such as tyrosine kinase inhibitors.

Suppression of inflammatory arthritis in human serum paraoxonase 1 transgenic mice.

Paraoxonase 1(PON1) is an HDL-associated protein, which metabolizes inflammatory, oxidized lipids associated with atherosclerotic plaque development. Because oxidized lipid mediators have also been implicated in the pathogenesis of rheumatoid arthritis (RA), we evaluated the role of PON1 in murine inflammatory arthritis. K/BxN serum transfer (STIA) or collagen antibody transfer (CAIA) was used for arthritis induction in B6 mice homozygous for the PON1 human transgene [PON1Tg], PON1 knock-out mice [PON1KO], and wild type littermate control mice [WT]. Experiments were also performed in K/BxN mice with chronic arthritis, and in RA patients and healthy controls. Arthritis activity in K/BxN mice was associated with a marked dyslipidemia, lower PON1 activity and higher bioactive lipid mediators (BLM), as well as a dysregulated hepatic lipid gene expression profile. Higher serum PON1 activity correlated with lower BLM and lower arthritis activity in both K/BxN mice and RA patients. Overexpression of the human PON1 transgene was associated with reduced inflammatory arthritis, which correlated strongly with higher circulating PON1 activity, upregulation of the hepatic glutathione pathway, and reduction of circulating BLM. These results implicate PON1 as a potential novel therapeutic target for joint disease in RA with potential for vascular benefit, which warrants further investigation.

Microscopic polyangiitis with dermatomyositis.

Dermatomyositis is a rare autoimmune disease with a heterogeneous presentation that often has multiple extramuscular manifestations, although it does not typically involve the renal function. A 62-year-old female presented with proximal muscle weakness and rashes, which are classic symptoms of dermatomyositis without creatine kinase (CK) elevation. Initial serologic evaluation revealed a positive p-ANCA, although she did not develop renal failure for several months, at which point renal biopsy findings were consistent with microscopic polyangiitis. The patient was initially treated with cyclophosphamide, maintained with rituximab, and has been in remission for more than 2 years. Dermatomyositis and microscopic polyangiitis are both uncommon diseases, but are concomitantly present in this patient. A positive p-ANCA and development of renal insufficiency should be promptly evaluated in dermatomyositis patients.

Suppression of collagen-induced arthritis with a serine proteinase inhibitor (serpin) derived from myxoma virus.

Many viruses encode virulence factors to facilitate their own survival by modulating a host's inflammatory response. One of these factors, secreted from cells infected with myxoma virus, is the serine proteinase inhibitor (serpin) Serp-1. Because Serp-1 had demonstrated anti-inflammatory properties in arterial injury models and viral infections, it was cloned and evaluated for therapeutic efficacy in collagen-induced arthritis (CIA). Clinical severity was significantly lower in the Serp-1 protocols (p<0.0001) and blinded radiographs indicated that the Serp-1 group had significantly less erosions than the controls (p<0.01). Delayed-type hypersensitivity was lower in the Serp-1 group but antibody titers to type II collagen were not significantly altered. Recipients had minimal histopathologic synovial changes and did not develop neutralizing antibodies to Serp-1. These results indicate that Serp-1 impedes the pathogenesis of CIA and suggests that the therapeutic potential of serine proteinase inhibitors in inflammatory joint diseases, such as rheumatoid arthritis, should be investigated further.

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.

Mucocutaneous leishmaniasis masquerading as Wegener granulomatosis.

A 43-year-old Brazilian female presented in 2001 with nasal stuffiness and sinusitis. A biopsy was consistent with limited Wegener's granulomatosis although antineutrophil cytoplasmic antibodies were negative. Her nasal inflammation progressed despite trials of prednisone, methotrexate, and azathioprine. A septal perforation developed and a repeat biopsy showed granulomatous inflammation. In 2006 the patient was referred to Division of Rheumatology, University of California, Los Angeles. The nose was grossly erythematous and a magnetic resonance imaging revealed nasal destruction and sinusitis. Palatine biopsies showed chronic inflammation. Cyclophosphamide at 150 mg/d resulted in markedly improved mucocutaneous lesions. The patient developed a leg and arm rash in 2007. A skin biopsy was positive for Leishmania braziliensis. The cyclophosphamide was discontinued and amphotericin B was initiated with transient benefit. Remission was achieved with pentavalent antimony. Despite multiple nasopharyngeal biopsies, for a 6-year span, mucocutaneous leishmaniasis masqueraded as Wegener's granulomatosis. Cyclophosphamide not only resulted in clinical improvement, due to reduced inflammatory response, but also allowed widespread cutaneous dissemination.

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 x NZW)F(1) (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.

Angiogenesis inhibitors for the treatment of chronic autoimmune inflammatory arthritis.

Angiogenesis, the formation of new blood vessels, is closely linked with both the initiation and progression of rheumatoid arthritis (RA). Rheumatoid joints contain elevated levels of proangiogenic molecules, such as VEGF, basic FGF, hypoxia-inducible factor 1 and angiopoietins. Increased angiogenesis is also associated with malignancies and proliferative retinopathies, and targeting this process therapeutically has proven beneficial in treating several of these diseases including colorectal, kidney and lung cancer. Adapting such a therapeutic strategy to the treatment of RA may prove beneficial, as data from preclinical studies have demonstrated that angiogenesis inhibitors reduce pannus formation, inflammation and joint erosion. New therapies that inhibit angiogenesis by blocking VEGFR tyrosine kinase signaling, integrin interactions, microtubule formation and endothelial cell proliferation may be applicable to the treatment of RA. There are several angiogenesis inhibitors that have been approved by the FDA or are currently being assessed in clinical trials which are safe for use in humans, although their effects on RA remain untested. This review discusses the potential of angiogenesis inhibition in the context of treating RA.

Involution of collagen-induced arthritis with an angiogenesis inhibitor, PPI-2458.

Pannus formation, in both rheumatoid arthritis (RA) and collagen-induced arthritis (CIA), is angiogenesis-dependent. PPI-2458 [(1R)-1-carbamoyl-2-methyl]-carbamic acid-(3R,3S,5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)oxiranyl]-1-oxaspiro(2*5)oct-6-yl ester], a new fumagillin derivative known to inhibit methionine aminopeptidase 2 (MetAP-2) and endothelial proliferation at the late G(1) phase, was evaluated in CIA rats to study its potential to involute synovitis. Arthritic syngeneic LOU rats received either a vehicle control or various dosages of oral, intravenous, or subcutaneous PPI-2458. Plasma samples were analyzed to determine a pharmacokinetic profile of PPI-2458, and whole blood was evaluated by flow cytometry to assess the effect on lymphocyte subsets. At 15 mg/kg i.v., 30 mg/kg s.c., or 100 mg/kg p.o., there was a significant reduction in clinical severity scores (p < 0.001) and blinded radiographic scores (p < 0.001) compared with vehicle control groups. Structural damage was virtually eliminated with PPI-2458. Continuous inhibition of MetAP-2 was needed to maintain benefits, although pannus involution could be achieved with the inhibitor when escape flares occurred. Pharmacokinetic analysis after a single p.o. dose showed a rapid T(max) value of 15 min followed by biphasic elimination (t(1/2), approximately 20 min and t(1/2), approximately 5 h) and an estimated oral bioavailability of approximately 15%. Flow cytometry revealed a dose-dependent decrease in white blood cells and lymphocytes manifested as decreases in circulating CD3+ T cells and natural killer cells. PPI-2458, however, did not seem to be immunosuppressive, as determined by delayed-type hypersensitivity or IgG antibody assays. These studies indicate that the MetAP-2 inhibitor PPI-2458 can regress established CIA and that angiogenic mechanisms might be important targets in the treatment of other pannus-mediated diseases such as RA.

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.

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.

Vanadate, an inhibitor of stromelysin and collagenase expression, suppresses collagen induced arthritis.

OBJECTIVE: Collagen induced arthritis (CIA) is a model of chronic inflammatory synovitis with pannus, neovascularization, and joint destruction similar to rheumatoid arthritis (RA). Matrix metalloproteinases (MMP) are involved in degradation of the extracellular matrix and joint destruction in RA. c-fos and c-jun are protooncogenes whose products combine to form activating protein (AP-1), a regulatory protein that is required for cell proliferation and the transcription of a variety of genes, including MMP such as collagenase and stromelysin. Administration of vanadium compounds suppresses c-fos/c-jun expression and AP-1 activity, resulting in inhibition of MMP expression in response to factors such as interleukin 1 (IL-1). We evaluated whether a vanadium AP-1 inhibitor could reduce MMP expression and subsequent joint damage in CIA. METHODS: Vanadate [bis (maltolato) oxovanadium (IV) (BMOV; 10 mg/kg/day)] and the reducing agent N-acetyl cysteine (NAC; 100 mg/kg/day) were given subcutaneously daily in an attempt to suppress established CIA in rats. NAC in combination with vanadate appeared to increase the efficacy of c-fos/c-jun inhibition, while decreasing toxicity. Controls were given NAC alone. Clinical, radiographic, and histologic measures were evaluated as well as synovial MMP and IL-1a expression. RESULTS: BMOV therapy, initiated on the day of onset of clinical arthritis, significantly reduced clinical arthritis within 2 days (p <0.05) compared to controls. Significance was maintained to the termination of the study on Day 18 post-arthritis onset (p < 0.005), with a maximum difference seen on Day 5 (p < 0.00001). Blinded radiographic scores at the completion of the protocols indicated less joint destruction in the experimental group compared to the control group (p < 0.005). Scanning and transmission electron microscopy confirmed the preservation of articular cartilage with therapy. In BMOV-treated rats, synovial mRNA expression of collagenase, stromelysin, and IL-la were reduced by 78%, 58%, and 85%, respectively, compared to controls. CONCLUSION: This is the first study of vanadate as a potential antirheumatic agent. Further study of this AP-1 and MMP inhibitor may lead to new treatment options in RA.

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 alpha(V)beta(3), 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.

New antiangiogenic strategies for the treatment of proliferative synovitis.

Angiogenesis inhibition, which has been extensively studied for the treatment of various malignancies, is beginning to emerge as a new potential therapy for proliferative synovitis, particularly rheumatoid arthritis (RA). The rheumatoid pannus, the site of inflammation and joint destruction in the rheumatoid synovium, relies on the development of new vasculature to sustain its growth. A host of mediators have been shown to induce angiogenesis at the site of the inflamed synovium; these include vascular endothelial growth factor, fibroblast growth factor, integrin alpha(V)beta3, angiopoietin, prosta-glandin E1 and prostaglandin E2, and matrix metalloproteinases. In addition, hypoxia at the site of synovial inflammation contributes to angiogenesis stimulation. Several naturally-occurring inhibitors exist, such angiostatin and endostatin. There are a number of drugs undergoing study in the treatment of proliferative synovitis, which capitalise on the correlation between angiogenesis inhibition and the reduction of signs and symptoms of RA. Paclitaxel and an anti-integrin alpha(V)beta3 antibody, LM-609, are currently in clinical trials. Other drugs that may inhibit angiogenesis in RA include TNP-470 (formerly called AGM-1470), PPI-2458, PTK-787, bevacizumab and thalidomide. Many of these drugs have shown promise for the treatment of oncologic disorders, and are now being evaluated for the treatment of proliferative synovitis.

Angiocentric T cell lymphoma of the central nervous system in a patient with Sjögren's syndrome.

Patients with Sjögren's syndrome (SS) have an increased risk of developing lymphoproliferative disorders, mainly non-Hodgkin's lymphoma and pseudolymphoma. We describe a young Caucasian woman with a 7 year history of SS, who presented with meningeal signs and symptoms and was found to have non-Hodgkin's lymphoma of the central nervous system.