Incidental retinal vascular occlusions on hydroxychloroquine screening in patients with systemic lupus erythematosus.

OBJECTIVE: The proportion of patients with systemic lupus erythematosus (SLE) who manifest retinal involvement increases many fold in patients with active systemic disease. The objective of this report is to stress upon the significance of comprehensive ophthalmic assessment of all SLE patients to prevent and manage blinding ocular manifestations of the disease. METHODS: Retrospective case review. RESULTS: Incidental retinal vascular complications seen in patients undergoing baseline hydroxychloroquine screening. CONCLUSION: The purpose of comprehensive ophthalmic screening in SLE patients is twofold. It will aid in the diagnosis and treatment of blinding ocular complications of the disease and monitor hydroxychloroquine macular toxicity.

Systemic lupus erythematosus presenting as Stevens-Johnson syndrome/toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)-like lesions in acute cutaneous lupus erythematosus [LE]) are an unusual manifestation of systemic LE. We describe a patient with widespread vesiculobullous lesions diagnosed as SJS/TEN-like acute cutaneous LE as the initial presentation of systemic LE. Stevens-Johnson syndrome/TEN-like LE may be differentiated from other vesiculobullous lesions by factors including a history of recent LE exacerbation, photodistribution of lesions, lack of a precipitating infection or medication exposure, minimal mucosal involvement, a prolonged course, response steroid treatment, and histologic and immunofluorescence findings. It is paramount to identify SJS/TEN-like LE as this condition requires early and aggressive intervention. The optimal treatment approach for SJS/TEN-like LE is unclear, and although some case reports have shown glucocorticoids to be useful, there are also reports of cases in which additional measures, such as intravenous immunoglobulin and plasmapheresis, were required to achieve a response. Our patient's condition was refractory to high-dose corticosteroids and intravenous immunoglobulin but was successfully treated using plasma exchange. As such, this treatment may hold potential for improving the care of other patients with refractory SJS/TEN-like LE.

Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response.

The unique sensitivity of early red cell progenitors to iron deprivation, known as the erythroid iron restriction response, serves as a basis for human anemias globally. This response impairs erythropoietin-driven erythropoiesis and underlies erythropoietic repression in iron deficiency anemia. Mechanistically, the erythroid iron restriction response results from inactivation of aconitase enzymes and can be suppressed by providing the aconitase product isocitrate. Recent studies have implicated the erythroid iron restriction response in anemia of chronic disease and inflammation (ACDI), offering new therapeutic avenues for a major clinical problem; however, inflammatory signals may also directly repress erythropoiesis in ACDI. Here, we show that suppression of the erythroid iron restriction response by isocitrate administration corrected anemia and erythropoietic defects in rats with ACDI. In vitro studies demonstrated that erythroid repression by inflammatory signaling is potently modulated by the erythroid iron restriction response in a kinase-dependent pathway involving induction of the erythroid-inhibitory transcription factor PU.1. These results reveal the integration of iron and inflammatory inputs in a therapeutically tractable erythropoietic regulatory circuit.

Contrast-enhanced magnetic resonance imaging positively impacts the management of some patients with rheumatoid arthritis or suspected RA.

OBJECTIVE: Early diagnosis of rheumatoid arthritis (RA) is important given the availability of highly effective disease-modifying antirheumatic (DMARD) medications, including biologics. However, because of associated risks and cost, accurately assessing disease activity is critical. Because magnetic resonance imaging (MRI) can detect synovitis and bone marrow edema, both of which may precede erosion development, we sought to determine the impact of enhanced MRI on patient management in a group of patients referred for MRI by rheumatologists. MATERIALS AND METHODS: After institutional review board approval, we evaluated all hand MRI examinations referred by the rheumatology department for synovitis evaluation between September 2007 and May 2009. The magnetic resonance images were classified as positive or negative and later reviewed by 2 musculoskeletal radiologists. A musculoskeletal radiologist and rheumatologist jointly reviewed the patients' medical records to determine the following: (1) Did the MRI findings alter treatment? (2) Were the treatment alterations beneficial? RESULTS: The study included 48 patients (39 women and 9 men) with a mean age of 51 years (range, 18-79 years). Significant management changes initially occurred in 79% (23/29) of the positive (DMARDs added in 20) and in 11% (2/19) of the negative MR examinations with average follow-up of ~300 days. Eighty percent (16/20) of the patients with DMARDs added experienced symptom improvement, none of the patients whose medications were discontinued experienced symptom relapse, and 18% (4/22) of patients without initial therapeutic changes required delayed treatment modifications. CONCLUSIONS: Enhanced MRI significantly altered clinical management in 50% of these patients with RA or suspected RA. Therefore, when the clinical picture in a patient with RA or suspected RA is unclear, enhanced MRI can provide useful guidance for treatment modifications.

Clinical implication of autoantibodies in patients with systemic rheumatic diseases.

Autoantibodies have been used extensively as a useful biomarker in systemic lupus erythematosus and other autoimmune rheumatic diseases. Antinuclear antibodies by immunofluorescence are a standard clinical test to screen for evidence of systemic autoimmunity. Different specific autoantibodies are associated with particular diagnoses, symptoms, unique syndromes, subsets of the disease and clinical activity. They are produced prior to the onset of clinical manifestations and have predictive value. This review focuses on a critical re-evaluation of the clinical significance of autoantibodies. Disease subsets defined by autoantibodies, coexistence of disease marker antibodies, and problems in testing and interpreting results are examined. Clinical approaches in differential diagnosis of antinuclear antibodies and the significance of antinuclear antibodies in healthy individuals are also discussed.

Animal models of rheumatoid arthritis and their relevance to human disease.

Rodent models of rheumatoid arthritis (RA) are useful tools to study the pathogenic process of RA. Among the most widely used models of RA are the streptococcal cell wall (SCW) arthritis model and the collagen-induced arthritis (CIA). Both innate and adaptive immune mechanisms are involved in these rodent models. While no models perfectly duplicate the condition of human RA, they are easily reproducible, well defined and have proven useful for development of new therapies for arthritis, as exemplified by cytokine blockade therapies. Besides SCW and CIA models, there are numerous others including transgenic models such as K/BxN, induced models such as adjuvant-induced and pristane models, and spontaneous models in certain mouse strains, that have been used to help understand some of the underlying mechanisms. This review provides an update and analysis of RA models in mice and rats. The array of models has provided rheumatologists and immunologists a means to understand the multifactorial disease in humans, to identify new drug targets, and to test new therapies.

Splenectomy attenuates streptococcal cell wall-induced arthritis and alters leukocyte activation.

OBJECTIVE: To investigate the role of the spleen in the pathogenesis of streptococcal cell wall (SCW)-induced arthritis and determine the impact of splenectomy on monocytes and T cells involved in the arthritis. METHODS: Female Lewis rats were separated into 4 groups: 1) saline-injected, sham-operated; 2) saline-injected, splenectomized; 3) peptidoglycan-polysaccharide (PG-PS)-injected, sham-operated; and 4) PG-PS-injected, splenectomized. After a 10-day recovery period, rats received a single intraperitoneal injection of saline or PG-PS (25 microg rhamnose/gm body weight). We evaluated the effect of splenectomy on joint inflammation, histopathology, leukocyte subtypes in blood and lymph nodes, cytokines, and cell surface expression of CD44 and CD45RC in the chronic phase of the disease (day 28). RESULTS: Splenectomy dramatically decreased chronic joint inflammation and histopathologic damage as well as altered cell types in lymph nodes and peripheral blood, as analyzed by flow cytometry. Nitric oxide (NO) production, levels of interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha, and a biomarker of Th1 cell predominance correlated with the level of joint inflammation. Surprisingly, in splenectomized animals, increased expression of adhesion molecules thought to track T cells to inflamed tissue were observed in lymph nodes. CONCLUSION: The result of splenectomy was attenuation of SCW-induced arthritis and changes in mediators of inflammation, including T cell subsets, proinflammatory cytokines, and NO production. Splenectomy may remove an important antigen reservoir and alter immune cell activation in the SCW-induced arthritis model.

Inhibition of platelet adherence to brain microvasculature protects against severe Plasmodium berghei malaria.

Some patients with Plasmodium falciparum infections develop cerebral malaria, acute respiratory distress, and shock and ultimately die even though drug therapy has eliminated the parasite from the blood, suggesting that a systemic inflammatory response contributes to malarial pathogenesis. Plasmodium berghei-infected mice are a well-recognized model of severe malaria (experimental severe malaria [ESM]), and infected mice exhibit a systemic inflammatory response. Because platelets are proposed to contribute to ESM and other systemic inflammatory responses, we determined whether platelet adherence contributes to experimental malarial pathogenesis. Indeed, a significant (P < 0.005) increase in the number of rolling and adherent platelets was observed by intravital microscopy in brain venules of P. berghei-infected mice compared with the number in uninfected controls. P-selectin- or ICAM-1-deficient mice exhibit increased survival after P. berghei infection. We observed a significant (P < 0.0001) reduction in the morbidity of mice injected with anti-CD41 (alpha(IIb) or gpIIb) monoclonal antibody on day 1 of P. berghei infection compared with the morbidity of infected controls injected with rat immunoglobulin G. Additionally, platelet rolling and adhesion in brain venules were reduced in P. berghei mice lacking either P-selectin or ICAM-1 or when the platelets were coated with anti-CD41 monoclonal antibody. Unlike other inflammatory conditions, we did not detect platelet-leukocyte interactions during P. berghei malaria. Because (i). leukocyte adhesion is not markedly altered in the absence of P-selectin or ICAM-1 and (ii). CD41 is not an adhesion molecule for parasitized erythrocytes, these findings support the hypothesis that inhibition of platelet adhesion to the brain microvasculature protects against development of malarial pathogenesis.

Streptococcal cell wall induced arthritis: leukocyte activation in extra-articular lymphoid tissue.

Rheumatoid arthritis (RA) is a common systemic inflammatory disease thought to be T-helper-1 cell driven, though current controversy involves the relative role of T cells versus other leukocytes. Thus, there is a need for better understanding of the role of various leukocytes and their subsets in RA. Using the streptococcal cell wall (SCW) induced arthritis model, we examined leukocytes isolated from peripheral blood, spleen, and lymph nodes using monoclonal antibodies directed against lineage specific cell surface markers. Activation status of these cells was assessed using CD44 and CD71 as markers. T cells in general, and CD4+ T cells in particular were found to be activated in spleen and lymph nodes. B cells and monocytes in spleen demonstrated increased activation as well. The activation of cells in the myeloid and lymphoid lineages in the chronic phase of arthritis indicates ongoing involvement of innate and cognate immunity. This study quantitates specific changes in B and T lymphocytes, and myeloid cells and is consistent with findings in human RA in which specific antibodies, T cells, and myeloid cells are all implicated in the pathogenesis of RA.

Intercellular adhesion molecule 1 is important for the development of severe experimental malaria but is not required for leukocyte adhesion in the brain.

Plasmodium berghei-infected mice, a well-recognized model of experimental cerebral malaria (ECM), exhibit a systemic inflammatory response. Most investigators hypothesize that leukocytes bind to endothelial cells via intercellular adhesion molecule 1 (ICAM-1), which causes endothelial damage, increased microvascular permeability, and, ultimately, death. ICAM-1-deficient mice on an ECM-susceptible C57BL/6 background were significantly (p = .04) protected from P. berghei mortality compared with ICAM-1 intact controls. ICAM-1 expression assessed by the dual radiolabeled monoclonal antibody technique was increased in the brain and lung in C57BL/6 mice on day 6 of P. berghei infection compared with uninfected controls (5.3-fold, p = .0003 for brain and 1.8-fold, p = .04 for lung). The increase in ICAM-1 expression coincided with significant (p < .05) increases in microvascular permeability in the brain and lung. In contrast to the hypothesized role for ICAM-1, in vivo analysis by intravital microscopy of leukocyte rolling and adhesion in brain microvasculature of mice revealed markedly increased levels of leukocyte rolling and adhesion in ICAM-1-deficient mice on day 6 of P. berghei infection compared with uninfected controls. In addition, ICAM-1 expression and microvascular permeability were increased in infected ECM-resistant BALB/c mice compared with uninfected BALB/c controls. These results collectively indicate that although ICAM-1 contributes to the mortality of experimental malaria, it is not sufficient for the development of severe experimental malaria. In addition, ICAM-1 expressed on the endothelium or on leukocytes is not required for leukocyte rolling or adhesion to the brain microvasculature of mice during P. berghei malaria. Leukocyte rolling and adhesion in the brain vasculature during P. berghei malaria use different ligands than observed during inflammation in other vascular beds.

Streptococcal cell wall arthritis: kinetics of immune cell activation in inflammatory arthritis.

The streptococcal cell wall model of arthritis in Lewis rats consists of an acute, non-T-cell-dependent initiation phase, followed by a remission and then a chronic, inflammatory T-cell-dependent phase. In this report, we define pertinent changes in the cognate and noncognate immune system of the Lewis rats during various phases of the disease. We examined changes in the population size of various cell types using lineage-specific markers in three different tissues (blood, spleen, and lymph nodes) over 28 days. Our results indicate that the T cell and monocyte populations were significantly altered in PG-PS-treated rats and the activation status of these cells parallel initiation, remission, and chronic phases of joint inflammation. Activation of B cells also increases in certain tissues in the chronic phase of the disease. In summary, our results confirm the involvement of both innate and cognate immunity in the development of arthritis and demonstrate that monocytes, in addition to T cells, play a substantive role in the induction and maintenance of the inflammatory process in this rat model.