Chronic inflammation in older people: recognition, consequences, and potential intervention.

In elderly individuals, some chronic inflammatory diseases appear to occur with increased frequency, and recent evidence suggests that some very common chronic, age-related disorders may be propagated and perpetuated by inflammatory processes, perhaps giving rise to the abnormal acute phase protein levels that are seen with increased frequency with aging. The consequences of chronic inflammation in the elderly undoubtedly contribute to excessive morbidity in this population. Treatment of chronic inflammation in the elderly is often difficult, requiring utmost care and close follow-up by a knowledgeable and dedicated physician.

Recurrent acute scleroderma renal crisis complicated by thrombotic thrombocytopenic purpura.

Acute renal crisis as an early manifestation of scleroderma is underemphasized, and its recurrence after initial successful therapy is rare. We describe a 32-year-old woman who presented with scleroderma renal crisis. A second episode of apparent renal crisis, however, was complicated by thrombotic thrombocytopenic purpura, which led to pancreatitis, a large cerebral infarction, and fatal outcome despite intensive therapy. This case illustrates the complexity and severity of diffuse systemic sclerosis presenting with multiple, major organ complications.

Quantitative and qualitative alterations of acute-phase proteins in healthy elderly persons.

To assess acute-phase proteins in relation to ageing, we measured serum concentrations of C-reactive protein of AGP in 131 healthy elderly individuals (aged >/= 65 years) living independently in the community, and 47 healthy younger individuals. Concentrations of CRP in the older persons (median = 3.0 microg/ml) were significantly greater than in the younger group (median = 0.9 microg/ml, p = 0. 0003). Concentrations of SAA and AGP were similar in the two groups, but AGP glycosylation forms with reduced binding affinity for concanavalin-A (changes that have been observed in chronic inflammatory states) were increased in the elderly sample (p<0.0001). These findings suggest that both quantitative and qualitative alterations of acute-phase proteins occur with physiological ageing in humans.

Tenidap in patients with rheumatoid arthritis. A 4-week, placebo-controlled study.

The present double-blind, placebo-controlled study was conducted to compare the safety and efficacy of tenidap in patients with rheumatoid arthritis (RA). Patients with flare of active RA following NSAID withdrawal were randomized to receive either placebo (n = 67) or tenidap (n = 131; 40-200 mg/day). The mean changes from baseline in efficacy and biochemical variables were compared between treatment groups at endpoint (4 weeks). The improvements in four of the five primary efficacy variables were significantly greater in the tenidap group compared with the placebo group (p < 0.01). Tenidap was also associated with an 18% reduction in erythrocyte sedimentation rate (ESR) and a marked, 51%, reduction in serum C-reactive protein (CRP) level, both of which were significantly greater than the changes in the placebo group (p < 0.05). The percentage of patients who discontinued because of side effects was the same in both groups (3%). In conclusion, tenidap 40-200 mg/day was effective and well tolerated in the treatment of patients with RA for 4 weeks.

An assessment of the Health Assessment Questionnaire functional ability index among women with systemic lupus erythematosus.

The validity of the Health Assessment Questionnaire (HAQ) functional ability instrument was tested in 120 women with definite systemic lupus erythematosus (SLE) from rheumatology clinics at 2 local tertiary care institutions. Reliability and validity results for this population of women (mean age: 41 years +/- 13; age at diagnosis 33 years +/- 13) indicate that (1) the HAQ was internally reliable (standardized alpha = 0.9443) with no interitem correlation exceeding (r = 0.75); (2) confirmatory factor analysis identified 2 predominant factors among the HAQ components suggestive of large limb gross movements (e.g., walking, arising) and small limb fine movements (e.g., the ability to eat and firmly grip objects). Cumulatively, the 2 factors accounted for 64% of the variation in HAQ ability response. The HAQ response was also valid when compared to the overall disability index (r = 0.65 to 0.82) and other common disease variables that were reported by the patient and collected by the physician at the time of clinical examination. In addition, when stratified by active and inactive disease as defined by the Lupus Activity Criteria Count, inactive patients reported lower disability components (dress, arise, eat, walk, hygiene, reach, grip and activity) than active patients. These findings confirm the valid use of the HAQ as a measure of disability, when compared with other clinical measures of disease status and activity, in female patients with SLE.

Induction of inflammatory cytokine release from cultured human monocytes by C-reactive protein.

The human acute phase protein, C-reactive protein (CRP), is capable of specifically binding to and modulating the function of mononuclear phagocytes. To investigate whether CRP can also affect the capacity of these cells to produce inflammatory cytokines, enzyme immunoassays and Western blot techniques were used to quantitate interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) produced by freshly-isolated normal human monocytes. CRP induced the rapid release of each cytokine, with significantly elevated levels in culture supernatants at 4 hours and maximal levels of TNF-alpha at 8 hours, and of IL-1 beta and IL-6 at 16 hours of culture. The effects of CRP were dose-dependent; greater than 10-fold increases of each cytokine were observed following culture with greater than or equal to 50 micrograms/ml CRP, concentrations which are often found in the presence of moderate to severe inflammation or tissue injury. The induction of cytokine release by CRP was unaffected by inclusion of 25 micrograms/ml polymyxin-B in culture media, but was completely abrogated by prior boiling of the CRP, a procedure which had no effect on induction of monocyte cytokine release by lipopolysaccharide. The dose-dependent induction of inflammatory cytokines by CRP provides further support for the hypothesis that interaction with mononuclear phagocytes constitutes an important biological role for this acute phase protein.

Effect of flurbiprofen on cytokine production by human monocytes and U-937 and THP-1 cell lines.

Possible effects of nonsteroidal antiinflammatory drugs (NSAID) on inflammatory mediators other than arachidonic acid metabolites which might contribute to the antiinflammatory effects of these drugs have not been fully explored. We investigated the effects of an NSAID, flurbiprofen, on production of the cytokines tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6) by human peripheral blood monocytes and by the human cell lines U-937 and THP-1. Cytokine production was induced by 1 microgram/ml bacterial lipopolysaccharide (LPS) in both monocytes and cell lines, and cytokine levels in supernatants were measured by enzyme immunoassay. In monocytes, IL-6 was the major product while in both cell lines, TNF alpha was the major product. Flurbiprofen caused moderate inhibition of IL-1 beta and TNF alpha production by stimulated monocytes, but did not affect IL-6 production. In contrast, flurbiprofen completely abolished IL-6 production by both cell lines and substantially inhibited IL-1 beta and TNF alpha production. These observations raise the possibility that inhibition of cytokine production by flurbiprofen may contribute to the antiinflammatory properties of this drug.

Binding of human C-reactive protein to monocytes: analysis by flow cytometry.

An opsonic role has been proposed as a major function of C-reactive protein (CRP) in humans. In support of this hypothesis, recent radiolabelled ligand binding studies have provided evidence for the presence of specific receptors for soluble human CRP on human phagocytic cells, including neutrophils and monocytes. In order to confirm specific binding of CRP to monocytes and to quantify the percentage of such cells capable of expressing binding sites, we employed a sensitive biotin-avidin fluorescence assay to study the CRP-monocyte interaction. It was observed that 67% of monocytes bound biotinylated CRP in a dose-dependent manner, that the binding was calcium dependent, and that it could be inhibited by 60% in the presence of a greater than 20-fold excess of competing native CRP. In other experiments, neither IgG nor heat-aggregated IgG inhibited the binding of CRP to monocytes; and no significant binding to lymphocyte population could be detected. These studies confirm the ability of human CRP to bind to a majority of human monocytes in a calcium-dependent and specific manner, and provide further support for a biologically important interaction of this acute-phase protein with phagocytic cells.

Direct quantitation of skin elasticity in systemic sclerosis.

A simple instrument, the "skin elastometer," was used to evaluate the elastic and plastic properties of volar forearm skin in 24 patients with systemic sclerosis and 24 healthy individuals matched for age, race and sex. Skin elastance in 17 patients with diffuse scleroderma was found to be significantly different from matched controls (p less than 0.001), and was associated with clinical skin scores independently determined by examination (r = 0.89, p less than 0.001). Seven patients with limited scleroderma (the CREST variant) had values for skin elastance which were intermediate between those of the patients with diffuse scleroderma and healthy persons. Plastic deformation of the stretched skin was similar in patients and controls. Quantitative measurement of skin elastance is a simple technique which may prove to be of value in the assessment of patients with systemic sclerosis.

Absence of a binding reactivity of human C-reactive protein for immunoglobulin or immune complexes.

Because C-reactive protein (CRP) has been identified as a component of circulating immune complexes from patients with inflammatory diseases, we sought to evaluate a potentially clinically important interaction of this acute-phase protein with immunoglobulin or experimentally-prepared immune complexes in vitro. Highly purified human CRP was incubated with a variety of immunoglobulin substrates, including monomeric immunoglobulin G1 (IgG1), a polyclonal IgG, heat-aggregated IgG, and human serum albumin/anti-serum albumin complexes. We were unable to detect a significant binding interaction of radioiodinated CRP with any of these materials, using either polyethylene glycol (PEG) precipitation or sucrose density gradient ultracentrifugation. In contrast, binding of radioiodinated human C1q to both aggregated immunoglobulin and immune complexes was readily detected by these techniques. Incubation of radiolabeled CRP with serum samples from 22 patients with active inflammatory diseases and high levels of circulating immune complexes disclosed no difference in the amount of PEG-precipitable CRP when compared with serum samples from healthy individuals. However, a radiolabeled commercial preparation of CRP did result in some PEG-precipitable radioactivity after incubation with aggregated IgG. These findings provide no support for a biologically important binding interaction of CRP with immunoglobulin or immune complexes, and they suggest that highly purified preparations of CRP should be used in functional studies of this acute-phase protein.

Specific binding of human C-reactive protein to human monocytes in vitro.

The precise biologic function of C-reactive protein (CRP), a major acute phase protein in man, is unknown. The abilities of CRP to bind biologic substrates and to activate the C pathway, and its localization at sites of inflammation argue for an opsonic role for this protein. Such a role has been supported by recent reports of specific binding of CRP to neutrophils. Using highly purified radioiodinated human CRP, we have observed specific binding of this protein to human monocytes in vitro. The binding was reversible and rapid, with a t1/2 for the dissociation reaction of approximately 3 min. Binding was saturable at a CRP concentration of approximately 0.2 microM, with an estimated K from Scatchard analysis of 1.1 x 10(-7) M. Specific binding was calcium-dependent, with optimal binding occurring at calcium concentrations of more than 1.0 mM. No specific binding could be demonstrated to a non-adherent population of mononuclear cells (more than 80% lymphocytes). In other experiments, a 100-fold excess of human IgG failed to inhibit binding, although rabbit CRP produced competitive inhibition of binding which was quantitatively similar to human CRP. The binding was maximal at pH 7.4 and was sensitive to prior trypsin treatment of cells. These studies provide direct evidence for specific binding of soluble human CRP to human monocytes in vitro and thus provide further support for an important functional interaction of this acute phase protein with phagocytic cells in man.

Clinical aspects of antibodies to DNA.

The detection of antibodies to DNA is one of the most important laboratory tests in rheumatology and immunology from both scientific and clinical points of view. The most useful methods for detection of anti-DNA are the liquid phase radioimmunoassay (Farr assay), solid phase enzyme-linked assays (ELISA) and immunofluorescence (Crithidia Luciliae). The clinical value of detection of anti-DNA can be summarized as follows: (a) Antibodies to DNA (particularly those reactive primarily with double-stranded DNA determinants) are highly specific for the disease SLE; (b) Levels of anti-DNA bear a close relation to disease activity in many patients. Rapidly rising levels are frequently associated with a subsequent exacerbation and clinical improvement is often accompanied by declining levels of anti-DNA. However, a minority of patients may have persistent elevations of anti-DNA for extended periods in the absence of overt clinical disease activity; (c) Although a single determination of anti-DNA has little prognostic value, the persistent presence of high levels or the absence of anti-DNA may define patient subsets with poor and good prognoses respectively; (d) Antibodies to single stranded DNA although present in some patients with discoid lupus and "ANA-negative" lupus, have little diagnostic specificity and are less valuable for disease follow-up as compared with antibodies to double-stranded DNA.

Systemic lupus erythematosus. Controversies in management.

At the core of the controversy surrounding the management of systemic lupus erythematosus are the two issues of when to treat and what treatment to use. On the basis of a review of the recent medical literature, the following conclusions can be drawn: Patients with isolated serologic or histologic renal abnormalities in the absence of clinical disease activity probably should not be treated. Such abnormalities primarily serve to indicate the need for close follow-up and to heighten the physician's concern about the possible development of clinical symptoms. For those patients with systemic manifestations who require corticosteroids, a regimen of single daily doses is appropriate. The dose should be tapered as rapidly as the degree of symptomatic control allows; a switch to alternate-day therapy can be considered as symptoms become quiescent. Intravenous methylprednisolone therapy may be used for patients with very severe systemic disease, particularly acute nephritis. In addition, use of immunosuppressive agents should be considered for all patients with clinically serious renal disease.

Intravenous pulse methylprednisolone followed by alternate day corticosteroid therapy in lupus erythematosus: a prospective evaluation.

We explored the feasibility of using intravenous pulse methylprednisolone followed by alternate day steroids for treatment of active systemic lupus erythematosus (SLE) in an attempt to avoid longterm daily steroid therapy. Our study was terminated after 11 trials because sustained control of disease activity was possible in only a minority of patients. Pulse therapy was initially very effective: there was rapid improvement in clinical symptoms, and significant improvement of serum anti-DNA (p less than .01) and C3 (p less than .05), but not in other laboratory tests, within 2 weeks of pulse treatment. On followup, alternate day steroids had to be discontinued in 7 trials; 3 patients experienced recurrence of their presenting symptoms, and 4 demonstrated worsening of laboratory abnormalities reflective of active renal disease. Despite the efficacy of pulse for initial management of active SLE, only 4 patients could be successfully maintained on a subsequent alternate day steroid regimen for prolonged periods.

Pregnancy and systemic sclerosis.

Pregnancy has been reported infrequently in patients with systemic sclerosis. Consequently, the outcome and appropriate management of such patients is uncertain. We review the obstetric experience of 19 female patients with systemic sclerosis, and report 2 women in whom 3 pregnancies occurred during the course of disease. Maternal complications included hypertension during 2 of these pregnancies and congestive heart failure during 1. There were 2 premature deliveries, although all 3 infants survived. Our experience with these patients and a review of the available literature suggest that, in patients with systemic sclerosis, fertility may be reduced and complications of pregnancy may be more frequent.