Seronegative rheumatoid arthritis, rheumatoid factor cross reactive idiotype expression, and hidden rheumatoid factors.

The major rheumatoid factor cross reactive idiotype (RCRI), defined by prototypic monoclonal rheumatoid factors (RFs), is expressed as a dominant idiotype by pokeweed mitogen induced plasma cells obtained from seropositive (RF+) patients with rheumatoid arthritis (RA). Some patients who meet clinical diagnostic criteria for RA set by the American Rheumatism Association fail to express RFs at any time during their clinical course. To determine if seronegative (RF-) patients with RA, so designated by the latex fixation, Rose-Waaler classic binding assays, or a RF enzyme linked immunosorbent assay (ELISA), express the RCRI in the absence of detectable RFs we examined pokeweed mitogen plasma cells from these patients by indirect immunofluorescence. In addition, we used an inhibition ELISA to detect RCRI bearing molecules in the sera of RF- patients with RA. Five of 10 RF- patients with RA had a high prevalence of RCRI+ plasma cells (16-49% of total pokeweed mitogen plasma cells in culture). Six of 20 RF- patients with RA had high serum concentrations of molecules marked by the RCRI, equivalent to 21-110 micrograms/ml of RCRI+ reference monoclonal IgM RF. Four of five patients who expressed the RCRI in high prevalence in pokeweed mitogen plasma cells, also demonstrated high concentrations of RCRI in their sera detected by inhibition ELISA. There was significant concordance of RCRI expression determined by the two different assays. Four RF- patients with RA who expressed RCRI in their whole sera had hidden RFs detected in their 19S and, in one case, 7S serum fraction. Detection of RF related molecules in whole sera by the expression of RCRI in RF- patients with RA identifies a subgroup of RF- patients with RA who possess hidden RFs. Some RF- patients with RA can express the major RCRI in pokeweed mitogen plasma cells and in their sera and therefore are related to patients with prototypic Waldenstrom's macroglobulinaemia, who produce RCRI+ 19S IgM monoclonal RFs.     

Hypothalamic-pituitary-adrenal axis in rheumatoid arthritis

The controlled data accumulated so far support only subtle alterations in HPA axis function in RA, mainly at the adrenal level, and particularly in a subset of premenopausal-onset women. Such interpretation is supported by consistent findings of lower levels of adrenal androgens, particularly DHEAS, in premenopausal-onset RA patients. Consequences of the subtle HPA alterations in RA for the disease development remain unclear. From a broader perspective, the unresponsiveness of the HPA axis to chronic inflammation in RA simply can be seen as an ongoing adaptation to the disease state with higher priority to proper regulation of core body functions over the immune homeostasis.     

Salmonella-specific antibodies in reactive arthritis

The development and persistence of Salmonella-specific serum antibodies of different immunoglobulin classes and subclasses were compared between those who developed reactive arthritis (n = 39) and those who did not (n = 58) after Salmonella infection. Antibodies against lipopolysaccharide and SDS-extract antigen were measured by ELISA. A significant difference was seen between the two patient groups after 4-14 months of follow-up; those with reactive arthritis had higher levels of Salmonella-specific IgM, IgG, and IgA class antibodies than those without arthritis. In the increased antibody response, secretory IgA, IgA1, and IgG2 classes were especially well represented. The persisting antibody response is a common feature in reactive arthritis and supports persistence of the pathogen or its components in the host. The differences observed in antibody profiles between Salmonella- and Yersinia-triggered reactive arthritides suggest certain dissimilarities (e.g., in the location of persisting microbes) in the arthritogenic process due to these two microbes.     

The hypothalamic-pituitary-adrenocortical and gonadal axis function in rheumatoid arthritis

Zusammenfassung Untersuchungen von bis dahin mit Glukokortikoiden unbehandelten Patienten mit rheumatoider Arthritis (RA) zeigen Abweichungen der Spiegel für Kortisol und adrenalen Androgenen (vor allem Dehydroepiandrosteronsulfat, DHEAS), die in der Relation zu gleichzeitig hohen Serumspiegeln von IL-6 eindeutig als relative Nebenniereninsuffizienz zu bezeichnen sind. Androgene dürften in der Pathogenese von Autoimmunerkrankungen, einschließlich der RA, als physiologische Immunosuppressoren eine Rolle spielen. Bei männlichen RA-Patienten wurden niedrige Testosteronspiegel sowohl im Plasma als auch in der Synovia gefunden, bei RA-Patientinnen waren die entsprechenden Spiegel für DHEAS erniedrigt. Die Häufund der RA um die Menopause legt weiter eine pathophysiologische Bedeutung sinkender Spiegel von Östrogenen und/oder Progesteron nahe. Zahlreiche Befunde deuten auf suppressive Effekte von Östrogenen auf die zelluläre Immunität, während sie stimulierend auf die humorale Immunität wirken (bzw. ein Östrogendefizit steigert die Th 1-Typ-vermittelte Immunität). Genetische Polymorphismen von Enzymen der Steroidbiosynthese scheinen zusätzlich die Rolle von Sexualsteroiden in der Entwicklung von autoimmunen Reaktionen zu begünstigen. Darüberhinaus beeinflussen erworbene Formen eines veränderten Steroidmetabolismus die peripheren Spiegel der Sexualsteroide. Zusammenfassend ist die pathogenetische Relevanz eines komplexen Zusammenwirkens der Achsen Hypothalamus-Hypophyse-Nebennierenrinde und Hypothalamus-Hypophyse-Gonaden bei RA evident. Summary The altered cortisol and adrenal androgen (i. e., dehydroepiandrosterone sulfate = DHEAS) secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with corticosteroids, should be clearly regarded as a "relative adrenal insufficiency" in the setting of a sustained inflammatory process, as shown by high serum IL-6 levels. Androgens seem implicated in the pathophysiology of autoimmune disorders, including RA, as natural immunosuppressors. Low plasma synovial fluid testosterone concentrations are observed in male RA patients; low plasma DHEAS levels are mainly observed in female RA patients. The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also 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). Gene polymorphisms for enzymes involved in the steroidogenesis seem to further complicate the role of sex hormones in the susceptibility to autoimmunity. Acquired changes of sex steroid metabolism seem to also play a role in the peripheral sex hormone levels. In conclusion, a complex interaction between the hypothalamus-pituitary-adrenocortical and gonadal axis functions is evident in RA.     

Anti-fab' antibodies in rheumatoid arthritis

High levels of anti-immunoglobulins that react with Fab′ fragments of IgG have been observed in sera of patients with rheumatoid arthritis (RA). To determine how much of these anti-Fab′ antibodies are incorporated within immune complexes (IC), we added ¹²⁵I-Fab′ to sera and then measured the amount of labeled Fab′ that could be precipitated by adding polyethylene glycol (PEG). Sera were either maintained at neutral pH during this procedure or acidified (pH 3) to dissociate IC. Acidification permitted the ¹²⁵I-Fab′ an equal chance to compete with other endogenous antigens for anti-Fab′ antibodies, once excess hydrogen ion was removed. Quantities of anti-Fab′ in sera of 20 seropositive RA patients were greater than in sera of 43 age-and sex-matched healthy controls, as measured by this assay and by a solid phase radioimmunoassay. However, significantly less anti-Fab′ antibody was incorporated in ICs in the RA patients' sera. Supernatants from cultured peripheral blood lymphocytes of RA patients also contained relatively more “free” and less “hidden” anti-Fab′ than culture supernatants from controls. Thus there appear to be qualitative as well as quantitative differences in the anti-Fab′ antibodies synthesized by RA patients. This may reflect different proportions of IgM and IgG anti-Fab′ in their sera, differences in the average avidity of these antibodies, or differences in the reciprocal relationships within the idiotypic network that result in release of antibodies by certain antibody-producing cells, but not by clones that produce complementary idiotypes.     

Anti-CCP antibodies in rheumatoid arthritis and psoriatic arthritis

Our aim is to assess the prevalence and associated clinical features of anti-CCP (cyclic citrullinated peptide) antibodies for RF (rheumatoid factor)-positive and RF-negative rheumatoid arthritis (RA) and psoriatic arthritis (PsA). In a prospective, cross-sectional, multi-centre study, we determined the titres of anti-CCP antibodies in 208 RA patients (129 RF-positive, 79 RF-negative), 56 PsA patients and 39 healthy controls (HC). Clinical parameters including disease activity (disease activity score 28-DAS28), physical disability (health assessment questionnaire-HAQ), functional capacity (functional class) and radiological erosions were investigated in patients with RA. In PsA patients, clinical and radiological features were determined. Anti-CCP2 antibodies were measured using a second-generation anti-CCP enzyme-linked immunosorbent assay (Euro-Diagnostica, Netherlands). One-hundred four of 129 RF-positive RA (81%), 16 of 79 RF-negative RA (20%), seven of 56 PsA patients (12.5%) and none of the HC had anti-CCP antibodies. RA patients with anti-CCP antibodies had significantly higher disease activity, greater loss of function and more frequent erosive disease than anti-CCP antibody-negative group. In subgroup analysis, anti-CCP antibodies in RF-negative patients were also associated with erosive disease. All PsA patients with anti-CCP antibodies had symmetric arthritis with higher number of swollen joints. The prevalence of anti-CCP antibodies in RF-positive RA patients was significantly higher than in RF-negative RA and PsA patients. Anti-CCP antibodies were also associated with erosive disease in RF-negative RA patients. Both anti-CCP and RF tests were negative in 30% of the patients. Anti-CCP positivity was a frequent finding in PsA and associated with symmetrical polyarthritis.     

The role of the hypothalamic-pituitary-adrenal axis in rheumatoid arthritis.

It has become clear that there is a bidirectional communication between the neuroendocrine and the immune system and that both systems influence each other and interact under physiological conditions and in response to inflammatory stimuli. The hypothalamic-pituitary axis plays an important role in regulating and controlling immune responses and dysfunction of the axis has been implicated in the pathogenesis of rheumatoid arthritis (RA). Corticotrophin-releasing hormone (CRH), one of the main hormones of the axis, is also released extra-hypothalamically, peripherally at the site of inflammation and may modulate inflammatory responses locally. In this chapter we will discuss the role of the hypothalamic-pituitary-adrenal (HPA) axis and peripheral CRH, its influences on immune function and what is known about the possible pathogenetic role of the HPA axis and peripheral CRH in RA.     

Mycoplasma antibodies in rheumatoid arthritis.

Sera of 100 patients under examination at the Outpatient Department of the Rheumatism Foundation Hospital were studied by the indirect hemagglutination technique, using both mycoplasma reference strains, and isolates from RA and SLE as antigens. The series consisted of five groups: I, definite RA (49 patients); II, probable RA (11); III, possible RA or nonspecific inflammatory arthritis (34); IV, osteoarthrosis (2); V, Reiter's disease (4). Mycoplasma antibodies in titres of 16 or higher were encountered in groups I-IV in 26, 8, 19, and one case respectively. Twenty-one out of 106 blood donors had antibodies against an isolate from RA and/or M. arthritidis strain PG 6. The titres found were 16 or 32, except in two cases, 128. In the definite RA group, 21 out of 26 patients possessing mycoplasma antibodies, showed titres of 16 or higher against isolates from RA and/or SLE, 12 against M. arthritidis strain PG 6 and/or Campo, 8 against M. fermentans, and 6 against a T-strain from NGU. Antibodies against M. arthritidis strain Campo were found more often than against strain PG 6. The longer the duration of the arthritic symptoms was, the more frequent seemed also to be the occurrence of mycoplasma antibodies.     

Hypothalamo-pituitary-adrenal axis and growth hormone axis in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic disease and is associated with cytokines (IL-1, IL-6, TNF-alpha) production. There is little information on hypothalamo-pituitary-adrenal (HPA) axis and growth hormone (GH) axis in the patients with RA. We have, therefore, investigated these systems in twenty patients with confirmed RA. Ten of the patients had active and 10 patients remitted RA. Serum cortisol, ACTH and GH levels were measured in the basal state and after insulin induced hypoglycaemia. Cortisol, adrenocorticotropic hormone (ACTH) and GH responses were impaired in 65%, 85% and 30% of the patients, respectively. The basal and peak hormone levels were similar between the patients with active RA and the patients in remission. These findings indicate that there is an impairment in HPA and GH axis in patients with active and remitted RA. The site of this impairment is probably hypothalamus and/or pituitary gland.     

Hypothalamic-pituitary-adrenal axis activity in patients with rheumatoid arthritis

OBJECTIVE: To study the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatoid arthritis (RA). METHODS: Fifty patients with RA participated in 3 groups: recent onset active RA (n = 20), longstanding active RA (n = 20) and long-standing RA in remission (n = 10), and were compared with 20 healthy controls. The activity of the HPA-axis was assessed under basal conditions and in response to stress (insulin tolerance test, ITT). In addition, patients with recent onset RA underwent a corticotropin releasing hormone (CRH) test and a dexamethasone suppression test. Plasma levels of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha) and IL-6 were also measured. RESULTS: Basal plasma, salivary and urinary cortisol levels and plasma adrenocorticotropic hormone (ACTH) levels were not different between patients with RA and healthy controls. During the ITT, cortisol levels were consistently lower in RA patients than in healthy controls. ACTH levels during the ITT were not different between patients with RA and healthy controls. ACTH and cortisol responses to CRH were assessed only in patients with recent onset RA and were found to be within normal limits. Basal circulating plasma IL-6 levels were significantly higher in patients with active RA than in the other groups. CONCLUSION: Under the standardized conditions of the ITT, patients with RA have decreased plasma cortisol levels compared to healthy controls, despite elevated levels of IL-6. The defect is probably located at the adrenal level and may be of pathogenetic significance for the development of chronic arthritis.     

Role of the hypothalamic-pituitary-adrenal axis in rheumatoid arthritis

ObjectiveA subnormal response of the hypothalamic-pituitary-adrenal (HPA) axis to inflammatory stimuli was found to be associated with the occurrence of chronic arthritis in Lewis rats. This study was carried out to determine the role of the HPA axis in patients with rheumatoid arthritis (RA).MethodsThirty patients with RA of less than 2 years duration were studied. Laboratory tests including ESR, RF and X-ray hands were performed in all patients. All patients were subjected to the standard insulin-induced hypoglycemia test to determine the integrity of the HPA axis. Serum cortisol was estimated at 11 PM on the day prior to the test in eight of these patients.ResultsTwelve out of 30 patients had subnormal cortisol response to insulin-induced hypoglycemia. (normal: cortisol >20 μg/dl and 7 μg > basal cortisol). Two patients had a maximal cortisol response 7 μg > basal but less than 20 μg/dl, i.e. a partial response. Seven patients had a supranormal basal cortisol with no further stimulation with hypoglycemia. Nine patients had an adequate response.Conclusion21/30 (70%) of patients showed some abnormality of HPA axis response. We propose that a primary abnormality of the HPA axis may play a significant role in the pathogenesis of RA.     

Antiphospholipid antibodies in rheumatoid arthritis: Identifying the dominoes

Antiphospholipid antibodies (aPL) occur in a variety of autoimmune, malignant, and infectious diseases, with or without the thrombotic or obstetric sequelae that characterize the antiphospholipid syndrome. Although many studies have focused on the clinical implications of aPL in systemic lupus erythematosus, few have specifically addressed the questions facing rheumatologists caring for rheumatoid arthritis patients who are concomitantly positive for aPL. Such a clinical scenario requires current knowledge of antiphospholipid syndrome diagnosis criteria, test reliability, conditions causing temporal positivity of aPL, and treatment risks and benefits. Recently researched factors possibly integral to rheumatoid arthritis’s increased morbidity and mortality and related to aPL include oxidatively modified low-density lipoprotein antibodies, homocysteine, annexins, infectious agents, β estradiol, and specific gene polymorphisms. This review presents current scientific research addressing the pathophysiologic mechanisms and clinical implications of aPL in rheumatoid arthritis.     

Clonally restricted anti-IgG antibodies in rheumatoid arthritis

Clonally restricted anti-IgG antibodies were detected, by isoelectric focusing (IEF) and chromatofocusing techniques, in the sera of patients with rheumatoid arthritis (RA). Anti-Fab antibodies were predominantly acidic proteins with isoelectric points of 4.5-6.5 and displayed restricted spectrotype patterns. Proteins reactive with the Fc portion of IgG showed polyclonal spectrotype patterns with alkaline pI of 7.5-9.0. A limited array of anti-Fab spectrotypes was consistently detected in RA sera when analyzed by IEF on 6M urea gels. Additional anti-Fab antibody bands were detected when the RA sera were dialyzed against 4-6M urea prior to IEF analysis, indicating that some anti-Fab antibodies exist in a complexed form in serum. Under these dissociating conditions, anti-Fab antibodies could also be detected in normal subjects, but the spectrotype patterns were more restricted than those in RA sera. Because anti-Fab antibodies may regulate normal immune responses, the increased quantity of clonally restricted anti-Fab antibodies in RA may indicate an abnormality of this immunoregulation.     

Anticardiolipin antibodies in patients with rheumatoid arthritis

Summary Anticardiolipin antibodies (ACA) were assayed by ELISA in 73 patients with rheumatoid arthritis. Twelve (16.48%) patients showed levels of ACA three standard deviations above the value of the control group and were considered positive; these patients were compared to the group with ACA within the normal levels regarding the following clinical and laboratorial characteristics: spontaneous abortions, central nervous system involvement, systematization and activity of disease, alterations in platelet counts, presence of antinuclear antibodies and rheumatoid factor. Significant statistical association could be demonstrated between systematization and presence of antinuclear antibodies (ANA) and positiveness to ACA (IgG, IgM or both). These findings might indicate that ACA in patients with RA could have relevance to morbidity of disease or perhaps to its pathogenesis.     

Studies on heterophile antibodies in rheumatoid arthritis

Sera and synovial fluids of patients with rheumatoid arthritis were studied for the presence of heterophile antibodies to sheep and bovine erythrocytes by means of hemolysis in agar gel. It was demonstrated that 18 of 146 sera had hemolytic antibody titers of 160 or more; all 18 (12%) against sheep and 8 (6%) against bovine erythrocytes. Of 31 synovial fluids examined, 5 showed hemolysin titers of 40 or more; all 5 (16%) against sheep and 3 (10%) against bovine erythrocytes. These heterophile antibodies were shown to belong to IgM and/or IgG class. Absorption and inhibition studies revealed that antibodies of 10 positive sera and 2 synovial fluids were of Forssman specificity and antibodies of 6 sera and 3 synovial fluids were of Hanganutziu-Deicher specificity. Two remaining sera were shown to contain a mixture of Forssman antibodies and immune anti-B antibodies.