High-sensitivity C-reactive protein and erythrocyte sedimentation rate in systemic lupus erythematosus.

Levels of C-reactive protein (CRP) have been shown to rise in acute illnesses such as infections and some autoimmune diseases, but not in flares of systemic lupus erythematosus (SLE). Our goal was to investigate the high-sensitivity CRP (hsCRP) response to infection versus disease flare in patients with SLE, and to compare this with the erythrocyte sedimentation rate (ESR) response in these patients. We aimed to determine the hsCRP level that distinguishes between infection and flare in SLE, and investigated the correlation between hsCRP and organ involvement in SLE. We reviewed electronic medical records of all patients with SLE admitted to Cedars Sinai Medical Center between 28 August 2001 and 27 April 2008. Patients were divided into three groups based on the reason for hospitalization: (1) lupus flare; (2) active infection; and (3) both lupus flare and active infection. Data were collected on patient demographics, medication use, microbial culture results, organ involvement in lupus flare, ESR and CRP levels. Data were collected on 85 eligible patients, of whom 54 had a lupus flare, 22 had active infection and eight had both. While the ESR levels did not differ significantly between patients with disease flare and active infection, the hsCRP level was significantly lower in the lupus flare group than in the infection group. Most patients in the lupus flare group who had a significantly high hsCRP level had serositis. We found that at a cut-off of above 5 mg/dl, hsCRP level was correlated with infection with a specificity of 80%. At a cut-off of above 6 mg/dl, hsCRP correlated with infection with a specificity of 84%. hsCRP level was found to be significantly higher in patients with pulmonary involvement than without. hsCRP levels are significantly lower in SLE patients with disease flare than in those with active infection. Elevated hsCRP levels can be used as a predictor of active infection in SLE patients with a high specificity. We review the relationship between IL-6 and hsCRP production in lupus patients.

Usage of intra-articular corticosteroid injections for the treatment of juvenile idiopathic arthritis: a survey of pediatric rheumatologists in the United States and Canada.

OBJECTIVE: To characterize the current usage of intra-articular corticosteroid injections (IACI) by pediatric rheumatologists and the perceived disadvantages of and obstacles to IACI therapy. METHODS: We mailed a 32-item questionnaire to pediatric rheumatologists in the United States and Canada (n=201) to assess treatment strategies for the initial treatment of monoarthritis of the knee in juvenile idiopathic arthritis (JIA). Information regarding the usage of IACI for all patients with JIA and physicians' perceptions of IACI therapy was obtained. Respondents were dichotomized into those who performed frequent pediatric IACI (greater than 50 IACI in the last 12 months) and those who did not. RESULTS: One hundred and twenty-nine (64%) completed questionnaires were returned. IACI were recommended as one therapy for JIA by 99% of respondents, and 90% personally perform IACI. Frequent IACI were performed by 22%, and 15% had performed greater than 10 IACI in a single pediatric patient at one time. Those who did not perform frequent IACI were more likely to report concern about the pain of the procedure, the availability of nursing support, and their own comfort with performing the procedure; they were less likely to have performed greater than 20 pediatric IACI during fellowship training and evaluated fewer clinic patients per week. CONCLUSION: IACI are essentially universally recommended in the treatment regimen for JIA. However, there are differences in the usage of IACI among pediatric rheumatologists. The frequency of IACI use is associated with different perceptions of and training received in IACI therapy.

Modeling therapeutic strategies in rheumatoid arthritis: use of decision analysis and Markov models.

OBJECTIVE: The management of patients with rheumatoid arthritis (RA) is controversial, with a number of different proposed treatment strategies based on different conceptions of the natural history of the disease and different interpretations of the efficacy and effectiveness of the drugs used for treatment. We attempted to develop a theoretical framework to assess the effectiveness of different treatment regimens for RA. METHODS: We used decision analysis to structure the problem of comparing sequential monotherapy to a combination strategy. Subsequently, we used 3 different estimates of drug effectiveness: one from expert rheumatologists; a metaanalysis; and a recent nationwide survey of American rheumatologists, in a Markov model. Last, we utilized published duration of therapy data to model drug treatment over time. RESULTS: Estimates of drug effectiveness differed substantially among rheumatologists, but regardless of the estimates and the treatment strategy used, the model predicted over 90% of patients improved by the 3rd drug trial. Over time, treatment patterns in our model resemble the "sawtooth" pattern previously observed. CONCLUSION: Treatment strategies in RA are difficult to model because of uncertainty in both the structure of the model and the data needed to perform the analysis. These models tend to overestimate the effectiveness of drug sequences because of nonindependence between therapies, probably due to sequence effects, a change in responsiveness over time, or resistant subgroups. Our preliminary analysis suggests that the most effective agent, possibly methotrexate, should be used first if the objective is to get as many patients into remission as quickly as possible.

Is lupus a syndrome or a disease?

Does it matter whether we call lupus a disease or a syndrome? Because both conditions can be rigorously defined, this has little effect on uniformity of entry criteria for clinical trials. However, because diseases are the product of a single pathophysiologic mechanism, and syndromes are not, whether lupus is a disease or a syndrome does have broad ramifications. For example, looking for the "cause" or the "cure" for lupus involves a disease-specific conceptual framework, whereas, for syndromes we investigate risk factors and treatment modalities. On the basis of current laboratory data, we contend that lupus is a syndrome and only has candidate status as a disease. This helps to explain heterogeneity in results of studies of therapeutic agents and laboratory investigations of etiology. Patients, funding organizations, and lay support groups need to be aware of this distinction to reduce unrealistic expectations.

Sealant use in public and private insurance programs.

Dental sealants are a safe and efficacious method for preventing caries in pits and fissures. An increase in sealant use has been observed in the NHANES III survey. However this increase still accounts for less than one fifth of children aged 5-17 having sealants on their teeth. Reimbursement and coverage of sealants by public and private insurance programs have lagged behind the widespread acceptance of this methodology by the profession. Medicaid preventive services are poorly used by patients and the profession: and the inclusion of sealants in traditional, indemnity, fee-for-service commercial plans has been inconsistent. Managed care programs include dental sealants, but lack financial incentives to increase their use.

Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcgamma receptors (FcgammaR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, lambdas > 10, purported linkage at 1q41-42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log10 of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14-23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26-27, and 12p12-11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcgammaRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.

A survey of United States rheumatologists concerning effectiveness of disease-modifying antirheumatic drugs and prednisone in the treatment of rheumatoid arthritis.

OBJECTIVE: To collect the ratings of American rheumatologists regarding relative short-term and long-term effectiveness of disease-modifying antirheumatic drug (DMARD) therapy in the treatment of rheumatoid arthritis and to compare these data with results of a meta-analysis of randomized, controlled clinical trials (RCTs) of these drugs. METHODS: A survey was mailed to 3,200 United States rheumatologists who were members of the American College of Rheumatology during the summer of 1996. The survey was completed by 645 rheumatologists. RESULTS: Methotrexate (MTX) was rated as substantially more effective than any other DMARD after both 1 year and 4 years of therapy. At 1 year, more than 90% of rheumatologists rated MTX as "good or excellent," compared with 35% giving a similar rating to intramuscular (IM) gold, the second-ranked DMARD. At 4 years, MTX was rated as "good or excellent" by 65%, compared with 53% for combinations, 30% for prednisone, and 11% for hydroxychloroquine, the second-ranked single DMARD. These ratings reflect results of long-term observational studies, but differ considerably from a meta-analysis of results of short-term RCTs, in which the efficacy of MTX, sulfasalazine, penicillamine, and IM gold were indistinguishable. CONCLUSION: The ratings of US rheumatologists regarding effectiveness of DMARD therapies are in agreement with observational data, but differ substantially from results of RCTs. These findings suggest that observational studies may yield useful and important information about treatment results, which are complementary to, but not available from, the RCT model. Regulatory agencies should consider long-term observational studies as a part of the evaluation of drugs.

Health services research and systemic lupus erythematosus: a reciprocal relationship.

Many other statistical and epidemiologic approaches have been used in studies of systemic lupus erythematosus. Many of these, such as multivariate analysis and cost-benefit analysis, have substantially added to our understanding of the disease. However, in these instances it has been a clear application of the technique to a clinical problem. In the four areas I described, there was a convergence of clinical dilemmas and methodologic improvements, with the clinical problem actually contributing to the development of the methodologic technique used to address the question. In conclusion, major methodologic advancements in health services research and clinical epidemiology have developed pari passu with studies of the natural history of systemic lupus erythematosus. In some circumstances the clinical questions drove methodologic innovation and in other cases the methodologic studies were rapidly adopted and adapted to clinical investigation. It is unlikely that this was happenstance. We can anticipate that future investigations in lupus will utilize innovative techniques in health services research.

A preliminary evaluation of hydroxyurea for the treatment of rheumatoid arthritis.

OBJECTIVE: To obtain preliminary evidence on the safety and efficacy of low dose hydroxyurea as a treatment for rheumatoid arthritis (RA). METHODS: Five patients with active RA unresponsive to conventional therapy were entered into a 12 week, open label trial of hydroxyurea followed by a one month postdrug evaluation. RESULTS: Three of the 4 patients completing the study had a decrease in morning stiffness and number of swollen and tender joints. All 4 patients had a decrease in pain and an increase in function as measured by a modified health assessment questionnaire. No patient had improvement in sedimentation rate, C-reactive protein, or subjective measures of global well being. However, 3 of the 4 patients had disease flare after the drug was withdrawn, demonstrated by increased number of swollen and tender joints. CONCLUSION: Low dose hydroxyurea may be effective in the treatment of RA, but confirmation will require further testing by a randomized double blind placebo controlled trial of patients with a broader spectrum of disease severity over a longer period of therapeutic intervention.

The effect of cyclic-AMP on the regulation of c-myc expression in T lymphoma cells.

Myc is implicated in the control of growth in a variety of cell types. I investigated c-myc gene expression in several lymphoid cell lines to determine the response to cyclic AMP. Cyclic AMP causes a precipitous decline in c-myc message concentration that precedes G1 cell cycle arrest in wild type S49 cells but not in KIN- cells that lack cAMP dependent PKA activity. In wild-type S49 cells washout of cyclic AMP restores c-myc message levels within 2 h but does not relieve the G1 arrest until 10 h later. Transcription runoff studies demonstrate inhibition of both transcriptional initiation and prolongation of initiated transcripts. However, the degree of inhibition is insufficient to explain the absence of detectable myc message suggesting that the predominant effect of cyclic AMP is to destabilize the c-myc message. In contrast to wild-type cells, the "Deathless" mutant S49 cell line is viable when arrested in G1 by exposure to cyclic AMP and has preserved c-myc expression. Thus, in S49 cells down regulation of c-myc expression appears to be associated with loss of viability rather than G1 cell cycle arrest. Interestingly, CEM human T lymphoma cells do not arrest in G1 phase when exposed to cyclic AMP in spite of losing detectable c-myc gene expression. This suggests that in some T lymphoma cells c-myc gene expression may not be necessary for cell cycle progression and proliferation.

The treatment of rheumatic carditis: a review and meta-analysis.

We performed a meta-analysis of the literature on the treatment of established rheumatic carditis to determine if corticosteroid therapy is superior to salicylates in preventing the sequela of inflammation--valvular damage. We identified 22 reports of comparative trials published since the introduction of corticosteroids in 1949. Five of the 22 studies met the criteria we established for the meta-analysis, which included using randomization and a 1-year follow-up for the presence of a new pathologic apical systolic murmur. Based on the meta-analysis, the advantage of corticosteroid treatment over salicylates in preventing a pathologic murmur at 1 year posttreatment is not statistically significant (estimated odds ratio 0.88; 95% confidence interval: 0.53 to 1.46). However, the meta-analysis is dominated by 1 large negative trial, and there was significant heterogeneity in the results obtained from the studies in the meta-analysis; thus, the question of whether corticosteroid therapy is marginally superior to salicylates for the prevention of valvular heart disease from rheumatic fever remains open.

Opposite effects of cyclic AMP on the expression of the genes encoding ribonucleotide reductase in Swiss 3T3 and RAT 1 cells.

RAT-1 and Swiss mouse 3T3 cells are fibroblast cell lines that differ in their response to agents that elevate cyclic AMP levels. We examined the effect of agents that increase cyclic AMP on the expression of the genes that encode the two subunits of ribonucleotide reductase in these two cell lines. While serum stimulation leads to comparable expression in both cell lines, agents that increase cyclic AMP result in increased gene expression in Swiss 3T3 cells but diminished expression in RAT-1 cells. In addition, forskolin could inhibit serum or insulin augmented entry into S phase in RAT-1 cells, while promoting entry in Swiss 3T3 cells. Thus, in fibroblasts differential response to cyclic AMP is evident at the level of ribonucleotide reductase gene expression.

Ribonucleotide reductase gene expression during cyclic AMP-induced cell cycle arrest in T lymphocytes.

In both 3T3 mouse fibroblasts and S49 mouse T lymphocytes the genes encoding both subunits of ribonucleotide reductase are expressed beginning in late G1 phase. In studies reported here, we compared the expression of the genes that code for the M1 and M2 subunits of ribonucleotide reductase in S49 cells, which are arrested in G1 phase by agents that increase cyclic AMP, with those from CEM human T lymphoma cells that are unaffected by exposure to dibutyryl cyclic AMP. Dibutyryl cyclic AMP treatment results in a prompt steady diminution of M2 mRNA concentration to levels at or below that of elutriated G1 cell-cycle-specific populations in S49 cells, in contrast to CEM cell M2 mRNA, which is unchanged. M1 mRNA concentration decreases more slowly than M2 mRNA in S49 cells and marginally, if at all, in CEM cells. The time course of diminution of the M2 message concentration by dibutyryl cyclic AMP in S49 cells is similar to that obtained when cells are treated with actinomycin D and to the combination of the two agents. This suggests that cyclic AMP and actinomycin D may act similarly on ribonucleotide reductase gene expression. Furthermore, cycloheximide pretreatment diminishes the effect of dibutyryl cyclic AMP, indicating that the effect might be mediated by a labile protein. Transcription runoff assays suggest a diminution of transcription rate for the M2 gene in S49 cells treated with dibutyryl cyclic AMP and a transient decline in the M1 transcription rate. These data suggest that dibutyryl cyclic AMP diminishes the transcription of ribonucleotide reductase genes in sensitive cells and that this and the short half-life of the M2 message are major factors in the disappearance of the M2 messenger RNA from dibutyryl cyclic AMP-treated cells although other mechanisms may also play a role. These events clearly precede any alteration in cell cycle distribution and thus they may contribute to G1 arrest.

Synergistic and coordinate expression of the genes encoding ribonucleotide reductase subunits in Swiss 3T3 cells: effect of multiple signal-transduction pathways.

Ribonucleoside-diphosphate reductase (ribonucleotide reductase, EC 1.17.4.1) is the enzyme responsible for the in vivo production of deoxyribonucleotides for DNA synthesis and is essential for cell proliferation. We examined the signal transduction pathways leading to expression of the M1 and M2 subunits of this enzyme in Swiss 3T3 mouse fibroblasts by Northern blot analysis. Stimulation of quiescent cells resulted in coordinate expression of both subunits, beginning at 8 hr after serum addition, in late G1 phase, and peaking at 18-24 hr. Serum increased M2 message to 30 to 50 times that of quiescent cells, in contrast with M1 message, which was increased 10 times. Agents that elevated cAMP, including forskolin, and the cAMP analogue 8-bromo-cAMP modestly stimulated gene expression. Each of these agents was synergistic with insulin, and these combinations induced expression equivalent to that induced by serum stimulation. Likewise, agents that activate protein kinase C such as phorbol 12,13-dibutyrate, bombesin, and vasopressin were also synergistic with insulin with respect to ribonucleotide reductase gene expression, as was epidermal growth factor, which stimulates receptor tyrosine kinase activity. The time course for induction of mRNA expression by each of these agents alone or in combination was identical to that for induction stimulated by serum. Finally, the synergistic effects apparent in Northern analysis of ribonucleotide reductase gene expression were mirrored in parallel determinations of DNA synthesis. Thus, the combinatorial nature of signal transduction pathways resulting in proliferation of Swiss 3T3 cells is expressed at the level of ribonucleotide reductase gene expression.

Ehlers-Danlos syndrome: a case report.

A 13-year-old male patient classified as Type VIII, Ehlers-Danlos syndrome, in which the typical periodontal findings are not seen, is presented. The patient has many partially erupted deciduous teeth and partially erupted mandibular permanent incisors. It is suggested that Type VIII has two subdivisions. In subdivision A there is periodontal involvement with a normal eruption pattern; subdivision B has no periodontal involvement, but the teeth do not erupt.

Deoxyadenosine- and cyclic AMP-induced cell cycle arrest and cytotoxicity.

We compared deoxyadenosine (AdR)- and cyclic AMP (cAMP)-induced cell cycle arrest and cytotoxicity in wild type and mutant S49 cells to determine whether they resulted from the same or different mechanisms. Cyclic AMP and deoxyadenosine are synergistic rather than additive in cytotoxicity assays, suggesting different mechanisms of toxicity. Although cyclic AMP causes cell death after 72 h, in concentrations sufficient to result in cell cycle arrest it is reversible with virtually no cytotoxicity for at least 24 h, whereas AdR-induced cell cycle arrest is lethal and irreversible. AdR-induced G1 cell cycle arrest results in diminished ribonucleotide reductase activity but the kinetics of this inhibition differ from cyclic AMP-induced cell cycle arrest. Cyclic AMP arrest and cytotoxicity depend on cyclic AMP-dependent protein kinase (PKA) activity, whereas AdR toxicity does not differ between cell lines with or without PKA activity. Furthermore, deoxycytidine prevents AdR cell cycle arrest and cytotoxicity but has no effect on cyclic AMP G1 arrest. Finally, comparison of cytofluorographic patterns of G1-arrested cells suggests that the AdR block is later in G1 than cyclic AMP-induced cell cycle arrest. In summary, these data show that while the mechanisms of cell cycle arrest and cytotoxicity of cyclic AMP and deoxyadenosine are uncertain, they do appear to involve different pathways.

Effect of cyclic AMP on the cell cycle regulation of ribonucleotide reductase M2 subunit messenger RNA concentrations in wild-type and mutant S49 T lymphoma cells.

Ribonucleotide reductase activity in S49 T lymphoma cells is cell cycle regulated by de novo protein synthesis of the M2 subunit. There is maximal enzyme activity in S and G2/M phase with low activity and low concentrations of the M2 subunit in G1 phase. Pharmacologic concentrations of cyclic AMP arrest S49 cells in the G1 phase of the cell cycle. We investigated the effect of cyclic AMP on M2 messenger RNA concentrations using RNA from exponentially growing and elutriated, cell cycle-enriched populations. To discern whether cyclic AMP-induced G1 arrest was associated with low concentrations of M2-specific messenger RNA, we probed blots with a full-length cDNA for M2. Cell cycle variation in M2 messenger RNA concentrations was similar in wild-type, hydroxyurea-resistant cells with amplified M2 activity, and cyclic AMP-dependent protein kinase-deficient cell lines. All lines had low amounts of M2-specific mRNA in early G1, an increase at the late G1/early S phase interface, a decrease in mid S phase, and another increase in late S phase that continued through G2/M. These concentrations did not directly correlate with enzyme activity, suggesting other regulatory effects might participate in determining ribonucleotide reductase activity. Cyclic AMP exposure appeared to induce cell cycle arrest in early G1 with low M2-specific messenger RNA concentration. This effect reversed upon washout of the cyclic AMP and was dependent on functional cyclic AMP-dependent protein kinase (PKA). These results suggest that cyclic AMP arrests S49 mouse T lymphoma cells in early G1 prior to transcriptional activation of the M2 gene.