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Objective: A number of non-HLA loci that have shown evidence (P < 0.05) for linkage with rheumatoid arthritis (RA) have been previously identified. The present study attempts to confirm these findings., Methods: We performed a second genome-wide screen of 256 new multicase RA families recruited from across the United States by the North American Rheumatoid Arthritis Consortium. Affected sibling pair analysis on the new data set was performed using SIBPAL. We subsequently combined our first and second data sets in an attempt to enhance the evidence for linkages in a larger sample size. We also evaluated the impact of covariates on the support for linkage, using LODPAL., Results: Evidence of linkage at 1p13 (D1S1631), 6p21.3 (the HLA complex), and 18q21 (D18S858) (P < 0.05) was replicated in this independent data set. In addition, there was new evidence for linkage at 9p22 (D9S1121 [P = 0.001]) and 10q21 (D10S1221 [P = 0.0002] and D10S1225 [P = 0.0038]) in the current data set. The combined analysis of both data sets (512 families) showed evidence for linkage at the level of P < 0.005 at 1p13 (D1S1631), 1q43 (D1S235), 6q21 (D6S2410), 10q21 (D10S1221), 12q12 (D12S398), 17p13 (D17S1298), and 18q21 (D18S858). Linkage at HLA was also confirmed (P < 5 x 10(-12)). Inclusion of DRB1*04 as a covariate significantly increased the probability of linkage on chromosome 6. In addition, some linkages on chromosome 1 showed improved significance when modeling DRB1*04 or rheumatoid factor positivity as covariates., Conclusion: These results provide a rational basis for pursuing high-density linkage and association studies of RA in several regions outside of the HLA region, particularly on chromosomes 1p, 1q, and 18q.

Objective: To screen for potential efficacy and assess the feasibility of intravenous (IV) doxycycline as a treatment for rheumatoid arthritis (RA)., Methods: The study was a (stratified, block) randomized, double blind, 12 week, pilot trial of IV doxycycline 300 mg/day versus identical appearing IV placebo given over 2 h for 14 days. The primary comparison was to a hypothesized placebo rate of 20% as described by Paulus. If a total of 14 consecutive subjects receiving doxycycline treatment did not respond, it would be considered futile to proceed to a Phase III trial. We planned a placebo group of 14 subjects to verify the placebo response rate and estimate sample size required for a definitive Phase III trial, if such a trial was warranted based on the pilot study. American College of Rheumatology (ACR) RA response criteria were used. After 23 subjects entered, the study was closed due to recruitment difficulties., Results: At baseline, mean (SD) tender joint count was 37 (11.9), swollen joint count 30 (9.6), morning stiffness 317 (319) min, and erythrocyte sedimentation rate 72 mm/h (27.5). Randomization resulted in 10 subjects receiving doxycycline and 13 receiving placebo. Treatment was stopped in 8 subjects: in 6, treatment was ineffective (one taking doxycycline, 5 placebo), and in 2, rashes occurred (one taking doxycycline, one placebo). Only one subject met ACR response criteria in the doxycycline group and none in the placebo group. Having no responders in the placebo group was consistent with placebo response rate of 20% or less. Several patients required peripherally inserted central catheters for venous access., Conclusion: The efficacy of IV doxycycline as a treatment for RA could not be ruled out. However, as the proportion of responders was small, it is unlikely that potential efficacy of IV doxycycline would outweigh potential disadvantages of IV administration.

Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

A number of hormonal abnormalities are present in RA patients. A major theme of these abnormalities seems to be that deficiencies in the production or action of gonadal (estrogens and androgens) and adrenal (corticosteroids and DHEA) hormones may be involved in regulating the onset, severity, and progression of RA. Differences in RA incidence and activity in the pregnant and postpartum periods provide the strongest support for this view. Hormonal changes during these periods clearly have the potential to exert profound effects on RA incidence and activity. The effect of pregnancy on RA activity is actually greater than the effect of some of the newer therapeutic agents. The striking increase in corticosteroids, estrogen, and progesterone during pregnancy may suppress RA onset or activity through the regulation of production or action of cytokines such as TNF alpha, IL-1, IL-6, IL-12, and IL-10. The relative adrenal- and gonadal-deficient environment of the postpartum period further supports the view that hormonal deficiencies predispose to the development or increased activity of RA. These observations justify the search for hormonal abnormalities in RA patients outside the pregnancy and postpartum periods. In particular, further studies on the period before the onset of disease are needed. Additional evidence does exist that a functional abnormality in the adrenal glands in RA patients results in dysregulation of corticosteroid and DHEA production. These abnormalities seem to be linked to aging and disease activity. It is still not established whether these abnormalities are primary or secondary, although data indicating adrenal hypofunction before the development of RA or within the first year of disease activity suggest a primary abnormality. Several hormonal abnormalities seem to be restricted by gender and age, particularly around perimenopause and menopause. These age- and gender-influenced effects may be the cause of some of the contradictory data reviewed here. Studies in the future should make greater efforts to segregate study populations by age, gender, and reproductive status. The identification of the specific hormonal abnormalities and patient populations that are at risk is important, because these factors may allow new therapeutic approaches that are less toxic than current regimens.

Rheumatoid arthritis (RA) is a common, chronic, autoimmune, inflammatory disease that is influenced by genetic factors including gender. Many studies suggest that the genetic risk for RA is determined by the MHC, in particular class II alleles with a 'shared epitope' (SE), and multiple non-MHC loci. Other studies indicate that RA and other autoimmune diseases, in particular insulin-dependent diabetes mellitus (IDDM) and autoimmune thyroid disease (ATD), share genetic risk factors. Rat collagen-induced arthritis (CIA) is an experimental model with many features that resemble RA. The spontaneous diabetes-resistant bio-breeding rat, BB(DR), is of interest because it is susceptible to experimentally induced CIA, IDDM and ATD, and it has an SE in its MHC class II allele. To explore the genetics of CIA, including potential gender influences and the genetic relationships between CIA and other autoimmune diseases, we conducted a genome-wide scan for CIA regulatory loci in the F(2) progeny of BB(DR) and CIA-resistant BN rats. We identified 10 quantitative trait loci (QTLs), including 5 new ones (Cia15, Cia16*, Cia17, Cia18* and Cia19 on chromosomes 9, 10, 18 and two on the X chromosome, respectively), that regulated CIA severity. We also identified four QTLs, including two new ones (Ciaa4* and Ciaa5* on chromosomes 4 and 5, respectively), that regulated autoantibody titer to rat type II collagen. Many of these loci appeared to be gender influenced, and most co-localized with several other autoimmune trait loci. Our data support the view that multiple autoimmune diseases may share genetic risk factors, and suggest that many of these loci are gender influenced.

Rat Chromosome 10 (RNO10) harbors Cia5, a non-MHC quantitative trait locus (QTL) that regulates the severity of type II collagen-induced arthritis (CIA) in DAxF344 and DAxBN F2 rats. CIA is an animal model with many features that resemble rheumatoid arthritis. To facilitate analysis of Cia5 independently of the other CIA regulatory loci on other chromosomes, DA recombinant QTL speed congenic rats, DA.F344(Cia5), were generated. These QTL congenic rats have a large chromosomal segment containing Cia5 (interval size < or =80.1 cM) from CIA-resistant F344 rats introgressed into their genome. Phenotypic analyses of these rats for susceptibility and severity of CIA confirmed that Cia5 is an important disease-modifying locus. CIA severity was significantly lower in the Cia5 congenic rats than in DA controls. We also generated DA Cia5 speed sub-congenic rats, DA.F344(Cia5a), which had a smaller segment of the F344 genome, Cia5a, comprising only the distal q-telomeric end (interval size < or = 22.5 cM) of Cia5, introgressed into their genome. DA.F344(Cia5a) sub-congenic rats also exhibited reduced CIA disease severity compared with the parental DA rats. The regulatory effects in both congenic strains were sex influenced. The disease-ameliorating effect of the larger fragment, Cia5, was greater in males than in females, but the effect of the smaller fragment, Cia5a, was greater in females. We also present an improved genetic linkage map covering the Cia5/Cia5a region, which we have integrated with two rat radiation hybrid maps. Comparative homology analysis of this genomic region with mouse and human chromosomes was also undertaken. Regulatory loci for multiple autoimmune/inflammatory diseases in rats (RNO10), mice (MMU11), and humans (HSA17 and HSA5q23-q31) map to chromosomal segments homologous to Cia5 and Cia5a.

Objective: Collagen-induced arthritis (CIA) is a polygenic model of experimentally induced autoimmunity and chronic joint inflammation. This study maps genetic loci that regulate CIA susceptibility in DA/Bkl (DA) and BN/SsNHsd (BN) rats., Methods: Genome scans covering chromosomes 1-20 and interval mapping techniques using 159 simple sequence-length polymorphism markers were used to identify quantitative trait loci (QTLs) that regulate CIA in (DA x BN)F2 hybrids. Serum antibody titers to type II collagen were determined by enzyme-linked immunosorbent assay., Results: DA rats were high responders to porcine type II collagen (PII) and developed severe CIA (100%). BN rats were low responders to PII and resistant to CIA (0%). BN genes strongly repressed PII-induced CIA. Only 12% of (DA x BN)F1 rats (7 of 60) and 31% of (DA x BN)F2 rats (307 of 1,004) developed CIA. Three new QTLs (Cia11, Cia12, and Cia13) with significant logarithm of odds (LOD) scores of 5.6, 4.6, and 4.5, respectively, plus a suggestive QTL (Cia14*, LOD 3.0) regulating arthritis severity were identified on chromosomes 3, 12, 4, and 19. A new QTL, Ciaa3, associating with anticollagen antibody titer (antibody to PII LOD 6.5; antibody to rat type II collagen LOD 5.2) mapped to chromosome 9. Of 10 CIA QTLs previously identified in (DA x F344) and (DA x ACI) rats, only Cia1 in the major histocompatibility complex and a region coincident to Cia5 on chromosome 10 (LOD >8.0) influenced CIA severity in (DA x BN)F2 rats., Conclusion: Since CIA exhibits many of the pathologic features of rheumatoid arthritis, the data indicate that the variety of genetic elements regulating human autoimmune and rheumatic diseases may be much larger and more varied than originally envisioned.

To determine whether alterations in adrenocortical function occur early in the development of inflammatory joint disease, we examined patients with new onset synovitis (<1 yr) prior to treatment with corticosteroids or other disease-modifying antirheumatic drugs. Thirty-two patients with new onset synovitis, including 15 fitting criteria for rheumatoid arthritis (RA), taking no medications, were referred for study by local rheumatologists; 32 age- and sex-matched healthy individuals were recruited as controls. Patients and controls had blood drawn under identical conditions between 0900 and 1100 h. Plasma ACTH, cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate, free and total testosterone, erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor were measured. Compared with controls, patients had higher inflammatory indices (erythrocyte sedimentation rate, C-reactive protein) and lower basal morning levels of free testosterone (lower in males age > or =45 yr), but similar levels of ACTH, cortisol, DHEA, DHEA sulfate, and total testosterone. In addition, the positive correlations between ACTH-cortisol, ACTH-DHEA, and cortisol-DHEA, observed in the normal controls, were weakened or abolished in the patients (both total and RA subset). No positive relations between inflammatory indices and ACTH or cortisol were noted, yet an inverse correlation between these indices and DHEA and testosterone was observed. Moreover, a steeper age-associated decline in DHEA was observed in our cross-sectional sample of patients with new onset synovitis. We conclude that patients with synovitis (including those fitting criteria for RA) have adrenocortical hormone alterations within a year of disease onset. Paradoxically, these patients have no positive relation between indices of inflammation and ACTH or cortisol, but rather serum androgen levels are inversely correlated with these indices. In addition, the relations between ACTH, the classic stimulus of cortisol and adrenal androgens, and these hormones are weakened or abolished, whereas the negative relation between age and zona reticularis function is steeper than that of controls.

STATEMENT OF FINDINGS: An inception cohort of 238 patients having peripheral joint synovitis of less than 12 months duration was evaluated clinically and followed prospectively for 1 year to determine the clinical significance of a number of rheumatoid arthritis (RA) associated autoantibodies. Serum samples collected at the time of the initial evaluation were tested for rheumatoid factor (RF) and antibodies to Sa (anti-Sa), RA-33, (pro)filaggrin [antifilaggrin antibody (AFA)], cyclic citrullinated peptide (anti-CCP), calpastatin, and keratin [antikeratin antibody (AKA)]. RF had a sensitivity of 66% and a specificity of 87% for RA. Anti-Sa, AFA, and anti-CCP all had a specificity of more than 90%, but a sensitivity of less than 50% for this diagnosis. Overall, there was a high degree of correlation between AFA, AKA, anti-Sa or anti-CCP, this being highest between anti-Sa and anti-CCP (odds ratio, 13.3; P < 0.001). Of the 101 patients who were positive for at least one of these four autoantibodies, 57% were positive for only one. Finally, anti-SA identified a subset of predominantly male RA patients with severe, erosive disease. Anti-SA, AFA and anti-CCP are all specific for early RA but, overall, have little additional diagnostic value over RF alone. Although these antibodies may preferentially recognize citrullinated antigens, the modest degree of concordance between them in individual patient sera suggests that it is unlikely a single antigen is involved in generating these responses.

The major, extensively studied, experimentally-induced rat and mouse models of arthritis with features resembling rheumatoid arthritis are reviewed here. Etiopathogenetic studies that were recently published are emphasized. In summary, multiple triggering stimuli can induce disease in genetically-prone strains of inbred rats and mice. Multiple genetic loci, including both MHC and non-MHC, regulate disease expression in these animals. By comparison with other models of autoimmune disease, clustering of regulatory loci within and among species is increasingly becoming evident. At the cellular level, both innate and acquired immune systems are involved in the disease manifestations. At the molecular level, unbalanced chronic production of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-6 and IL-12, as opposed to IL-4 and IL-10, is correlated with arthritis disease susceptibility and severity.

Objective: To investigate the role of c-myc in the pathogenesis of rheumatoid arthritis (RA) and the mechanism of synovial apoptosis., Methods: Using cultured human synoviocytes from patients with RA and c-myc antisense oligodeoxynucleotides (AS ODN), we examined the inhibition of cell proliferation by the MTT assay and the induction of apoptosis with TUNEL staining and fluorescence microscopy. In addition, the effect of c-myc on down-regulation of Fas expression was analyzed by flow cytometry, cytotoxicity assay, and reverse transcriptase-polymerase chain reaction., Results: Treatment with c-myc AS ODN induced inhibition of cell proliferation, along with down-regulation of c-Myc protein and c-myc messenger RNA (mRNA) expression. The morphologic changes of synovial cell death were typical of apoptosis. In addition, c-myc AS ODN treatment down-regulated expression of Fas mRNA but not Fas antigen. Analysis of the involvement of the caspase cascade revealed that the cytotoxic activity of c-myc AS ODN was completely blocked by inhibitors of both caspase 1 (YVAD-FMK) and caspase 3 (DEVD-FMK)., Conclusion: Our results strongly suggest that c-myc AS ODN might be a useful therapeutic tool in RA and clarify that cell death by c-myc AS ODN is induced through the caspase cascade, similar to Fas-induced apoptosis. In addition, combination therapy with anti-Fas antibody and c-myc AS ODN reduced Fas-dependent cytotoxicity.

Previous studies have shown that rheumatoid arthritis aggregates within families. However, no formal genetic analysis of rheumatoid arthritis in pedigrees together with other autoimmune diseases has been reported. We hypothesized that there are genetic factors in common in rheumatoid arthritis and other autoimmune diseases. Results of odds-ratio regression and complex segregation analysis in a sample of 43 Caucasian pedigrees ascertained through a rheumatoid arthritis proband or matched control proband, revealed a very strong genetic influence on the occurrence of both rheumatoid arthritis and other autoimmune diseases. In an analysis of rheumatoid arthritis alone, only one inter-class measure, parent-sibling, resulted in positive evidence of aggregation. However, three inter-class measures (parent-sibling, sibling-offspring, and parent-offspring pairs) showed significant evidence of familial aggregation with odds-ratio regression analysis of rheumatoid arthritis together with all other autoimmune diseases. Segregation analysis of rheumatoid arthritis alone revealed that the mixed model, including both polygenic and major gene components, was the most parsimonious. Similarly, segregation analysis of rheumatoid arthritis together with other autoimmune diseases revealed that a mixed model fitted the data significantly better than either major gene or polygenic models. These results were consistent with a previous study which concluded that several genes, including one with a major effect, is responsible for rheumatoid arthritis in families. Our data showed that this conclusion also held when the phenotype was defined as rheumatoid arthritis and/or other autoimmune diseases, suggesting that several major autoimmune diseases result from pleiotropic effects of a single major gene on a polygenic background.

Objective: To compare patterns of cytokine secretion in patients with new onset synovitis (< 1 yr duration, n = 14), chronic rheumatoid arthritis (RA) (n = 16), and healthy controls (n = 17)., Methods: ELIspot assays were used to detect mononuclear cells in the peripheral blood (PMBC) and synovial fluid (SFMC) secretion the type 1 cytokines interleukin 2 (IL-2) and interferon-gamma (IFN-gamma), the type 2 cytokines IL-4, IL-6 and IL-10, and the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Results were correlated with measures of disease activity., Results: Patients with new onset synovitis had increased (p < 0.05) numbers of PBMC secreting IL-2. The number of PBMC secreting IFN-gamma correlated with the joint score in the new onset synovitis population (p = 0.006). By comparison, patients with chronic RA had significantly increased numbers of PBMC secreting IL-6, IL-10, and TNF-alpha (p < 0.05). The production of these cytokines correlated with joint score in chronic RA (p = 0.008, 0.06, 0.001, respectively)., Conclusion: Patients with new onset synovitis have increased numbers of PBMC secreting IL-2 and IFN-gamma, while patients with chronic RA have increased numbers of PBMC secreting IL-6, IL-10, and TNF-alpha. Correlations between joint score and number of PBMC secreting cytokines suggest the number of PBMC secreting IFN-gamma is most relevant in new onset synovitis, while the number of PBMC secreting IL-6, IL-10, and TNF-alpha is of greater relevance in chronic RA.

It has been reported that the mRNA of the type 1 cytokine, interferon-gamma (IFN-gamma)--but not the type 2 cytokine interleukin-4 (IL-4)--is detected in synovial tissues of rheumatoid arthritis (RA) patients, whereas both IFN-gamma and IL-4 mRNA are detected in reactive arthritis (ReA). To evaluate such data more extensively, we obtained 208 synovial specimens in a prospective study of 52 early synovitis patients (13 RA, 11 ReA, 28 undifferentiated oligoarthropathy) and analyzed type 1 and type 2 cytokine mRNA expression in specimens containing sufficient mRNA. Using a nested reverse transcriptase polymerase chain reaction technique, we measured the relative mRNA levels of 10 cytokines and CD3 delta chain. We detected IL-10, IL-15, and CD3 delta chain mRNA in all RA and ReA patients and frequently detected tumor necrosis factor-alpha, IL-1 beta, and IFN-gamma mRNA. IL-6 and IL-12 p40 mRNA were detected in approximately one-half of the patients. We also detected greater amounts of IL-2 and IFN-gamma mRNA in ReA than were detected in RA. However, we rarely detected IL-4 or IL-13 mRNA. Similar cytokine profiles were observed in undifferentiated oligoarthropathy. The amounts of cytokine mRNAs, except for IL-10, in specimens from the patients taking prednisone or second-line antirheumatic drugs tended to be less than in specimens from the patients taking neither prednisone nor second-line antirheumatic drugs. These results suggest that cytokine mRNA profiles in patients with RA, ReA, and undifferentiated arthritis in their early stages are skewed toward proinflammatory macrophage-derived and type 1 cytokines. IL-10--not IL-4 or IL-13--mRNA appears to be the major antiinflammatory cytokine mRNA. Drug therapy is associated with depressed proinflammatory and type 1 cytokine mRNA production. The differences in the expression of IL-2 and IFN-gamma mRNA between RA and ReA may reflect unique etiological or host factors associated with the early stages of these diseases.

Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and this cytokine is also a potent stimulus of the hypothalamic-pituitary-adrenal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, cortisol, and IL-6 and their interactions in patients with early untreated RA, we recruited and studied five newly diagnosed, untreated RA patients early in the course of their disease and five age-, gender-, and race-matched control subjects. We collected serial blood samples over 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 every hour. The 24-h collection was followed by administration of ovine CRH (oCRH) and post-oCRH serial blood samples over 2 h. We analyzed the 24-h overall levels of these hormones and their circadian variations and performed time-lagged cross-correlation analyses among them. The untreated RA patients had 24 h time-integrated plasma ACTH, plasma cortisol levels, and urinary free cortisol excretion that were not significantly different from control subjects, in spite of their disease activity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCRH were similar in RA patients and controls. IL-6 levels were significantly increased in the RA patients compared with control subjects during the early morning hours (P < 0.05). There was pronounced circadian variation of plasma Il-6 levels. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with elevated levels of IL-6 before the elevations of ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. The data presented here suggest that although endogenous IL-6 may stimulate secretion of ACTH and cortisol, overall activity of the hypothalamic-pituitary-adrenal axis remains normal and apparently is insufficient to inhibit ongoing inflammation in early untreated RA patients.

Objective: Treatment with high-dose (400 mg/kg/day) intravenous immunoglobulin (IVIg) shows benefit in many autoimmune diseases but is very expensive. Low-dose IVIg has also been shown to be effective in inhibiting adjuvant arthritis in the rat. This pilot, randomized, double-blind, placebo-controlled trial was conducted to assess the use of low-dose IVIg in patients with treatment-refractory rheumatoid arthritis (RA)., Methods: Twenty patients with active RA were recruited. Ten patients received IVIg and 10 received albumin. Study subjects were given 6 courses of either IVIg (5 mg/kg) or albumin (5 mg/kg), once every 3 weeks. Baseline medications were continued and not changed throughout the study., Results: There were no complications. Five patients dropped out before the 18-week followup visit. No significant differences between treatment groups were noted during the 18-week trial in terms of global activity indices (patient or physician assessment), joint swelling, joint pain or tenderness, erythrocyte sedimentation rate, C-reactive protein level, or rheumatoid factor. The protocol was terminated prematurely because of reported contamination of IVIg by hepatitis C virus. None of the patients showed evidence of hepatitis C infection by serologic analysis or by polymerase chain reaction., Conclusion: Low-dose IVIg, as administered in this trial, does not show a therapeutic effect in patients with refractory RA.

Hormones, particularly those involved in the hypothalamic-pituitary-gonadal and -adrenal axes (HPG and HPA), play important roles in various animal models of autoimmunity such as systemic lupus erythematosus in mice and collagen-induced arthritis (CIA) in mice and rats, and the streptococcal cell wall, adjuvant and avridine arthritis models in rats. Intimately linked to the subject of hormones and autoimmunity are gender, sex chromosomes and age. The importance of these factors in the various animal models is emphasized in this chapter. Several major themes are apparent. First, oestrogens promote B-cell dependent immune-complex mediated disease (e.g. lupus nephritis) but suppress T-cell dependent pathology (CIA in mice and rats), and vice versa. Second, testosterone's effects are complicated and depend on species and disease model. In rats, testosterone suppresses both T-cell and B-cell immunity. In mice, the effects are complex and difficult to interpret, e.g. they tend to enhance CIA arthritis and suppress lupus. Sex chromosome/sex hormone interactions are clearly involved in generating these complicated effects. Third, studies in Lewis and Fischer F344 rats exemplify the importance of corticosteroids, corticotrophin releasing hormone and the HPA axis in the regulation of inflammation and the predisposition to autoimmune diseases. Fourth, the HPA axis is intimately linked to the HPG axis and is sexually dimorphic. Oestrogens stimulate higher corticosteroid responses in females. The animal model data have major implications for understanding autoimmunity in humans. In particular, adrenal and gonadal hormone deficiency is likely to facilitate T-cell dependent diseases like rheumatoid arthritis, while high oestrogen levels or effects, relative to testosterone, are likely to promote B-cell dependent immune-complex-mediated diseases such as lupus nephritis.

Rheumatoid arthritis (RA) is a multifactorial disease in which both environmental and genetic factors play a role. Data also suggest that neuroendocrine factors are involved. I briefly summarize observations that support this hypothesis. RA is characterized by striking age-sex disparities. The incidence of disease in women increases steadily from the age of menarche to its maximal incidence around menopause. The disease is uncommon in men under age 45, but its incidence increases rapidly in older men and approaches the incidence in women. These observations strongly suggest that androgens play a major suppressive role, and, in fact, testosterone levels are depressed in most men with RA. Mechanistically, many data indicate that testosterone suppresses both cellular and humoral immune responses. Dehydroepiandrosterone (DHEA), an adrenal product, is the major androgen in women. Its production is strikingly dependent upon age. Peak production is in the 2nd and 3rd decades, but levels decline precipitously thereafter. DHEA levels are low in both men and women with RA, and recent data show that levels of this hormone may be depressed before the onset of disease. The role of DHEA in immune diseases, however, is controversial. The menopausal peak of RA onset suggests estrogen and/or progesterone deficiency play a role in the disease, and many data indicate that estrogens suppress cellular immunity but stimulate humoral immunity, i.e., deficiency promotes cellular (Th1-type) immunity. Recent data also indicate that progesterone stimulates a switch for Th1 to Th2-type immune responses. RA often develops or flares in the postpartum period, particularly if the mother breastfeeds. This is again consistent with gonadal steroid deficiency playing a role in the onset of disease. Breastfeeding is associated with blunted hypothalamic-pituitary-adrenal function and elevated prolactin synthesis. Gonadal and adrenal steroid hormone deficiency, plus elevated prolactin, probably greatly facilitates the expression of Th1-type immunity, which is widely believed to be critical in the pathogenesis of RA. By contrast, RA typically remits during pregnancy, in parallel with the increasing levels of corticosteroids, estrogens, and progesterone. Pregnancy is characterized by a shift in immune function from Th1-type to Th2-type. Oral contraceptives, which generate a condition of pseudopregnancy, also decrease the risk of RA. These data argue that adrenal and gonadal steroid hormones suppress the development of RA. Several studies indicate that corticosteroid production is inappropriately low in patients with RA, and are reminiscent of observations in Lewis rat models of chronic erosive arthritis. In summary, a growing body of data indicate that RA develops as a consequence of a deficiency in both adrenal and gonadal steroid hormone production. This hypothesis clearly has potential clinical implications.

Inflammatory mediators such as prostaglandin E2 (PGE2) and interleukin-1 (IL-1) induce angiogenesis by yet undefined mechanisms. We demonstrate that PGE2 and IL-1 induces the expression of vascular endothelial growth factor (VEGF), a selective angiogenic factor by rheumatoid synovial fibroblast cells. Transcripts for the EP1 and EP2 subtypes of PGE receptors are expressed in synovial fibroblasts. Activators of protein kinase A pathway stimulated the expression of VEGF whereas down-regulation of protein kinase C did not influence the PGE effect, suggesting that signalling from the EP2 receptor via the protein kinase A pathway is important. The induction of VEGF expression by PGE2 and interleukin-1 alpha may be an important mechanism in inflammatory angiogenesis.

Because rheumatoid arthritis rarely remits, refractory disease is common. Attention should be paid to aggravating comorbid conditions. Pharmacologic options currently available include cyclosporin, high-dose methotrexate, combination second-line agents, and creative use of corticosteroids. The available literature is reviewed in this article and the potential risks and benefits of the various options are discussed.

Over the past year, convincing direct evidence that rheumatoid arthritis is caused by a retrovirus has not been presented. Strong support for this hypothesis, however, comes from an impressive body of recent work demonstrating that human T-cell lymphotropic virus type I causes a destructive arthropathy that has many of the same features as rheumatoid arthritis. Additional strong support for the hypothesis is provided by the resemblance of the arthropathies induced by caprine arthritis encephalitis and the ovine maedi-visna viruses to rheumatoid arthritis. These retroviral infections emphasize the potential complexity of detecting retroviral involvement and proving its importance in the causation of rheumatoid arthritis. Retroviruses clearly possess diverse pathways for involvement in autoimmune diseases.

High levels of immunoreactive cyclooxygenase (Cox; prostaglandin H synthase) are present in synovia from patients with rheumatoid arthritis (RA). We now show that the recently identified inducible isoform of Cox, Cox-2, is expressed in synovia from patients with RA. To further explore modulation of the Cox isoforms in RA synovial tissues, we examined the expression and modulation of Cox-1 and -2 in rheumatoid synovial explant cultures and cultured rheumatoid synovial fibroblast-like cells (synoviocytes). Immunoprecipitation of in vitro labeled proteins and Western blot analysis demonstrated the presence of both Cox-1 and -2 under basal conditions in freshly explanted rheumatoid synovial tissues. De novo synthesis of Cox-2 polypeptide was enhanced by IL-1 beta or PMA, and dramatically suppressed by dexamethasone (dex). Cox-1 expression, under the same conditions, showed only minor variation. Since mRNA for Cox-2 is highly unstable, we examined the regulation of Cox-2 transcripts in cultured rheumatoid synoviocytes. Under basal conditions both Cox-1 and -2 mRNAs were present at low levels, but Cox-2 mRNA was markedly increased by treatment with IL-1 beta or PMA. dex markedly suppressed the induction of Cox-2 mRNA. In sharp contrast, Cox-1 transcripts were not modulated by IL-1 beta or dex. These data suggest that modulation of Cox-2 expression by IL-1 beta and corticosteroids may be an important component of the inflammatory process in synovial tissues from patients with RA.

Inflammation normally results in enhanced synthesis and secretion of hypothalamic corticotropin-releasing hormone (CRH) which, in turn, exerts antiinflammatory effects by virtue of increased adrenal glucocorticoid production. CRH and CRH binding sites are also expressed in the peripheral nervous and immune systems. Our groups have recently shown that CRH is secreted locally in acute carrageenin-induced inflammation in rats and has predominantly proinflammatory effects. We have also shown that CRH is expressed in the joints of Lewis rats with experimental arthritis. To determine if CRH is present in human inflammatory arthritis, we examined synovial fluids and tissues from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) and normal individuals. We found markedly enhanced expression of immunoreactive CRH in situ in synovium from patients, which was significantly greater in RA than in OA (p < 0.01). CRH concentrations were also significantly higher in RA (140 +/- 33 pg/ml, mean +/- SEM; n = 10) than OA (25 +/- 4 pg/ml; n = 6) synovial fluids (p < 0.005). HPLC showed immunoreactive CRH extracted from RA and OA synovial tissues and fluids coeluted with CRH 1-41. CRH mRNA was present in low levels in synovial tissue from patients with RA and, to a lesser extent, OA. In summary, immunoreactive CRH is locally secreted in the synovium of patients with RA and, at lower levels, OA. These data support the view that CRH functions as an autocrine and/or paracrine mediator of inflammation in humans.

Fibroblast growth factor (FGF)-1 and PDGF-B-like factors have been implicated in the pathobiology of RA and animal models of this disease. Since the receptors for FGF-1 and PDGF are tyrosine kinases, we examined the expression of tyrosine phosphorylated proteins (phosphotyrosine, P-Tyr) in synovial tissues from patients with RA and osteoarthritis (OA), and rats with streptococcal cell wall (SCW) and adjuvant arthritis (AA). Synovia from patients with RA and LEW/N rats with SCW and AA arthritis, in contrast to controls, stained intensely with anti-P-Tyr antibody. The staining colocalized with PDGF-B and FGF-1 staining. Comparative immunoblot analysis showed markedly enhanced expression of a 45-kD P-Tyr protein in the inflamed synovia. Treatment with physiological concentrations of dexamethasone suppressed both arthritis and P-Tyr expression in AA. P-Tyr was only transiently expressed in athymic nude Lewis rats and was not detected in relatively arthritis-resistant F344/N rats. These data suggest that (a) FGF-1 and PDGF-B-like factors are upregulated and may induce tyrosine phosphorylation of proteins in vivo in inflammatory joint diseases, (b) persistent high level P-Tyr expression is T lymphocyte dependent, correlates with disease severity, and is strain dependent in rats, (c) corticosteroids, in physiological concentrations, downregulate P-Tyr expression in these lesions.

Ovine corticotropin-releasing hormone (oCRH) stimulation tests were performed in 8 female patients with active rheumatoid arthritis treated chronically with daily low dose prednisone and 16 age matched female controls. Patients were tested on the day of treatment, 12 h after their last prednisone dose, and after withholding prednisone for 36 h. Basal levels of plasma ACTH and to a lesser extent plasma cortisol levels were elevated before each test, and significant increases in ACTH and cortisol were induced with oCRH. The dose response relationship between total ACTH and total cortisol was shifted to the right, suggesting that the patient group had mildly deficient adrenocortical responsiveness compensated for by elevated basal evening ACTH concentrations. It is not known whether the neuroendocrine abnormalities demonstrated are due to an intrinsic preexisting abnormality, active disease, drug therapy or all these factors.

Massive intrahepatic hemorrhage occurred in a patient with rheumatoid arthritis (RA) after a routine liver biopsy done to assess possible methotrexate (MTX) hepatotoxicity. Major complications of liver biopsy occur about once in every 600 biopsies, and mortality from liver biopsy has been reported. Life threatening hepatic toxicity occurs rarely during low dose MTX administration, and it is unclear whether routine liver biopsies identify patients at high risk for these complications. Until the relative risks of liver biopsy and serious MTX liver toxicity are better defined, the use of routine liver biopsies should be recommended only after careful consideration of potential procedural complications in patients with RA treated with MTX.

As diagrammed in Figures 1 and 2, the central and peripheral nervous systems, the endocrine system, and immune and inflammatory systems are extensively integrated. The boundaries defining these systems are both anatomically and molecularly blurred. This realization has been driven by the ongoing revolution in molecular biology. Normally the deleterious effects of excessive or persistent inflammation are prevented by homeostatic neuroendocrine feedback loops. Conversely, dysfunction in these counter-regulatory responses may lead to important clinical phenomena such as autoimmunity and chronic inflammation in association with behavioral alterations such as fatigue, depressed mood, and loss of libido. Continued research into the neurobiology of inflammation appears likely to explain some of the fundamental abnormalities in diseases such as RA and lead to new, more effective therapies.

The pathology of rheumatoid arthritis (RA) is characterized by massive tumor like hyperplasia of synovial connective tissues. Fibroblast like cells and microvascular endothelial cells are the predominant cell types present in this invasive tissue, particularly at sites of bone erosions. Identification of growth factors or cytokines that drive this process is an important goal of current research. Here we review evidence that platelet-derived growth factor (PDGF)-like and heparin-binding fibroblast growth factor (HBGF)-like polypeptides play a significant role in this process. For example, messenger RNA transcripts for PDGF-A, PDGF-B, HBGF-1, and HBGF-2 are present in RA synovial tissue specimens, and immunoreactive PDGF-like and HBGF-1- and -2-like polypeptides are present in RA synovia. Levels of expression are significantly higher in RA synovia than in osteoarthritis (OA) synovia, and their expression correlates with the extent and intensity of mononuclear cell infiltration. Similarly, PDGF-receptor expression is elevated in RA synovia compared with OA synovia. High levels of tyrosine phosphorylation and Fos and Myc expression are also characteristic of RA synovia and occur in cells after PDGF- and HBGF-receptor interaction. These and other observations strongly support the view that PDGF-like and HBGF-like factors are involved in stimulating the proliferative and invasive phenotype of RA synovial connective tissue cells.

We have characterized the VH and VL genes of three low-affinity polyreactive and two high-affinity monoreactive IgM and IgA1 rheumatoid factor (RF) mAb generated using circulating CD5+ B cells from a single rheumatoid arthritis patient. We found that four and one RF mAb utilized genes of the VHIV and VHIII families, respectively. The VHIV gene usage by these RF mAb differs from the preferential VHIII, VHI, and, to a lesser extent, VHII gene usage by the IgM with RF activity found in patients with mixed cryoglobulinemia, Waldenstrom's macroglobulinemia, and other monoclonal gammopathies. In addition, in contrast to the preponderant kappa L chain usage by the RF in these patients, a lambda L chain was utilized by all RF mAb from our rheumatoid arthritis patient. Two RF mAbs utilized V lambda I, two V lambda IV, and one V lambda III L chains. The VH genes of the two low-affinity polyreactive IgM RF mAb were in germline configuration. When compared with the deduced amino acid sequence of the putatively corresponding genomic segment, the VH gene of the high-affinity monoreactive IgM RF mAb displayed five amino acid differences, all of which are in the complementarity determining regions (CDR), possibly the result of a process of somatic point mutation and clonal selection driven by Ag. The unavailability of the corresponding genomic VH segment sequences made it impossible to infer whether the VH genes utilized by the two IgA1 RF were in a germline or somatically mutated configuration. Sequencing of the genes encoding the H chain CDR3 (D segments) revealed that all three low-affinity polyreactive RF mAb displayed a much longer D segment (36-45 bases) than their high-affinity monoreactive counterparts (15-24 bases), raising the possibility that a long D segment may be one of the factors involved in antibody polyreactivity.

Although rheumatoid arthritis (RA) has been widely suspected to have an infectious etiology, this hypothesis has remained difficult to prove. Epstein-Barr virus, parvoviruses, and retroviruses are considered by some investigators to be the primary candidates. An increasing body of data, on the other hand, appears to implicate bacteria or their products in the syndrome. Important evidence has surfaced in support of this view. Lyme arthritis, a disease caused by a bacterium, can mimic RA. Bacteria and their products have been conclusively linked to many forms of inflammatory "reactive" arthropathies. RA-like diseases can be induced in certain inbred strains of rats with bacterial cell-wall fragments, e.g., streptococcal and other bacterial peptidoglycans. Immunologic relationships between host and bacterial peptidoglycans, relevant to RA, have been well documented, e.g., heat shock proteins, bacterial IgG Fc binding proteins, and rheumatoid factors. These data not only support the hypothesis that bacteria may play an important role in RA but also indicate that current concepts of infection and autoimmune disease are broadening and overlapping.

Endothelial cells play a fundamental role in the pathogenesis of chronic inflammatory arthritis in humans such as rheumatoid arthritis (RA), as well as experimental animal models such as streptococcal cell wall (SCW) arthritis in Lewis (LEW/N) rats. This review summarizes data in support of this concept. The earliest apparent abnormalities in synovial tissues of patients with RA and Lewis rats with SCW arthritis appear to reflect microvascular endothelial cell activation or injury. At the molecular level, the abnormalities include enhanced expression by endothelial cells of activation markers such as class II major histocompatibility complex antigens, phosphotyrosine, leukocyte adhesion molecules, oncoproteins such as c-Fos and c-Myc, and metalloproteinases such as collagenase and transin/stromelysin. The development of severe, chronic, destructive arthritis is dependent upon thymic-derived lymphocytes and is accompanied by tumorlike proliferation of cells in the synovial connective tissue stroma (blood vessels and fibroblastlike cells), which results in resorptive destruction of bone and cartilage. Multiple criteria support the analogy to a neoplastic process. Paracrine and autocrine factors such as interleukin-1 (IL-1), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), and heparin-binding fibroblast growth factors (HBGF, FGF) appear to play important roles in the generation of these lesions. Finally, in addition to the autocrine and paracrine regulatory factors, neuroendocrine factors, particularly the hypothalamic-pituitary-adrenal axis, appear to be involved in the counterregulation of the inflammatory process. The counterregulatory effects are mediated, in part, by inhibition of endothelial cell activation by corticosteroids.

We present evidence supporting the hypothesis that locally produced platelet derived growth factor (PDGF) B-like polypeptides, as well as heparin binding growth factor-1 (HBGF-1), are involved in stimulating the pronounced hyperplasia of rheumatoid synovial stromal fibroblastlike cells. Explanted rheumatoid synovial tissues in vitro spontaneously secreted, in a time dependent manner, mitogenic activity for rheumatoid synoviocytes that was neutralizable by anti-PDGF antibody. PDGF B/c-sis mRNA transcripts were detected in synovium from patients with rheumatoid arthritis (RA) (n = 5). Spontaneous PDGF B-like synthesis was detected by immunoprecipitation of radiolabeled PDGF B-like polypeptides secreted by explanted tissues. Furthermore, rheumatoid synovial tissues, particularly macrophage-like cells, immunostained specifically with anti-PDGF B chain. The extent and intensity of staining and mononuclear cell infiltration were highly correlated. Immunostaining of osteoarthritic and normal synovial tissues was significantly less than RA synovium. PDGF-B immunostaining of synovial specimens previously characterized for expression of HBGF-1, the precursor of acidic fibroblast growth factor (aFGF), revealed that the extent and intensity of expression of HBGF-1 and PDGF-B were highly correlated.

Thirty-one patients with seropositive rheumatoid arthritis treated with cyclosporin A (CsA) were evaluated for immune function prior to, during, and after 1 year of therapy. Patients whose pretreatment peripheral blood mononuclear cells were hypoproliferative in vitro to soluble recall antigens responded better clinically to CsA treatment than did the other patients. During therapy, proliferative responses became normal and remained so until 1-2 months after CsA was discontinued. At that time, the lymphocyte proliferation defect reappeared. In addition, patients who responded clinically to CsA had a higher percentage of Leu-7+ natural killer cells in their peripheral blood prior to therapy. All patients exhibited greater frequencies of cells that expressed interleukin-2 receptors, which decreased with CsA treatment. The clinical response to CsA appears to be associated with distinct immunologic parameters in rheumatoid arthritis.

The synovium from patients with rheumatoid arthritis (RA) and LEW/N rats with streptococcal cell wall (SCW) arthritis, an experimental model resembling RA, is characterized by massive proliferation of synovial connective tissues and invasive destruction of periarticular bone and cartilage. Since heparin binding growth factor (HBGF)-1, the precursor of acidic fibroblast growth factor (FGF), is a potent angiogenic polypeptide and mitogen for mesenchymal cells, we sought evidence that it was involved in the synovial pathology of RA and SCW arthritis. HBGF-1 mRNA was detected in RA synovium using the polymerase chain reaction technique, and its product was immunolocalized intracellularly in both RA and osteoarthritis (OA) synovium. HBGF-1 staining was more extensive and intense in synovium of RA patients than OA and correlated with the extent and intensity of synovial mononuclear cell infiltration. HBGF-1 staining also correlated with c-Fos protein staining. In SCW arthritis, HBGF-1 immunostaining was noted in bone marrow, bone, cartilage, synovium, ligamentous and tendinous structures, as well as various dermal structures and developed early in both T-cell competent and incompetent rats. Persistent high level immunostaining of HBGF-1 was only noted in T-cell competent rats like the disease process in general. These observations implicate HBGF-1 in a multitude of biological functions in inflammatory joint diseases.

Paracrine growth factors probably stimulate the pathologic proliferation of synovial fibroblast-like cells (synoviocytes) in rheumatoid arthritis (RA), but the relative importance of various factors is highly controversial. To address this problem, we compared the effects of highly purified or recombinant cytokines, in serum-free medium, on the in vitro long-term growth of synoviocytes from patients with RA and rats with streptococcal cell wall (SCW) arthritis. Of the factors tested (PDGF, aFGF, bFGF, EGF, TGF-beta, IL-1-alpha, TNF-alpha and IFN-gamma), PDGF, was clearly the most potent stimulant of long-term growth of both rat and human synoviocytes. The strong mitogenic activity of rheumatoid synovial fluids was significantly inhibited by neutralizing anti-PDGF antibody, thus confirming the importance of PDGF. EGF, TGF-beta, IL-1-alpha, TNF-alpha, and IFN-gamma had minimal effects. Similar to the effects on anchorage-independent growth, TGF-beta 1 and 2, inhibited serum- or PDGF-stimulated anchorage-dependent growth. Considered in the context of other reports, these data support the view that cytokines such as PDGF, and possibly aFGF and bFGF, play major roles in stimulating synoviocyte hyperplasia in RA and SCW arthritis, whereas TGF-beta may inhibit synoviocyte growth.

The growth of synovial fibroblast-like cells from patients with rheumatoid arthritis and rats with streptococcal cell wall (SCW)-induced arthritis in vitro under anchorage-independent conditions is inhibited by transforming growth factor-beta (TGF-beta). Because this growth factor is present in rheumatoid synovial fluids, we studied whether this cytokine might be secreted by cells in rheumatoid synovial tissue. We show that synovial tissues from patients with rheumatoid arthritis and osteoarthritis, and rats with SCW-induced arthritis, contain TGF-beta-1 mRNA. TGF-beta, predominantly type 1, was spontaneously secreted in vitro by synovial tissue explants and synovial fibroblast-like cells. In addition, TGF-beta could be detected immunohistochemically in cells throughout rheumatoid and SCW-induced arthritic rat synovial tissues. Finally, exogenous TGF-beta induced collagen and inhibited collagenase mRNA levels by cultured synoviocytes. These data support an autocrine role for TGF-beta in the regulation of synoviocytes in rheumatoid arthritis and, in light of its demonstrated effects on the immune system, suggest that TGF-beta might also have important paracrine effects on infiltrating inflammatory cells.

We show that platelet-derived growth factor (PDGF) and IL-1 interact in both a synergistic and antagonistic manner to regulate synovial fibroblast-like cells (synoviocytes) derived from patients with rheumatoid arthritis. PDGF and IL-1 operated synergistically in vitro to stimulate synoviocyte proliferation in the presence of indomethacin. However, when these same cells were treated with PDGF and IL-1 in the absence of indomethacin, IL-1 inhibited PDGF-stimulated synoviocyte proliferation. Moreover, exogenous PGE2, a PG known to be produced in response to IL-1, dramatically inhibited synoviocyte proliferation induced by PDGF. PDGF also acted synergistically to markedly increase production of PGE2 stimulated by IL-1. This is in contrast to the antagonistic effect PDGF had on IL-1-stimulated collagenase transcription. IL-1 stimulated collagenase transcription, but PDGF did not. It in fact inhibited IL-1 stimulation of collagenase gene expression. These data differ somewhat from those reported for dermal fibroblasts. Our data further indicate that the effects of cytokines vary from one cell type to another, even amongst "fibroblasts," and illustrate the complexity of cytokine regulation of rheumatoid synoviocyte function.

In order to study the clinical and immunologic effects of a brief course of leukapheresis, 14 patients with clinically similar rheumatoid arthritis were segregated into 2 subgroups. Group A (7 patients) had subnormal lymphocyte tritiated thymidine incorporation to soluble antigens. After a brief course of leukapheresis, 6 of these 7 patients demonstrated substantial clinical improvement associated with significantly enhanced lymphocyte tritiated thymidine incorporation to soluble antigens. In contrast, none of the 7 patients in group B (normal immune functions) demonstrated similar changes in articular indices or lymphocyte proliferation. Thus, clinical improvement induced in a subset of rheumatoid arthritis patients appears to reflect modulation of function, and not simply immunosuppression.

In patients with rheumatoid arthritis (RA), circulating CD5+ B lymphocytes, but not CD5- B lymphocytes, are increased in number and size, exist in an activated state, spontaneously proliferate, and secrete Ig that binds to the Fc fragment of IgG. By constructing continuous mAb-secreting cell lines from CD5+ B lymphocytes, the properties and dissociation constants (Kd) of these antibodies were determined. Two types of rheumatoid factors (RFs) with discrete reactivities were produced. The first type is polyreactive and binds with relatively low affinity (Kd, 10(-5) mol/liter) to the Fc fragment of IgG. These antibodies are similar to those produced by CD5+ B cells from healthy subjects. The second type of RF is monoreactive and binds with higher affinity (Kd, 10(-7) mol/liter) to the Fc fragment of IgG. These latter autoantibodies are produced by CD5+ B cells of RA patients, but not healthy subjects. Long-term longitudinal studies are needed to determine the role of these two types of RFs in the pathogenesis of RA.

Rheumatoid arthritis is a proliferative and erosive disease which has been described as tumor-like. Streptococcal cell wall-induced arthritis in the LEW/N rat is also tumor-like and closely simulates the features of joint destruction that develop in rheumatoid arthritis. This article discusses the mechanisms of bone and cartilage destruction in streptococcal cell wall arthritis with particular emphasis on the tumor-like behavior of synovial connective tissue cells and the role of cytokines, such as platelet-derived growth factor, transforming growth factor beta and interleukin 1, in regulating this abnormal behavior.

The immunohistology of synovium from a tender, swollen knee and peripheral blood cellular immune function were correlated in 24 clinically similar patients with active, seropositive rheumatoid arthritis who were not taking cytotoxic or long-acting antirheumatic drugs. The patients were classified as anergic (n = 6) or nonanergic (n = 18) on the basis of peripheral blood mononuclear cell proliferative responses to a battery of soluble recall antigens. The peripheral blood mononuclear cells of anergic patients failed to respond significantly to any soluble recall antigen, whereas cells from nonanergic patients responded to at least one such antigen. Multiple pieces of synovial tissue were obtained from each patient at arthroscopy. To minimize intrajoint variability, all pieces were analyzed and averaged to determine a composite profile of abnormalities. Synovial specimens from all six anergic patients had "high intensity" lymphocytic infiltration (group A). In sharp contrast, synovial specimens from 15 of 18 nonanergic patients had "low intensity" lymphocytic infiltration (group B) (P = 0.002). Group A tissues typically showed higher intensity T cell and plasma cell infiltration, more synovial lining layer hyperplasia, more HLA-DR bearing cells, and a higher ratio of Leu 3A/Leu 2A T cells than did group B. Group B tissues had fewer infiltrating cells (most of which were OKM1 and HLA-DR bearing), more extensive fibrin deposition, and far fewer T and plasma cells. Although these data do not imply that synovium from different joints in an individual patient are immunohistologically identical, they do provide evidence that peripheral blood mononuclear cell immune function reflects immunopathologic events in the biopsied joint. Moreover, the data further support the view that clinically active rheumatoid arthritis is, like certain other chronic inflammatory conditions, a heterogeneous disorder with polar subgroups.

We have previously reported that patients with active rheumatoid arthritis and depressed in vitro peripheral blood mononuclear cell proliferation to soluble recall antigens (anergic subgroup) improve clinically after repeated short-term leukapheresis, whereas patients with normal responses (nonanergic subgroup) do not. This observation prompted us to examine the mononuclear cell subset profiles in the peripheral blood of anergic and nonanergic seropositive rheumatoid arthritis patients with severe, active, clinically similar disease not taking long-acting anti-rheumatic drugs. In the present study, 42 patients were categorized as anergic (n = 14) or nonanergic (n = 28) on the basis of in vitro peripheral blood mononuclear cell proliferation to soluble recall antigens. The anergic patients had a decreased frequency of OKT4+ mononuclear cells (p less than 0.01), and an increased frequency of OKT8+ cells (p less than 0.02), with a lower OKT4+ :OKT8+ ratio (p less than 0.01) than the nonanergic patients. Anergic patients also had a higher frequency of HLA-DR+ mononuclear cells and HLA-DR+ T cells (p less than 0.001). About 50% of the OKT8+ cells were HLA-DR+, whereas only about 20% of the OKT4+ population expressed HLA-DR antigens. These data suggest that the decreased lymphocyte function described in the anergic patient subgroup is associated with characteristic peripheral blood mononuclear cell subset profiles. Moreover, when considered in the context of other data indicating that anergic patients have characteristic synovial immunopathologic abnormalities, these data provide insight into potential pathogenic mechanisms of this disorder.