Luis M. Amezcua-Guerra

Joint and tendon subclinical involvement suggestive of gouty arthritis in asymptomatic hyperuricemia: an ultrasound controlled study

IntroductionIn this study, we aimed to investigate ultrasonographic (US) changes suggestive of gouty arthritis in the hyaline cartilage, joints and tendons from asymptomatic individuals with hyperuricemia.MethodsWe conducted a cross-sectional, controlled study including US examinations of the knees and first metatarsal-phalangeal joints (first MTPJs), as well as of the tendons and enthesis of the lower limbs. Differences were estimated by χ2 or unpaired t-tests as appropriate. Associations were calculated using the Spearmans correlation coefficient rank test.ResultsFifty asymptomatic individuals with hyperuricemia and 52 normouricemic subjects were included. Hyperechoic enhancement of the superficial margin of the hyaline cartilage (double contour sign) was found in 25% of the first MTPJs from hyperuricemic individuals, in contrast to none in the control group (P < 0.0001). Similar results were found on the femoral cartilage (17% versus 0; P < 0.0001). Patellar enthesopathy (12% versus 2.9%; P = 0.01) and tophi (6% versus 0; P = 0.01) as well as Achilles enthesopathy (15% versus 1.9%; P = 0.0007) were more frequent in hyperuricemic than in normouricemic individuals. Intra-articular tophi were found in eight hyperuricemic individuals but in none of the normouricemic subjects (P = 0.003).ConclusionsThese data demonstrate that morphostructural changes suggestive of gouty arthritis induced by chronic hyperuricemia frequently occur in both intra- and extra-articular structures of clinically asymptomatic individuals.

Overlap between systemic lupus erythematosus and rheumatoid arthritis: is it real or just an illusion?

The association between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) has been debated for many years. Based on their different genetic background and pathogenic mechanisms, it has been argued that both diseases are complex, mutually exclusive entities. However, recent knowledge is challenging this notion, suggesting that both diseases can indeed overlap. In this issue of The Journal, Icen and colleagues explore the frequency of SLE features and their influence on mortality in an incident cohort of 603 subjects with RA followed over time1. This study was conducted in the Rochester Epidemiology Project, a centralized medical record-linkage system that encompasses all healthcare data from residents of Rochester and Olmsted County, Minnesota, USA, since 1909. This kind of project provides an extraordinary opportunity to conduct comprehensive population-based studies over long periods. A cumulative incidence of ≥ 4 SLE features (including arthritis) was found in 15.5% of patients after 25 years of followup, this being associated with a 2fold increase in the risk of death. Is there an explanation for the high incidence of SLE features found in this cohort of RA patients? Information about SLE and RA association is scarce and discrepant. Cohen and colleagues reported that 11 of 309 (3.6%) patients with SLE fulfilled classification criteria for RA, suggesting that both diseases are more frequently associated than expected by chance2. In contrast, in a retrospective study including about 7000 new patients, Panush and colleagues identified only 6 patients with overlapping criteria for RA and SLE, with a 10-fold lower concurrent prevalence rate (0.09%) than that expected by chance (1.2%)3. With these data, whether RA and SLE are directly or inversely related entities remains unclear; nonetheless, the surprising finding of 15.5% of RA patients fulfilling classification criteria for SLE opens 2 options for interpretation: (1) the existing gaps in the classification systems make them not specific enough for differentiating some cases of RA from SLE, and/or (2) there is a real association between both diseases, in which case the pathogenic mechanisms underlying each of them should be revised. Regarding classification criteria for rheumatic diseases, almost all have been performed on cross-sectional evaluations, hence they seem to neither adequately evaluate clinical and serological features collected over time nor assess the dynamic course of the corresponding disease. When the 1982 revised classification criteria for SLE were formulated, the objective was to reliably discriminate SLE patients from a heterogeneous group of inflammatory arthritides (most of them RA)4. In spite of that, some of these criteria are also common manifestations in RA (i.e., arthritis, pleuritis, pericarditis, or proteinuria) or are related to therapy (i.e., rash, photosensitivity, oral ulcers, proteinuria, leukopenia, and antinuclear antibodies). Thus, a significant number of RA patients potentially meet SLE classification criteria. Similarly, the 1987 revised classification criteria for RA intended to improve the specificity of the former criteria, with a better discrimination between patients with well established RA versus patients with other rheumatic diseases (20% of them with SLE)5. Since a number of non-RA patients also met some RA classification criteria, a warning was included: “four conditions (systemic lupus erythematosus, psoriatic arthritis, mixed connective tissue disease, and Reiter’s syndrome) appear likely to have substantial numbers of patients who might fulfill the requirements of the new criteria, and caution should be observed in these circumstances”. Following this line of thought, it may be concluded that sequential concurrence of RA manifestations that are also included in the SLE classification criteria explains the high frequency of SLE features. However, it is clear that some patients with a well classified autoimmune rheumatic disease also may have features considered hallmarks of another one; for instance, a patient with established RA who presents with proliferative glomerulonephritis, psychosis, antidsDNA or anti-Sm antibodies, or other hallmarks of SLE. Do these clinical manifestations and autoantibodies reveal

Anti-tumor necrosis factor VNAR single domains reduce lethality and regulate underlying inflammatory response in a murine model of endotoxic shock.

BackgroundIn sepsis, tumor necrosis factor (TNF) is the key factor triggering respiratory burst, tissue injury and disseminated coagulation. Anti-TNF strategies based on monoclonal antibodies or F(ab’)2 fragments have been used in sepsis with contradictory results. Immunoglobulin new antigen receptors (IgNAR) are a unique subset of antibodies consisting of five constant (CNAR) and one variable domains (VNAR). VNAR domains are the smallest, naturally occurring, antibody-based immune recognition units, having potential use as therapy.Our aim was to explore the impact of an anti-TNF VNAR on survival in an experimental model of endotoxic shock. Also, mRNA expression and serum protein of several inflammatory molecules were measured.ResultsEndotoxic shock was induced by lipopolysaccharide (LPS) in male Balb/c mice. Animals were treated with anti-TNF VNAR domains, F(ab’)2 antibody fragments, or saline solution 15 minutes before, 2 h and 24 h after lethal dose100 (LD100) LPS administration. TNF blockade with either VNAR domains or F(ab’)2 fragments were associated with lower mortality (60% and 75%, respectively) compared to LD100. Challenge with LPS induced significant production of serum TNF and interleukins -10 and -6 at 3 h. After that, significant reduction of IL-6 at 24 h (vs 3 h) was shown only in the VNAR group. Nitrites level also increased in response to LPS.In liver, TNF and IL-10 mRNA expression showed a pro-inflammatory imbalance in response to LPS. Blocking TNF was associated with a shift towards an anti-inflammatory status; however, polarization was more pronounced in animals receiving F(ab’)2 fragments than in those with VNAR therapy. With regard to IL-6, gene expression was increased at 3 h in all groups. TNF blockade was associated with rapid and sustained suppression of IL-6 expression, even more evident in the VNAR group. Finally, expression of inducible-nitric oxide synthase (iNOS) increased in response to LPS at 3 h, but this was decreased at 24 h only in the anti-TNF VNAR group.ConclusionsAnti-TNF VNAR single domains improved survival in a murine model of endotoxic shock. Protection was associated with regulation in the TNF/IL-10 balance, attenuation of IL-6 and iNOS gene expression in the liver as well as decreased serum IL-6 concentration.

DcR3 as a diagnostic parameter and risk factor for systemic lupus erythematosus.

In this study, we investigated the diagnostic value of serum death decoy receptor 3 (DcR3) for systemic lupus erythematosus (SLE). The possible pathogenic role of DcR3 in SLE was also assessed. Serum DcR3 levels of 90 SLE patients, 11 patients with rheumatic conditions and 123 healthy controls were determined by ELISA. In all, 43% of the SLE patients, 9% of patients with rheumatic conditions and 2.4% of the normal healthy individuals presented elevated serum DcR3 levels. A higher percentage of DcR3-positive SLE patients, compared with DcR3-negative SLE patients, showed abnormally high serum IgE levels, a surrogate marker of T(h)2-type immune responses. To determine the cause and effect relationship of DcR3 expression and a T(h)2-prone status, we studied young DcR3 transgenic (Tg) mice, whose transgene was driven by an actin promoter. These mice had IL-4 overproduction and augmented serum IgE levels, signs of dominant T(h)2 immune responses. To determine possible SLE pathogenic roles of DcR3, the T-cell-depleted bone marrow of DcR3 Tg mice was transplanted into lethally irradiated syngeneic C57BL/6 female mice. The recipients developed an SLE-like syndrome. They presented anti-dsDNA and anti-nuclear antibodies, along with renal and liver pathology compatible with that of SLE. In total, 90% of Tg bone marrow-transplanted mice, compared with 20% of wild-type bone marrow-transplanted mice, perished within 12 months after the transplantation. Our results showed that serum DcR3 could serve as an additional parameter for SLE diagnosis and that DcR3 secreted from cells of hematopoietic origin was SLE pathogenic in mice.

Pulmonary hypertension in systemic lupus erythematosus: echocardiography-based definitions predict 6-year survival

OBJECTIVE The aim of this study was to investigate whether a core of echocardiography-based definitions of pulmonary hypertension (PH), as proposed by the European Society of Cardiology, European Respiratory Society and International Society of Heart and Lung Transplantation (ESC/ERS/ISHLT), may predict long-term survival in patients with SLE. METHODS A post hoc analysis from a cohort of SLE patients followed over 6 years was performed. Clinical associations, serum biomarkers, autoantibody profile, length of survival and all-cause mortality were assessed. RESULTS Out of 115 patients from the original cohort, 55 satisfied our inclusion criteria and were grouped according to echocardiography as unlikely (n = 26), possible (n = 16) or likely (n = 13) to have PH. Likely PH was associated with a history of pulmonary thromboembolism, higher cumulated organ damage and active arthritis. The 6-year survival rate was 88% in the unlikely PH group, 87% in the possible PH group and 68% in the likely PH group (P < 0.05). Serum levels of endothelin-1, monocyte chemotactic protein-1, IL-17, and IFN-γ as well as a number of autoantibodies were no different between groups. CONCLUSION The ESC/ERS/ISHLT echocardiography-based definitions of PH are useful to predict 6-year mortality in SLE patients. A history of pulmonary thromboembolism and lung vasculitis/haemorrhage, cumulated organ damage and long-lasting disease are associated with PH in SLE.

Interleukin 6 Is Associated with Pulmonary Involvement in Primary Sjögren’s Syndrome

Primary Sjogren’s syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration leading to destruction of acinar and ductal cells and loss of glandular parenchyma. Although sicca symptoms are pivotal manifestations of pSS, extraglandular involvement also occurs. Pulmonary involvement in pSS consists of interstitial lung disease, obstructive small airway disease, pulmonary arterial hypertension (PAH), bullous disease, and lymphoma1. Recent evidence suggests that cytokine-mediated mechanisms are critical in pSS, but the precise cytokine pattern driving lung injury remains unclear2–4. Because of current availability of therapies that modulate selected cytokines, in-depth knowledge of the cytokine profile associated to specific tissue damage is necessary. We analyzed circulating concentrations of several prototypical TH1 [interferon-γ (IFN-γ)], TH2 [interleukin 4 (IL-4), IL-6, IL-10], and TH17 (IL-17) cytokines in patients with pSS according to the presence or absence of pulmonary involvement. From an outpatient cohort with pSS according to the preliminary classification criteria5 we selected patients who had pulmonary involvement demonstrated by high-resolution computed tomography scans of the lungs, and at least one of the following: pulmonary function test, spirometry, or lung biopsy. For comparisons, we selected age and gender-matched pSS patients without pulmonary manifestations and normal chest radiograph. We excluded … Address correspondence to Dr. L.M. Amezcua-Guerra; E-mail: lmamezcuag{at}gmail.com