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Background The What Matters Most (WMM) study was initiated to evaluate symptoms, AD-related impacts, treatment-related needs, preferences, and priorities among individuals with or at risk for Alzheimer’s disease (AD) and their care partners. The objective of this qualitative study phase was to identify a comprehensive set of concepts of interest that are meaningful to individuals across the AD continuum. Methods Interviews were conducted with 60 clinically referred individuals and care partners across 5 AD stages (n = 12 each): group 1 (non-clinically impaired individuals with AD pathology), group 2 (individuals with mild cognitive impairment and AD pathology), group 3 (individuals with mild AD), group 4 (individuals with moderate AD and their care partners), and group 5 (care partners of individuals with severe AD). Interviews were conducted by experienced interviewers, audio-recorded, and transcribed. Dominant trends were identified in each interview and compared across subsequent interviews to generate themes or patterns in descriptions of AD symptoms, impacts, and desired treatment outcomes. Results All participants endorsed current issues related to memory; nearly all participants (n = 55; 92%) across the five groups endorsed symptoms related to communication and language. Groups 1–3 reported an impact on mood/emotions (n = 23; 64%) and a decrease in social activities or outgoingness (n = 17; 47%). Current and future concerns reported by the overall sample included memory (n = 48; 80%), dependence (n = 40; 67%), and “other” concerns (n = 33; 55.0%) (e.g., uncertainty about the future, burdening others). The most desired AD treatment outcomes were improvement or restoration of memory (n = 40; 67%) and stopping AD progression (n = 35; 58.3%). Group-level differences were observed in the symptoms, impacts, and desired treatment outcomes among patients and care partners across the AD continuum. Conclusions Cognitive functioning issues—particularly in memory and communication—are present even in preclinical and early-stage AD, including among those without a formal AD diagnosis. While the impacts of AD vary across the disease-severity spectrum, improved memory and disease modification were treatment outcomes considered most important to participants across all 5 AD stages. Neuropsychological assessments traditionally used in AD clinical trials may not evaluate the often-subtle concepts that are important to patients and care partners. Results from this study will inform the second phase of the WMM project—a quantitative study to elicit the relative importance of these concepts of interest to people at risk for and living with AD and their care partners.

Objective.To develop a fibromyalgia (FM) survey questionnaire for epidemiologic and clinical studies using a modification of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010). We also created a new FM symptom scale to further characterize FM severity.Methods.The ACR 2010 consists of 2 scales, the Widespread Pain Index (WPI) and the Symptom Severity (SS) scale. We modified these ACR 2010 criteria by eliminating the physician’s estimate of the extent of somatic symptoms and substituting the sum of 3 specific self-reported symptoms. We also created a 0–31 FM Symptom scale (FS) by adding the WPI to the modified SS scale. We administered the questionnaire to 729 patients previously diagnosed with FM, 845 with osteoarthritis (OA) or with other noninflammatory rheumatic conditions, 439 with systemic lupus erythematosus (SLE), and 5210 with rheumatoid arthritis (RA).Results.The modified ACR 2010 criteria were satisfied by 60% with a prior diagnosis of FM, 21.1% with RA, 16.8% with OA, and 36.7% with SLE. The criteria properly identified diagnostic groups based on FM severity variables. An FS score ≥ 13 best separated criteria+ and criteria− patients, classifying 93.0% correctly, with a sensitivity of 96.6% and a specificity of 91.8% in the study population.Conclusion.A modification to the ACR 2010 criteria will allow their use in epidemiologic and clinical studies without the requirement for an examiner. The criteria are simple to use and administer, but they are not to be used for self-diagnosis. The FS may have wide utility beyond the bounds of FM, including substitution for widespread pain in epidemiological studies.

Objective To assess the performance of a generic health-related quality of life (HRQOL) measure in a rheumatology clinic population. Methods Participants (n = 619) with fibromyalgia, rheumatoid arthritis, or osteoarthritis receiving care from rheumatologists completed mailed questionnaires that included the Behavioral Risk Factor Surveillance System (BRFSS) HRQOL measure and condition-specific measures assessing disability, pain, fatigue, and helplessness. The BRFSS assesses global health and number of days in the past 30 of poor physical or mental health or activity limitation. The overall sample was described, followed by comparison of adjusted scores on all HRQOL measures by diagnosis. Results Participants reported mild difficulty with activities of daily living, marked pain and fatigue, and moderate helplessness. Participants reported a mean of 8 or more days out of 30 of poor physical and mental health and activity limitations; more than 40% reported poor or fair health. Participants with fibromyalgia reported more ill health on condition-specific measures and the BRFSS HRQOL measures than did participants with osteoarthritis or rheumatoid arthritis. Conclusion The BRFSS HRQOL measure is a brief, easily administered, generic health indicator that shows differences among rheumatic disease diagnoses.

Fibromyalgia and other chronic pain and fatigue syndromes constitute an increasingly greater societal burden that currently is not being approached effectively by traditional Western medicine. Although the hallmarks of fibromyalgia--chronic widespread pain, fatigue, and multiple other somatic symptoms--have neurophysiologic and endocrinologic underpinnings, these biological aspects derive primarily from psychological variables. Female gender, adverse experiences during childhood, psychological vulnerability to stress, and a stressful, often frightening environment and culture are important antecedents of fibromyalgia. To understand fibromyalgia and related syndromes and to provide optimum care requires a biopsychosocial, not a biomedical, viewpoint.

DNA-dependent protein kinase (DNA-PK) consists of a DNA binding subunit (Ku autoantigen), and a catalytic subunit (DNA-PKcs). In the present study, human autoantibodies that recognize novel antigenic determinants of DNA-PK were identified. One type of autoantibody stabilized the interaction of DNA-PKcs with Ku and recognized the DNA-PKcs–Ku complex, but not biochemically purified DNA-PKcs. Another type recognized purified DNA-PKcs. Autoantibodies to Ku (p70/p80 heterodimer), ‘stabilizing’ antibodies, and antibodies to DNA-PKcs comprise a linked autoantibody set, since antibodies recognizing purified DNA-PKcs were strongly associated with stabilizing antibodies, whereas stabilizing antibodies were strongly associated with anti-Ku. This hierarchical pattern of autoantibodies specific for components of DNA-PK (anti-Ku>stabilizing antibodies>anti-DNA-PKcs) may have implications for the pathogenesis of autoimmunity to DNA-PK and other chromatin particles. The data raise the possibility that altered antigen processing and/or stabilization of the DNA-PKcs–Ku complex due to autoantibody binding could play a role in spreading autoimmunity from Ku to the weakly associated antigen DNA-PKcs.

Objective. To determine the specificity of anti-CD45 autoantibodies in systemic lupus erythematosus (SLE) for native CD45 and for CD45 expressed by T cells and B cells, and at different stages of cellular activation. Methods. CD45 purified from different types of lymphocytes was examined by immunoblotting with sera from patients with SLE. Indirect immunofluorescence experiments were performed with purified anti-CD45 autoantibodies. Results. IgM anti-CD45 autoantibodies in SLE recognize native CD45 expressed on the surface membrane of viable lymphocytes and CD45 purified from activated peripheral T cells and certain T cell lines, but not CD45 purified from B cells or resting peripheral T cells. The presence or absence of reactivity is independent of the individual isoforms expressed. Conclusion. Recognition of CD45 by IgM antilymphocyte autoantibodies in SLE varies with the lineage and state of activation of the lymphocyte target. This pattern of reactivity is consistent with autoantibody specificities involving CD45 glycoforms, rather than CD45 isoforms.

Patients with SLE develop IgM autoantibodies to different isoforms of CD45, the major surface membrane protein tyrosine phosphatase on lymphocytes and other nucleated hemopoietic cells. Because such autoantibodies could have a potential role in the development of immune dysfunction in this disorder, we performed a series of experiments to characterize their antigenic specificity further. Blots of recombinant E. coli fusion proteins encoded by exons 3-7 of the p220 and p180 isoforms were uniformly non-reactive with SLE IgM, suggesting that anti-CD45 autoantibodies in SLE are directed against conformational and/or carbohydrate epitopes, rather than linear polypeptide epitopes. This issue was examined further using chemically and enzymatically modified CD45 purified from T cells by lectin affinity chromatography as substrates. Treatment of CD45 with 25 mM sodium-m-periodate, sufficient to abrogate binding to various lectins, abolished the reactivity with SLE anti-CD45 autoantibodies. On the other hand, digestion of CD45 with neuraminidase enhanced the binding of anti-CD45 autoantibodies from some of the SLE sera. This result probably reflects decreased steric hindrance or charge repulsion because the binding of mouse monoclonal antibodies directed against linear polypeptide epitopes of CD45 was similarly enhanced. Digestion of CD45 with N-glycosidase F had no effect on autoantibody staining. Taken together, these data suggest that IgM anti-CD45 autoantibodies in SLE recognize non-sialylated carbohydrate determinants in the highly O-glycosylated polymorphic domains of CD45.

IgM autoantibodies to nucleolin and histone H1 are strongly associated in the serum of patients with systemic lupus erythematosus. IgM eluted from immobilized nucleolin specifically stained histone H1 blotted to nitrocellulose; conversely, IgM eluates prepared from immobilized histone H1 stained nucleolin blots. We conclude that the linkage of anti-nucleolin and anti-histone H1 autoantibodies in SLE is due, at least in part, to immunologic cross-reactivity between these two autoantigens, which share certain similar structural features.

Autoantibodies in the sera of patients with systemic lupus erythematosus were examined with respect to their specificity for proteolytic fragments of histone H1 that retain, or do not retain, DNA-binding domains. 16 of 31 sera contained IgG and IgM antibodies to histone H1. IgM antibodies to H1 in 8 sera (50%) were directed at 18 kD and 20 kD alpha-chymotrypic H1 fragments that bore binding sites for DNA, as identified by staining immunoblots containing the fragments with ssDNA plus 6/0, a mouse monoclonal antibody against ssDNA, IgM with this type of histone H1 specificity did not react with comparably-sized V8 protease fragments of H1. IgM antibodies to H1 in the other patients were directed against entirely different epitopes which were preserved in V8 protease digests of H1. In serial studies of three patients during different phase of their SLE, the level of antibodies against the 18 kD and 20 kD histone H1 fragments varied in parallel with the level of anti-ssDNA antibodies in one and varied inversely in the other two. The data suggest that a significant proportion of autoantibodies to histone H1 are directed at a limited number of epitopes localized to H1 fragments containing DNA-binding sites.

The clinical and serologic characteristics of 17 patients with onset of systemic lupus erythematosus (SLE) after age 50 were compared with those of 49 younger patients. All patients were followed prospectively for a mean duration of 47 months. A clinical and serological data base was established for each patient, and information collected at each visit to a lupus clinic was analyzed by computer. The clinical featured distinguishing old-age SLE were a low incidence of significant renal disease and prominent pleuropericarditis and arthritis throughout the period of followup. Serologic abnormalities were milder in older patients. Thus, hypocomplementemia, anti-DNA antibodies, and C1q precipitins occurred less frequently, and rheumatoid factor was more often present than in younger patients with SLE. Regression analysis suggested linear change in disease expression with age rather than distinct age-related subgroups.

Circulating T cells bearing receptors for the Fc portion of IgG (T gamma) were identified by sensitive immunofluorescent techniques with rabbit IgG b4 allotype/anti-b4 complexes. A twofold decrease in both proportion and absolute number of T gamma cells was found in patients with active systemic lupus erythematosus (SLE) relative to values obtained during disease remission. The reduction in T gamma cells was most evident in patients with severe hypocomplementemia. A deficit of T gamma cells in active patients was not demonstrated. The percentage of total T cells rosetting with sheep erythrocytes was reduced in peripheral blood of most patients regardless of disease activity status, but particularly during SLE exacerbation. Cells lacking intrinsic surface immunoglobulin, IgG Fc receptors, and receptors for sheep erythrocytes were increased. These cells, operationally termed null, exhibited an inverse linear relationship with T cells that was not apparent in regression analyses performed against other lymphocyte subpopulations. Such differences were not found for B cells and IgG receptor-bearing non-B/non-T cells which were present in normal proportions in virtually all patients. The origin and functional significance of these unusual lymphocyte subpopulation abnormalities are discussed.

Monoclonal antibodies to known surface antigens on B cells and on resting and activated T cells of various types were used in several approaches to examine the specificity of IgM antilymphocyte antibodies in systemic lupus erythematosus (SLE). Surface determinants that were sought included: T3, T11, Leu-1, Leu-8 (pan-T); T4, T8 (T subset); beta 2-microglobulin (beta 2m); L243, Leu-10 (DR and DS/DC framework, respectively); anti-Tac (interleukin-2 receptor); 5E9 (transferrin receptor); and 4F2, AA1 (other activation antigens). The first strategy was based on inhibition of rosette formation between mouse monoclonal antibody-coated targets and anti-mouse IgG-coated erythrocytes by SLE sera, either directly at 4 degrees C or after modulation of IgM antilymphocyte antibody-reactive target cell antigen at 37 degrees C. Significant rosette inhibition, defined as greater than 2 standard deviations from the mean value for 10 control sera, was seen only for beta 2m (13 of 20 SLE sera were positive; inhibition = 15-58%). Next, relative fluorescence intensity of lymphocyte staining by monoclonal antibodies was assessed by flow microfluorometry after preincubation of cells with SLE serum at 4 degrees C or after modulation of SLE antibody-reactive antigen. Modulation markedly reduced or eliminated SLE antilymphocyte antibody IgM staining. Except for beta 2m, neither cold nor warm temperature preincubations altered the relative fluorescence intensity for the known surface antigens. These data confirm anti-beta 2m as a common antibody specificity in SLE and suggest that antilymphocyte antibodies in this disorder are not directed to Ia or to certain other defined lymphocyte antigens of functional interest.

Fifteen serum cryoprecipitates from 28 patients with systemic lupus erythematosus (SLE) contained DNA demonstrable by counterimmunoelectrophoresis after exhaustive digestion of cryoimmunoglobulin with pronase. The majority of these cryoprecipitates also exhibited increased DNA binding activity in a modified Farr assay. Both DNA and anti-DNA antibody were enriched in the cryoprecipitates relative to the supernatant serum level. These data provide direct evidence for the presence of DNA/anti-DNA complexes in the circulation of patients with SLE.

Members of the American Rheumatism Association (ARA) were surveyed to determine their views on the content and quality of their annual meeting. Responses were received from 1,208 members. ARA members were generally positive about the major components of the annual meeting program, but there were significant differences in opinion between practitioners and academicians. Practitioners favored a reduction in basic science material and an increase in didactic clinical sessions. Academicians were more likely to feel that recent annual meetings have adequately addressed their educational needs. These findings have implications for the planning of future annual meetings of the ARA.

In a prospective study 26 of 29 patients with systemic lupus erythematosus had cold-reactive antilymphocyte antibodies cytotoxic for autologous lymphocytes and lymphocytes from normal subjects. The level of antilymphocyte antibodies was highly correlated, by linear regression analysis, with lymphopenia in these patients. The data suggested that both the avidity and the concentration of these antibodies were important determinants in this relationship. A clear association between increased antilymphocyte antibody activity and exacerbation of SLE was demonstrated. Apart from lymphopenia, however, neither type of clinical manifestation nor any particular serologic abnormality appeared to be related to the presence of antilymphocyte antibodies.

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Using indirect immunofluorescence and flow cytometry, we determined the proportion and number of T3+, T4+, and T8+ cells in the peripheral blood of patients with systemic lupus erythematosus whose sera were positive for cold-reactive antilymphocyte antibodies versus values in patients whose sera were negative for these antibodies. There was a disproportionate reduction in T4+ peripheral lymphocytes when cold-reactive antilymphocyte antibodies preferentially cytotoxic for this subpopulation were present in autologous serum. The decrease in this subset was responsible for a reduction in the T4:T8 ratio; variation in the number and proportion of T8+ cells was insignificant. A similar, but autoantibody-independent, alteration in the T4+ subpopulation was found in patients who were receiving prednisone therapy. A relationship between T cell population abnormalities and systemic lupus erythematosus disease activity, per se, was not observed.

The influence of genetic and nongenetic factors on abnormalities of the immune response in systemic lupus erythematosus (SLE) was studied in 9 sets of twins in which one or both twins had SLE. Particular emphasis was placed on contrasting the results between the sibs of 3 monozygotic pairs discordant for clinical SLE. Depression of cell-mediated immunity, determined by lymphocyte blastogenic response to mitogens, was associated with the clinical expression of illness. In contrast, autoreactive antilymphocyte antibodies and lymphocyte tubuloreticular structures were found in both clinically affected and unaffected subjects and were more prominently associated with the presence of other serologic abnormalities. No evidence of antigens or cell surfaces determinants unique to affected sibs was encountered.

Antilymphocyte antibodies in serum from patients with systemic lupus erythematosus (SLE), as detected by microcytotoxicity and indirect immunofluorescence, were predominantly cold reactive and of the IgM class. These IgM antibodies were most active at 4 degrees C. IgG antibodies were infrequent, and were only minimally lymphocytotoxic. Most sera were cytotoxic for autologous lymphocytes and were equally reactive with normal and SLE lymphocytes, as well as with B- and T-cell preparations. Separate T- and B-cell specificities, which appeared not to be related to HL-A determinants, were identified by differential absorption experiments. The functional significance of these antilymphocyte antibodies is discussed.

Stress proteins have been highly conserved during evolution not only because of their fundamental importance in the response of the cell to stressful assaults, but also because they have critical roles in cellular activation and cell growth, regulation of protein function, protein transport, and protein assembly. Research focusing on the basic cell biology of stress proteins is intense at present, and will surely continue to be for some time to come. Of particular interest to immunologists and rheumatologists is the convergence of data in several fields that suggest that stress proteins in microorganisms that commonly infect humans may be triggers of humoral and cellular autoimmune responses and consequent overt autoimmune disease expression. Thus, stress proteins of M tuberculosis and other bacteria are close homologs of stress proteins in mammals, and may be involved in the pathogenesis of adjuvant-induced arthritis in rats and, possibly, of RA and reactive arthritis in humans. A great deal of work remains to be done in this area, including (a) generation and propagation of specifically reactive T cell clones, (b) molecular delineation of the immune recognition elements and critical epitopes shared by microbial stress proteins and host proteins, (c) definition of the relative contribution of alpha beta and gamma delta TCRs to T cell reactivity to stress proteins, and (d) clarification of the circumstances that enable persistent T cell autoreactivity to stress proteins. The data at hand are sufficiently compelling, however, to suggest that vaccination against T cells that recognize stress proteins may eventually become part of our therapeutic armamentarium to prevent or cure some forms of arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)

The relative specificity of systemic lupus erythematosus antilymphocyte antibodies for T cell subsets bearing the OKT4, OKT8, or autologous erythrocyte rosette (A-RFC) markers was examined in complement-dependent microcytotoxicity assays and by indirect immunofluorescence. Target cells included normal OKT4+ or OKT8+ T cell clones established from mitogen-activated blasts, resting or phytohemagglutinin-activated peripheral T cells highly enriched for OKT4+ cells or OKT8+ cells, and A-RFC+ and A-RFC- populations. In the majority of sera, cytotoxicity for T4+ cells was greater than that for T8+ cells regardless of cellular activation status. Overall cytotoxicity was considerably higher for activated cells, however, especially when warm assay temperatures were used. A-RFC+ targets were more reactive than nonrosetting T cells, and this was associated with strikingly higher relative fluorescence intensity of IgM staining. Despite these consistent differences in relative cytotoxicity or staining, antibody titers against all cell types were strongly correlated in individual sera. Absorption experiments failed to demonstrate distinct antibody specificities for T4+ and A-RFC+ cells. These data suggest that the major determinant of cytotoxic reactivity may be a single or limited number of surface antigens common to all T cells. Superimposed on this dominant system(s) is a special reactivity with certain distinct subsets and with activated T cells generally.

Bovine serum albumin (BSA) associated with thymus cells from a donor differing for 2 or 3 allotypic markers (a, b, A14–15) from recipient animals was immunogenic when administered to newborn rabbits. The same dose (15 μg)of antigen, as well as larger doses, administered in solution were usually tolerogenic. Recipients of thymus cells develop detectable levels of donor type immunoglobulin markers persisting for 8–10 weeks. The anti-BSA appeared to be exclusively of host origin; no relationship existed between the presence of the donor type immunoglobulin and the antibody response. Cellular chimeras in the peripheral blood were not demonstrated using sex chromosomes as markers.

Serologic studies were performed on 25 patients with systemic lupus erythematosus (SLE) during 29 acute episodes of central nervous system (CNS) disease. Increased anti-DNA antibody and decreased total serum hemolytic complement activity were observed only in those patients with associated extra-CNS disease manifestations. Patients with isolated CNS disease were otherwise in apparent clinical and serological remission regarding these two indices. No special association of cold-reactive IgM antilymphocyte antibodies was demonstrable in patients with ongoing CNS injury. Of special interest was an increased incidence of anti-Sm antibodies in the patients with CNS dysfunction relative to that in a large group of patients without neuropsychiatric disease. The incidence of anti-RNP was not increased. The data do not support direct involvement in SLE brain injury of either DNA/anti-DNA complexes or of lymphocytotoxic antibodies cross-reactive with brain cells, but do suggest an association of anti-Sm with CNS disease in this disorder.

Both putatively native(n) commercial calf thymus DNA and 14C labeled human KB DNA contained significant amounts of denatured DNA (dDNA) as determined by methylated albumin-kieselguhr chromatography. The proportion of dDNA in these preparations was sufficient to cause confusion regarding the antigenic specificity of anti-DNA antibody when unfractionated DNA was used in either the counterimmunoelectrophoresis or the Farr assays for anti-DNA antibody. Serum from patients with systemic lupus erythematosus contained both anti-nDNA and anti-dDNA antibodies. About 50% of patients with symptomatic procainamide-induced lupus (PLE) exhibited anti-dDNA; none had anti-nDNA. Procainamide treated patients with a positive ANF who did not have symptomatic PLE had neither anti-dDNA nor anti-nDNA.