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Background: There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE).Objective: To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE.Design: Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002.Setting: 16 university-affiliated rheumatology clinics or practices in 11 U.S. states.Patients: 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE.Interventions: 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group.Measurements: The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite.Results: Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis.Limitations: Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis.Conclusions: Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo. [ABSTRACT FROM AUTHOR]

Objectives: The primary aim of the CHANGE survey is to determine the current state of gender equity within rheumatology, and secondarily, to review the physician perspective on bullying, harassment and equipoise of opportunities within rheumatology., Methods: The CHANGE e-survey is a cross-sectional self-reported questionnaire adapted from EULAR's gender equity in academic rheumatology task force. The survey was launched in January 2023; it is available in six languages and distributed widely via rheumatology organizations and social media. Eligible participants include rheumatologist physicians and rheumatology health-care professionals. Survey responses will undergo descriptive analysis and inter-group comparison aiming to explore gender-based discrimination using logistic regression, with subgroup analyses for country/continent variations., Conclusion: This e-survey represents a comprehensive global initiative led by an international consortium, aimed at exploring and investigating the gender-related disparities and obstacles encountered by rheumatologists and rheumatology health-care professionals across diverse communities and health-care environments. By pursuing this initiative, we aim to take the broader rheumatology community a step closer to understanding the underlying origins of inequities and their determinants. Such insights are pivotal in identifying viable interventions and strategies to foster gender equity within the field. Ultimately, our collective objective is to ensure equitable access to opportunities for every individual, irrespective of gender, thereby promoting inclusivity and fairness across the entire spectrum of professional practice and career development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Lupus nephritis (LN) is among the most severe organ manifestations of systemic lupus erythematosus (SLE), affecting between 31% and 48% of patients, usually within five years of SLE diagnosis. SLE without LN is associated with a high economic burden on the healthcare system, and although data are limited, several studies have shown that SLE with LN could increase this burden.  Aim: We aimed to compare the economic burden of LN versus SLE without LN among patients managed in routine clinical practices in the USA and describe the clinical course of these patients., Materials and Methods: This was a retrospective observational study of patients with commercial or Medicare Advantage health insurance. It included 2310 patients with LN and 2310 matched patients who had SLE without LN; each patient was followed for 12 months after diagnosis (the patient's index date). Outcome measures included healthcare resource utilization (HCRU), direct healthcare costs, and SLE clinical manifestations.  Results: In all healthcare settings, the mean (SD) use of all-cause healthcare resources was significantly higher in the LN versus SLE without LN cohort, including the mean number of ambulatory visits (53.9 (55.1) vs 33.0 (26.0)), emergency room visits (2.9 (7.9) vs 1.6 (3.3)), inpatient stays (0.9 (1.5) vs 0.3 (0.8)), and pharmacy fills (65.0 (48.3) vs 51.2 (42.6)) (all p<0.001). Total all-cause costs per patient in the LN cohort were also significantly higher compared with the SLE without LN cohort ($50,975 (86,281) vs $26,262 (52,720), p<0.001), including costs for inpatient stays and outpatient visits. Clinically, a significantly higher proportion of patients with LN experienced moderate or severe SLE flares compared with the SLE without LN cohort (p<0.001), which may explain the difference in HCRU and healthcare costs., Conclusion: All-cause HCRU and costs were higher for patients with LN than for matched patients with SLE without LN, highlighting the economic burden associated with LN., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Bell et al.)

The objective of the study is to determine the risk factors for the development of reactive arthritis (ReA) and examine the factors associated with the persistence of symptoms. Patients with a new diagnosis of ReA and controls with a gastrointestinal (GI), urogenital, or sexually transmitted infection in the 3-6 months prior to study entry were prospectively enrolled in Guatemala City. ReA patients fulfilled the Assessment in Spondyloarthritis International Society criteria for peripheral spondyloarthropathy (SpA). Patients underwent history, examination, Achilles tendon ultrasound, and blood draw. Human leukocyte antigen (HLA) type and serum biomarkers were measured. t tests and nonparametric equivalents were used to examine the association of clinical, laboratory, and imaging factors with ReA. Patients were contacted 2 years later to assess for persistence of symptoms. Study subjects included patients with ReA (N = 32) and controls (N = 32). ReA patients were most frequently infected in April whereas controls were most frequently infected in August. Two ReA patients and two controls were HLA-B27-positive. Serum cathepsin K and C-reactive protein were higher in ReA patients compared to controls (p = 0.03 for both), while total cholesterol and low-density lipoprotein were lower (p = 0.008 and 0.045, respectively). Among those with ReA, 15 (47%) patients had continued symptoms at 2 years. These patients had a lower matrix metalloproteinase-3 level at diagnosis than patients for whom ReA resolved (p = 0.004). HLA-B27 was not associated with development of ReA in Guatemala; however, the month of infection was associated with ReA. The most striking finding was the persistence of arthritis at 2 years in nearly half of the patients.

Objective: To quantify muscle outcomes, independent of fat mass, in rheumatoid arthritis (RA) patients compared to healthy controls., Methods: Quantitative computed tomography scans measured calf muscle and fat cross-sectional area (CSA) and muscle density (an index of intramuscular adipose tissue), and isometric dynamometry was used to measure ankle muscle strength in 50 participants with RA ages 18-70 years and 500 healthy controls. Multivariable linear regression models assessed muscle deficits in RA after adjusting for group differences in adiposity and assessing for an altered muscle-fat association. Associations between RA disease characteristics and fat-adjusted muscle outcomes were also assessed., Results: Compared to controls, RA subjects had significantly greater body mass index (BMI) and fat area, and lower muscle area, muscle density, and muscle strength (P < 0.001 for all). Strength deficits were eliminated with adjustment for the smaller muscle area. The magnitude of muscle deficits, relative to controls, was significantly greater (P < 0.03 for interaction) in participants with lower fat area and BMI. Among those in the lower tertiles of adiposity, RA subjects demonstrated more significant deficits compared to controls with similar adiposity. In contrast, among those in the highest tertile for adiposity, RA was not associated with muscle deficits. Among RA, greater Sharp/van der Heijde scores were associated with lower muscle CSA and muscle density. Greater disease activity and disability were associated with low muscle density., Conclusion: Deficits in muscle area and muscle density are present in RA patients compared to controls and are most pronounced in subjects with low fat mass. Greater joint destruction is associated with greater muscle deficits., (Copyright © 2014 by the American College of Rheumatology.)

Circulating endothelial progenitor cells (EPCs) are reduced in patients with systemic lupus erythematosus (SLE). A reduced number of EPCs are associated with the presence of atherosclerosis in other populations. We sought to determine whether the reduction in EPC numbers in SLE is dependent on the presence of advanced coronary artery calcification (CAC). Patients with SLE had previous coronary calcium scores which placed them in either the >75th percentile or <25th percentile for their age. Seventeen patients with SLE and 13 healthy controls (HC) were included in the study. White blood cells were stained for EPC and progenitor cell markers including CD34, CD133, and VEGFR and analyzed by flow cytometry. SLE patients had repeated coronary imaging as well as carotid ultrasound. There was no difference in age between groups. SLE patients with advanced CAC were more likely to be hypertensive, to be smokers, and to have longer disease duration than SLE patients without CAC. SLE patients without evidence of CAC had a significantly lower number of EPCs (CD34+/CD133+/VEGFR+) compared to HC (median (IQR)) 0 (0, 6.7) vs. 10.2 (5.8, 12.3) (P = 0.02). Total numbers of PCs (CD133+/CD34+) were not significantly decreased in patients with SLE ((mean ± SEM) 1,007 ± 154 vs. 824 ± 170 (P = 0.20)). No significant difference was seen in EPC number between SLE patients without CAC and those with advanced CAC. Increased carotid intima-media thickness did not correlate with CAC or EPC number in SLE patients. Reduced numbers of EPCs in SLE patients may be observed compared to HC even in the absence of CAC. Differences in measured risk factor profiles and depletion of total circulating PCs do not fully explain this finding.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: "A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment." The LFA proposes this definition for lupus flare on the basis of its high face validity.

Objective: This study examined adherence, discontinuation, and switching of rheumatoid arthritis (RA) biologics over a 1-year period after initiation of the biologic treatment in Medicaid patients with RA., Methods: The study sample consisted of Medicaid patients with RA in California, Florida and New York who had newly initiated etanercept (n=1359), anakinra (n=267), or infliximab (n=1012) between January 1, 2000 and December 31, 2002. Adherence (proportion of days covered (PDC)≥0.80), discontinuation (90-day continuous gap), and switching (initiation of second biologic within 90days of discontinuation date of index biologic) were measured during the 12-month postindex biologic initiation. Sensitivity analyses were conducted by varying the thresholds to define these measures. Logistic regressions examined the factors associated with RA biologic adherence and discontinuation., Results: Anakinra users had the lowest mean PDC (0.36) and percent adherent patients (11%) followed by etanercept users (mean PDC: 0.57; % adherent: 32%) and infliximab users (mean PDC: 0.64; % adherent: 43%). All three groups had high discontinuation rates (41% etanercept, 76% anakinra, and 41% infliximab). Few patients who discontinued the index biologic switched to another biologic. Logistic regressions found that patients in Florida had lower odds of being adherent and higher odds of discontinuing their index biologic than patients in California. Anakinra users had lower odds and infliximab users had higher odds of being adherent than etanercept users. Anakinra users had higher odds of discontinuation than etanercept users., Conclusion: This study highlights the poor adherence to and premature discontinuation without concurrent switching of RA biologics that should raise concern for clinicians as well as payers., (© 2010, International Society for Pharmacoeconomics and Outcomes Research (ISPOR).)

Objective: To search for molecular evidence of Chlamydial infection in systemic lupus erythematosus (SLE) subjects and to assess if there is an association of this infectious agent with coronary artery calcification (CAC), a marker of total atherosclerotic burden., Methods: 28 SLE subjects had blood samples drawn and DNA extracted from peripheral blood mononuclear cells (PBMC) and an electron beam computed tomography (EBCT) scan. Polymerase chain reaction (PCR) analysis was performed for Chlamydia trachomatis 16srRNA and major outer membrane protein (MOMP) and for C. pneumoniae 16srRNA, MOMP, as well as nested PCR for MOMP., Results: Four of 28 subjects (14.2%) had evidence of C. pneumoniae nucleic acid in PBMC. The 16srRNA primers detected C. pneumoniae in one patient (3.57%) and the nested PCR MOMP primers in 3 subjects (10.71%). None were positive for Chlamydia trachomatis. Two of the 4 subjects with C. pneumoniae DNA had abnormal EBCT scans and 2/11 (18.3%) subjects with abnormal EBCT were positive for C. pneumoniae. There were significant associations of C. pneumoniae DNA with smoking (OR = 3) and corticosteroid use. The odds ratio for subjects with abnormal CAC and detectable C. pneumoniae was 1.67., Conclusion: This pilot study demonstrates for the first time that C. pneumoniae DNA can be identified in the PBMC of some SLE subjects and there may be an association with CAC. Smoking may be an additional risk factor for infection in this population. Determination of pathogenicity of this organism in atherosclerotic coronary vascular disease in SLE will require further study.

Medical treatment of low back pain is at best palliative. While no drugs are specifically labeled for back pain treatment, analgesics, muscle relaxants, and corticosteroids are used in practice to augment rest and exercise programs. Invasive therapy remains contentious. This article reviews the available literature on the various pharmacologic therapies. In addition, newly postulated outcome measures for future back pain studies are discussed.

Objective: To evaluate the utility of polymerase chain reaction (PCR) amplification in detecting DNA from venereal-associated microorganisms in the synovial fluid of patients with inflammatory arthritis., Methods: Oligonucleotide primers were developed for nested PCR based on Chlamydia, Ureaplasma, and Neisseria DNA sequences. PCR products were detected by gel electrophoresis and dot-blot hybridization. Primers specific for the target bacterial DNA were used to search for bacterial DNA in 61 synovial fluid specimens from patients with inflammatory arthritis, including several clinically associated with venereal infection., Results: Five of the 61 synovial fluid specimens were positive for Neisseria gonorrhoeae DNA. Four of the 5 patients had clinical diagnoses of gonococcal arthritis; the other patient had an unexplained monarthritis. One specimen from a patient with a clinical diagnosis of gonococcal arthritis was negative for N gonorrhoeae. Three of the 61 specimens were positive for Chlamydia DNA. Two were derived from patients with clinical diagnoses of reactive arthritis or Reiter's syndrome, and 1 was from a patient with unexplained monarthritis. One of the 61 specimens was positive from Ureaplasma DNA; this sample was from a patient with a clinical diagnosis of Reiter's syndrome. In an additional patient with Reiter's syndrome, Ureaplasma DNA was also found in prostate biopsy tissue and a urine sample obtained after prostate massage (synovial fluid not available)., Conclusion: These data support the classification of these 3 venereal-associated arthritides as infectious processes, and suggest that PCR for bacterial DNA is a useful method for detecting infectious agents in synovial fluid.

In most western countries, scurvy has become a rare clinical entity. However, it may still be encountered in selected situations. It can mimic connective tissue disease, because of multiorgan involvement. Panniculitis has not previously been described in association with scurvy.

Systemic lupus erythematosus (SLE) is a multisystem disease that predominantly affects women. Probable causative factors include genetic predisposition, complement deficiencies, persistence of antigen, drugs, and environmental factors. The widely varying presentations of SLE include skin, musculoskeletal, cardiovascular, renal, pulmonary, gastrointestinal, neuropsychiatric, systemic, hematologic, and immunologic manifestations. Milder symptoms can be managed with nonsteroidal anti-inflammatory drugs and antimalarial agents. Corticosteroids and cytotoxic drugs are given in more severe disease.

Several syndromes involving antiphospholipid antibodies have been described in the literature. Although the varied clinical manifestations have been well delineated, the vascular pathophysiology in patients with these antibodies remains unclear. Vascular damage is often described as a vasculopathy; however, several case reports have described an associated vasculitis. We report two patients with manifestations of antiphospholipid antibody syndrome (APLS) and concurrent vasculitis. The first patient, a 42-year-old man, presented with abdominal pain and fevers. The second patient, a 39-year-old man, presented with fever and testicular pain. Both were ultimately felt to have polyarteritis nodosa associated with APLS. Their complicated hospital courses and difficulties we encountered in diagnosing and treating them are discussed. The literature describing other cases of vasculitis associated with antiphospholipid antibody syndrome is reviewed. Whether the presence of antiphospholipid antibodies favors the development of vasculitis or vice versa is not clear. Further studies are needed to address this question and to determine optimal therapeutic regimens in these critically ill patients.

Synovial tissue is rarely available from patients with early synovitis, with the exception of synovial biopsies. However, T cell populations early in the development of synovitis may be enriched in antigen-specific cells and critical to disease pathogenesis. To investigate the T cell repertoire in early synovitis, we utilized a PCR protocol for detection of T cell receptor (TCR) transcripts present in small amounts of synovial tissue. To expand the substrate for PCR, preamplification of cDNA was performed with a 3' constant region primer plus either a mixture of variable region primers or random hexanucleotides. Utilizing this method improved the sensitivity of detection. This technique is applied here to the analysis of TCR transcripts in synovial biopsies from individuals with early rheumatoid arthritis (RA) and non-RA synovitis. TCR alpha-chain transcripts were detectable in 5/5 RA and 4/4 non-RA specimens evaluated, with beta-chain transcripts detected in 4/5 early RA and 4/4 non-RA specimens evaluated. Confirmation of transcripts by sequencing of cloned PCR products verified the specificity of amplification. The most frequently expressed TCR V region families in early RA synovitis were V alpha 11, V alpha 14, V alpha 28, V beta 7, V beta 9 and V beta 17. Several of these V regions have previously been implicated in studies of chronic RA synovitis. J alpha and J beta region usage was similar to that seen in chronic RA, and conserved N region motifs were apparent. We conclude that it is possible to detect TCR transcripts in small synovial biopsies from individuals with early arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)

In many autoimmune diseases autoantibodies are intimately involved in disease manifestations. Molecular characterization of these autoantibodies should provide insights into the pathogenesis of these diseases, as well as suggest novel avenues for development of therapeutics. While some prior studies suggest that DNA binding may be a characteristic of individual heavy chain variable regions, the ability of these V regions to bind DNA in isolation has not been investigated. We have utilized a bacterial vector for cloning and expressing isolated antibody heavy chain variable regions. RNA was extracted from peripheral blood mononuclear cells of patients with active SLE, cDNA synthesized and heavy chain V regions amplified with VH specific oligonucleotide primers. The VH fragments were cloned into a bacterial expression plasmid including the pelB leader peptide to direct appropriate expression. Recombinant antibodies were screened for binding to 32P-labeled double-stranded plasmid DNA and later also characterized for binding to single-stranded DNA. Binding was confirmed by standard ELISA methodology. Sequence analysis of seven DNA binding VH fragments revealed that they utilized the VH gene family previously described to be associated with autoimmune responses, with a JH6 segment. On VH sequence analysis only one residue substitution in the consensus sequence is needed to form a VH4 germline gene. Potential contact residues with DNA were delineated by three-dimensional structure analysis. We concluded that the DNA binding characteristics of VH regions can be examined in the absence of light chain. DNA binding specificity appears to be a property of the germline VH4 gene. Analysis of such V regions can aid in the identification of hypervariable region contact residues important for DNA binding.

Immunotherapy against autoreactive T-cell receptors (TCRs) has been reported to have promise in several animal models of autoimmune diseases. Facilitated DNA inoculation has many potential advantages as a modality for development of specific immune responses. Specifically, this technology is able to deliver exogenous antigens for processing via both the endogenous pathway, with subsequent presentation by class-I major histocompatibility (MHC) antigens, and the exogenous pathway, with subsequent presentation by class-II MHC antigens. This allows for induction of both arms of the cellular immune system. These cellular immune responses may be particularly important in targeting and controlling pathogenic cell populations. The application of this technology to the treatment of human autoimmune diseases depends on the availability of readily manipulated systems for the evaluation of specific interventions. Here we report the full length cloning and expression of TCRs from rheumatoid arthritis synovial tissue. These were developed by recombinant polymerase chain reaction, cloning and retroviral transduction into a TCR-alpha/beta-negative murine T-cell hybridoma. Reconstitution of CD3 expression was confirmed by flow cytometry. Similar constructs have been developed for TCR-based immunotherapy by facilitated inoculation of DNA intramuscularly. Preliminary analysis of immune responses in mice indicates that these constructs elicit anti-TCR responses. These studies indicate the ability to reconstitute expression of potentially autoreactive human TCRs in a model system wherein specific immune responses elicited against these TCRs by various immunogens can be evaluated.

Development of small molecular mimics of larger polypeptide ligands is an important approach to pharmacophore design. One strategy for the development of such mimics is analysis of alternative ligands that bind to the same site as the native ligand. These allow examination of the structural and chemical constraints for binding within the setting of diverse backbone geometries. The use of antireceptor antibodies as alternative ligands has allowed the development of biologically active peptides in several ligand-receptor systems. This technology has been applied to the study of interactions between human granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFR). GM-CSF is one of a family of signal-transducing cytokines and growth factors characterized by a four-helix bundle core structure. The GM-CSFR is comprised of an alpha-chain (GM-CSFR alpha) specific for GM-CSF, and a beta-chain (beta c) shared with the interleukin-3 and interleukin-5 receptors. At least two sites on GM-CSF have been implicated in the GM-CSF-GM-CSFR alpha/beta c ternary complex. In studies summarized here, synthetic peptide analogs of GM-CSF sequences were designed and used to map neutralizing epitopes. One neutralizing epitope corresponded to the A helix of GM-CSF, and a synthetic analog displayed biological activity as a GM-CSF antagonist in vitro, suggesting interaction with the GM-CSFR alpha/beta c complex. A second peptide comprising the B and C helices was recognized by monoclonal neutralizing antibodies and similarly displayed antagonist activity. Recombinant antibody (rAb) technology was also employed. An expression library of rAbs from mice immunized with neutralizing anti-GM-CSF antibodies was developed and screened with a neutralizing anti-GM-CSF monoclonal antibody. One clone which displayed receptor binding activity exhibited structural similarity with epitopes on GM-CSF previously implicated as interaction sites with the neutralizing monoclonal antibody. A synthetic peptide analog of the rAb inhibited GM-CSF bioactivity. Critical contact residues were predicted on the basis of structural similarity of the rAb peptide and GM-CSF. These studies indicate the feasibility of using rAbs in bioactive peptide design, providing lead compounds and information regarding contact residues for drug design.

Rheumatoid arthritis is genetically linked to major histocompatibility complex (MHC) molecules (HLA-DR4 and related molecules) and characterized pathologically by high levels of HLA-DR expression and infiltration of proliferative of synovial tissue with CD4+ T lymphocytes. T-lymphocyte activation is driven by specific signaling through polymorphic alpha/beta T-cell receptors (TCRs) that are reactive with antigen-MHC complexes present at the sites of inflammation. We are interested in characterizing rheumatoid TCRs molecularly to ascertain potential binding surfaces for antigen+MHC in synovial tissue. Accordingly, we have recently investigated the TCR alpha and beta chain heterogeneity in a series of 10 rheumatoid synovia obtained at the time of joint surgery. The most frequently detected V beta families were V beta 12, 14, and 17, each of which was found in 80% of specimens. We report here the molecular cloning and sequence analysis of 20 cloned V beta segments amplified with a V beta 14 family-specific TCR primer, and six cloned V beta segments amplified with a V beta 17 family-specific TCR primer from four rheumatoid synovia. Comparison with the data base revealed that these sequences belonged to the closely related V beta 3, V beta 14, and V beta 17 families. Dominant clones were apparent in two of the individuals by the presence of identical V-D-J regions, suggesting an antigen-driven process. Amino acid sequence analysis revealed a conserved motif in the putative fourth hypervariable region or CDR4. Molecular modeling of this epitope suggests that charged side chains are available for binding to ligand structures (e.g., antigen, MHC, or superantigen). We suggest this epitope may play a role in the molecular pathogenesis of rheumatoid arthritis.

Granulocyte/macrophage colony-stimulating factor (GM-CSF) plays a critical role in myeloid differentiation and in several immune and inflammatory processes. GM-CSF binds to specific cellular receptors (GM-CSFR) which belong to a recently described supergene family. These receptors are potential targets for pharmacologic design and such design depends on a molecular understanding of ligand-receptor interactions. We present our initial studies evaluating the potential active sites of the molecule. The sites on the GM-CSF molecule that were studied represent two alpha-helices predicted to be critical for GM-CSF activity, as implicated by human-murine chimeric molecule studies. These helices are predicted to be adjacent in native GM-CSF. Peptides corresponding to amino acids 17-31 and 78-99 of GM-CSF were synthesized and cross-linked to one another in two different orientations. The ability of anti-GM-CSF to bind the individual and complexed peptides was evaluated by both ELISA and radioimmunoassay. Significant binding to all peptides was demonstrated. A preferred orientation of the two peptides was apparent, and this agreed with the predicted model structures. Antibodies were developed against the coupled peptides, and these demonstrated significant cross-reactivity with recombinant human GM-CSF. Additionally, analyses of anti-peptide antisera binding studies predict these two amino acid sequences to lie in parallel planes to one another in the native human GM-CSF molecule.

The CNS afflictions in AIDS are myriad and suggest a tropism of HIV to neural tissue. Ocular involvement is a frequent manifestation of the HIV infection, resulting in a high incidence of blindness within this patient population. Ocular lesions include cotton wool spots, presumably from HIV-induced microvasculopathy, retinal hemorrhage in cytomegalovirus retinitis and conjunctival Kaposi's sarcoma. These manifestations have been noted in up to 71% of AIDS patients. In fact, ocular disease is often the presenting symptom in an HIV-infected individual. Despite the high incidence of ocular involvement in AIDS patients, the etiology and pathogenesis of these manifestations are not well understood. The immunosuppressive action of HIV is the most likely primary cause for the development of ocular complications in AIDS. Here we review some of the important immunological and pathological features of AIDS affliction in the eye.