Biomedical subjects

Hani S El-Gabalawy

Publications and source records attributed to Hani S El-Gabalawy.

9 recordsLinked to original sources

PubMed2005

Early undifferentiated arthritis.

Patients who cannot be classified as having a well-defined arthropathy typically are labeled as having undifferentiated arthritis. Some patients develop sufficient features to permit classification, whereas others remain undifferentiated, but with persistent joint inflammation, functional disability, and development of radiographic damage. Identifying the subset of patients destined to develop rheumatoid arthritis, spondyloarthropathy, or a more severe and persistent form of undifferentiated arthritis and choosing appropriate treatment strategies remain challenges for clinicians. Numerous investigative strategies are available with which to characterize undifferentiated arthritis and assess prognosis. This article discusses the characteristics of undifferentiated arthritis at presentation and the investigative strategies that can be used to predict prognosis and outcome early in the disease course. Therapeutic strategies also are explored.

Arthritis↗

PubMed2005

Emerging biologic therapies in rheumatoid arthritis: cell targets and cytokines.

PURPOSE OF REVIEW: Biologic therapy for rheumatoid arthritis targets specific molecules, both cell-bound and soluble, that mediate and sustain the clinical manifestations of this complex disease. The aim of all the therapeutic strategies is to achieve complete and sustained suppression of inflammation, in the absence of unacceptable short-term and long-term toxicity. Despite the success of the currently available biologic inhibitors of tumor necrosis factor-alpha and interleukin-1, a substantial number of rheumatoid arthritis patients are refractory to these treatments. The purpose of this review is to highlight recent clinical trials of emerging biologic treatments for rheumatoid arthritis. RECENT FINDINGS: T cell co-stimulation has been targeted by the use of cytotoxic T lymphocyte-associated antigen 4-Ig, a genetically engineered fusion protein. In a large controlled clinical trial, this nondepleting approach was shown to achieve impressive clinical responses, without evidence of short-term toxicity. Likewise, rituximab, a B cell-deleting monoclonal antibody, was shown in a controlled clinical trial to have sustained benefit in patients with refractory rheumatoid arthritis. Despite profound B cell depletion with rituximab, there was an acceptable safety profile with this treatment. MRA, a monoclonal antibody that inhibits interleukin-6 by binding to its receptor interleukin-6R, demonstrated clinically significant improvement in rheumatoid arthritis and a particularly impressive reduction in the acute phase response. SUMMARY: The response of rheumatoid arthritis to a wide spectrum of therapeutic strategies attests to the complexity and heterogeneity of the disease and provides further impetus for studies that use these therapies to enhance our understanding of disease pathogenesis.

Animals↗

PubMed2005

Familial seropositive rheumatoid arthritis in North American Native families: effects of shared epitope and cytokine genotypes.

OBJECTIVE: A number of North American native (NAN) populations have high prevalence rates of both rheumatoid arthritis (RA) and the shared epitope (SE). We examined the phenotype and familial incidence of RA in a NAN population, and investigated how the SE and cytokine genes may affect disease risk within affected families. METHODS: NAN patients with seropositive RA or polyarthritis rheumatoid factor (RF) positive juvenile idiopathic arthritis (JIA) were identified from clinical databases. Patients were recruited consecutively as they presented for clinic visits. Family pedigrees were constructed and consenting relatives were interviewed and examined. The risk of RA within families was calculated by multiple logistic regression. Input variables were the SE and cytokine genotypes. Probands and affected relatives were entered as the affected group, and unaffected relatives within families as the unaffected group. Results were confirmed among unrelated subjects, i.e., unrelated patients and unaffected relatives of other probands. RESULTS: The familial prevalence of RA was 0.50 (95% confidence intervals 0.30, 0.70) among 28 families studied. The interleukin 10 (IL-10) promoter -1082 G/A genotype decreased the odds of RA relative to the A/A genotype in affected families (OR 0.247, 95% CI 0.081, 0.751; p = 0.014) and among unrelated subjects (OR 0.203, 95% CI 0.064, 0.640; p = 0.006). The G/G genotype yielded an OR of 0.093 (95% 0.013, 0.676; p = 0.019) among unrelated subjects. The SE had no effect in these calculations. CONCLUSION: There was a high familial prevalence of RA in this NAN cohort. In susceptible NAN families, the risk of RA was reduced by IL-10 genotypes, whereas the SE did not affect risk. Study of healthy NAN controls is required to determine if these conclusions apply to this NAN population as a whole.

Adolescent↗

PubMed2004

Oxidation in rheumatoid arthritis.

Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis. Reactive oxygen species (ROS) produced in the course of cellular oxidative phosphorylation, and by activated phagocytic cells during oxidative bursts, exceed the physiological buffering capacity and result in oxidative stress. The excessive production of ROS can damage protein, lipids, nucleic acids, and matrix components. They also serve as important intracellular signaling molecules that amplify the synovial inflammatory-proliferative response. Repetitive cycles of hypoxia and reoxygenation associated with changes in synovial perfusion are postulated to activate hypoxia-inducible factor-1alpha and nuclear factor-kappaB, two key transcription factors that are regulated by changes in cellular oxygenation and cytokine stimulation, and that in turn orchestrate the expression of a spectrum of genes critical to the persistence of synovitis. An understanding of the complex interactions involved in these pathways might allow the development of novel therapeutic strategies for rheumatoid arthritis.

Antioxidants↗

PubMed2004

Anti-Sa antibodies: prognostic and pathogenetic significance to rheumatoid arthritis.

Anti-Sa antibodies are detected in the serum of 20-47% of patients with rheumatoid arthritis. These antibodies have a high degree of specificity for the disease, and appear to identify a subset of early rheumatoid arthritis patients destined to have aggressive and destructive disease. It has recently been confirmed that anti-Sa antibodies are directed to citrullinated vimentin, thus placing them in the anti-citrulline family of autoantibodies. The Sa antigen has previously been shown to be present in synovium. This, along with the demonstration of citrullinated proteins in rheumatoid synovium, suggests that anti-Sa antibodies may play a pathogenetic role in the initiation and/or persistence of rheumatoid synovitis.

Antibody Specificity↗

PubMed2004

A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis.

OBJECTIVE: Early inflammatory arthritis is clinically heterogenous and biologically-based indicators are needed to distinguish severe from self-limited disease. Anti-cyclical citrullinated peptides (CCP) have been identified as potential prognostic markers in early arthritis cohorts. Since cytokine networks are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, a panel of pro- and antiinflammatory cytokines was measured to identify biologically-based subsets of early arthritis, relating cytokine profiles to clinical measures and to the presence of RA-associated autoantibodies. METHODS: Plasma concentrations of cytokines [interleukin 1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-7, CXCL8 (IL-8), IL-10, IL-12p70, IL-13, IL-17, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-g (IFN-g), CCL2 (monocyte chemoattractant protein-1, MCP-1), CCL4 (MIP-1beta), and tumor necrosis factor-a (TNF-a)] were measured in patients with early, untreated inflammatory arthritis [symptom duration < or = 12 months; > or = 1 swollen joint; RA, n = 41; undifferentiated arthritis (UA), n = 23]. Cytokine expression patterns were determined using cluster analysis. RESULTS: Both pro- and antiinflammatory cytokines were elevated in patients over controls (n = 21). RA clustered into subgroups based solely on cytokine profiles. The "mild" RA subgroup (n = 23) had higher CCL4 (MIP-1beta), CXCL8 (IL-8), IL-2, IL-12, IL-17, IL-5, and IL-10 levels, lower IL-6, IFN-g, GM-CSF, and IL-4 levels, less CCP positivity (52% vs 82%; p < 0.05), and lower CCP titers [71 (78) vs 153 (94); p < 0.01], but similar erythrocyte sedimentation rate, C-reactive protein, and joint counts compared to the "severe" RA groups. CCL4 (MIP-1beta), IL-13, IL-12, TNF-a, and IL-4 best distinguished the groups. Combining UA with RA samples preserved cytokine subgroups and strengthened the autoantibody associations. Fewer UA patients in the "mild" cluster (n = 16) were RF-positive (24% vs 100%; p < 0.002) or CCP-positive (24% vs 66%; p < 0.08) compared to the "severe" group. CONCLUSION: Early untreated inflammatory arthritis can be categorized into distinct subgroups based on cytokine profiles. These subgroups are associated with CCP and RF autoantibodies. Integration of cytokine profiles with autoantibody status may assist prognostication and treatment decisions in these patients.

Analysis of Variance↗

PubMed2003

Advanced glycation end-product (AGE)-damaged IgG and IgM autoantibodies to IgG-AGE in patients with early synovitis.

Advanced glycation end-product (AGE)-damaged IgG occurs as a result of hyperglycemia and/or oxidative stress. Autoantibodies to IgG-AGE were previously demonstrated in patients with severe, longstanding rheumatoid arthritis (RA). We investigated whether IgG-AGE and anti-IgG-AGE antibodies were present early in the course of RA and other inflammatory arthropathies. We prospectively followed a cohort of 238 patients with inflammatory arthritis of duration less than 1 year. Patients were evaluated clinically and serologically, and radiographs were obtained at initial and 1-year visits. Sera were assayed for IgG-AGE and anti-IgG-AGE antibodies by enzyme-linked immunosorbent assay (ELISA). Rheumatoid factor (RF) was determined by nephelometry and ELISA. Of all patients, 29% had RF-positive RA, 15% had RF-negative RA, 18% had spondyloarthropathy, and 38% had undifferentiated arthritis. IgG-AGE was present in 19% of patients, and was similar in amount and frequency in all groups. Patients with elevated IgG-AGE levels had significantly higher levels of the inflammatory markers C-reactive protein and erythrocyte sedimentation rate, but there was no correlation with blood glucose levels. Overall, 27% of the patients had IgM anti-IgG-AGE antibodies. These antibodies were highly significantly associated with RFs (P < 0.0001) and with swollen joint count (P < 0.01). In early onset arthritis, IgG damaged by AGE was detected in all patient groups. The ability to make IgM anti-IgG-AGE antibodies, however, was restricted to a subset of RF-positive RA patients with more active disease. The persistence of the anti-IgG-AGE response was more specific to RA, and was transient in the patients with spondyloarthropathy and with undifferentiated arthritis who were initially found to be positive for anti-IgG-AGE antibodies.

Adult↗

PubMed2002

Immune features of seronegative and seropositive arthritis in early synovitis studies.

Synovitis of recent onset is a challenging problem, both from a diagnostic and a mechanistic point of view. The role of the immune system in mediating the systemic and synovial inflammatory response remains an area of active investigation. Studies in early synovitis cohorts have confirmed the relatively specific association of rheumatoid factor positive polyarthritis with a number of autoantibodies, particularly anticyclical citrullinated peptide (CCP) antibodies, antifilaggarin antibodies (AFA), and anti-Sa antibodies. Immunopathologic studies of synovial tissue samples from patients with early synovitis have generally suggested quantitative rather than qualitative differences between various forms of synovitis. In particular, Th1 cytokines appear to predominate in rheumatoid arthritis and psoriatic synovitis, while Th2 cytokines are more often detectable in the synovium of reactive arthritis patients. This latter observation is consistent with an immune response profile that favors persistence of intracellular organisms.

Arthritis, Rheumatoid↗

PubMed2002

Gelatinase expression and activity in the synovium and skin of patients with erosive psoriatic arthritis.

OBJECTIVE: Matrix metalloproteinases (MMP), especially the gelatinases (MMP2, MMP9), have been implicated in several features of inflammatory arthritis including angiogenesis and bone erosions. We examined the expression and activity of the gelatinases and their regulators in psoriatic skin and synovium using tissue immunohistochemistry and a sensitive tissue based zymographic technique. METHODS: Lesional and perilesional skin biopsies and synovial samples obtained by closed needle biopsy from 15 patients with erosive psoriatic arthritis (PsA) were analyzed by immunohistochemistry for the expression of the gelatinases and their regulators, tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1, TIMP-2) and membrane type metalloproteinases (MTI-MMP. MT2-MMP), using immunohistochemistry. Synovial tissue from 8 patients with erosive rheumatoid arthritis (RA) was used as a comparison. MMP tissue expression was quantified by 2 blinded independent observers. Immunohistochemical data are reported as the mean percentage positive cells per total nucleated cells in 10 high power fields +/- SD. Functional activity of the gelatinases was measured using a sensitive tissue based zymography technique and corrected for protein content. Zymography data are presented as ng/mg +/- SE. RESULTS: MMP expression was greater in the synovial lining layer (LL) than in the synovial sublining layer (SL) in both PsA and RA tissue for most MMP except collagenase I (MMPI), which was equally distributed between the LL and SL. Expression of MMP or their regulators did not differ between PsA synovial membrane (SM) and RA SM in LL. Moreover, although latent gelatinase A (MMP2) staining in PsA SM was equivalent to RA SM, increased gelatinase A activity was found in PsA SM over RA SM using zymography L82.4 (SD 62.8) vs 10.1 (SD 1.7); p = 0.02]. Compared to PsA SM, lesional skin had lower levels of MT1-MMP (MMP14) (1.4 +/- 1.7 vs 15.7 +/- 8.4; p = 0.009) and MT2-MMP (MMP15) (12.1 +/- 8.7 vs 21.6 +/- 9.9; p = 0.001). CONCLUSION: We characterized the expression and activity of gelatinases in PsA and demonstrate that gelatinase activity in SM of PsA patients with erosive disease is comparable to if not greater than that in RA synovium.

Adult↗