Association of rheumatoid factor with complement activation in rheumatoid arthritis and other diseases.

Rheumatoid factor (RF) is a complement activating autoantibody. In rheumatoid arthritis (RA) the rate of catabolism of complement is closely related to the titre of RF. Therefore, we have examined whether these relationships are unique to RA or will be found in non-RA disorders in which RF may be found in the circulation. We studied patients with subacute bacterial endocarditis, leprosy, tuberculosis, and a variety of other rheumatic and vasculitic disorders. We found that in all the disorders examined the RF had a complement activating potential which was equivalent to that of the RF of RA patients. Furthermore in vivo activation of complement, as exhibited by the appearance of C3 degradation products, was significantly related to higher titres of haemolytically active RF in non-RA as well as the RA group. In these respects, therefore, the RF in RA and non-RA patients is indistinguishable. A possible survival value for RF is discussed.     

Synovial fibroblasts and synovial macrophages from patients with rheumatoid arthritis and other inflammatory joint diseases show chromosomal aberrations

Chromosomal aberrations were investigated in nuclei extracted from synovial tissue and first-passage synovial fibroblasts (P-1 SFB, 98% enrichment) or macrophages (P-1 Mphi) from patients with rheumatoid arthritis (n=10). The findings were compared with those in other rheumatic diseases (osteoarthritis, n=14; reactive arthritis, n=1), as well as with those in chronic obstructive pulmonary disease (n=8). Controls were paired peripheral blood lymphocytes from arthritic patients, synovial tissue or SFB/Mphi from joint trauma/normals (n=9), and peripheral blood monocytes from normal donors (n=10). GTG banding of metaphase chromosomes and interphase fluorescence in situ hybridization with centromere-specific probes were used. Comparable chromosomal aberrations were observed in synovial tissue and P-1 SFB of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis (polysomy 7 and aneusomies of chromosomes 4, 8, 9, 12, and 18). Notably, aneusomies of chromosomes 4, 6, 7, 8, 9, 11, 12, and/or X were also detected in P-1 synovial Mphi from rheumatoid arthritis (90% of the cases), osteoarthritis (93%), and reactive arthritis (1/1), as well as bronchial Mphi from chronic obstructive pulmonary disease (25%). No aberrations were detected in paired peripheral blood lymphocytes (except for one osteoarthritis case with a karyotype 45,X[10]/46,XX[17]), or in peripheral blood monocytes and synovial tissue of normals/joint trauma. Because Mphi aberrations were common to chronic joint and pulmonary disease, chronic inflammatory stress may induce chromosomal aberrations with potential functional relevance in local mesenchymal cells and infiltrating leukocytes in an organ-independent fashion.     

Conjugal prevalence of rheumatoid arthritis, rheumatoid factor and other autoantibodies in rheumatoid arthritis

The prevalence of rheumatoid arthritis, rheumatoid factor, antinuclear autoantibodies, thyroglobulin and thyroid `microsomal'' autoantibodies and gastric parietal cell autoantibodies has been studied in 327 husbands and 181 wives of 508 probands with seropositive `definite'' or `classical'' rheumatoid arthritis as defined by the American Rheumatism Association diagnostic criteria. Two husbands and three wives had definite rheumatoid arthritis: this prevalence is no higher than one might expect. A higher prevalence of all five autoantibodies was found in husbands compared with age matched controls, but only in respect of antinuclear autoantibodies and thyroglobulin autoantibody were the differences statistically significant. In the wives only rheumatoid factor showed a significantly higher prevalence as compared with controls. The presence of autoantibodies in husbands and wives showed no relationship to the duration of marital contact nor to the presence of the autoantibodies in the probands. The prevalence of autoantibodies in spouses of probands who developed their arthritis after marriage showed no difference when compared with that in probands who developed their arthritis before marriage.     

Induction of auto-immune syndromes by penicillamine therapy in rheumatoid arthritis and other diseases

Conclusion Penicillamine and some structurally related compounds have been shown to be inducers of autoimmune phenomena when administered to patients, regardless of the underlying disease for which they are being given. Most of these reactions are serious and often mandate discontinuance of treatment, but the development of a particular adverse reaction to one SH compound does not necessarily mean that others will elicit a similar or indeed any adverse effect. Of great theoretical interest is the mechanism by which penicillamine, as the prototype of this class, results in apparent breakdown of tolerance to self-antigens. No clear answer to this extremely important question is forthcoming, probably due to limitations in contemporary methodology. It is believed that if the mechanism of these drug-induced events were understood, new insights into the immunologic aberrations in RA might be achieved.     

Cytokine profile in systemic lupus erythematosus,rheumatoid arthritis,and other rheumatic diseases

We investigated serum levels of interleukin-6 (IL-6), interferon-gamma (IFN-), and tumor necrosis factor alpha (TNF) from patients with systemic lupus erythematosus (SLE) and its various clinical manifestations of disease and from patients with rheumatoid arthritis (RA) and other rheumatic diseases. The serum levels of IL-6 and IFN- were highly elevated from patients with SLE associated with lymphadenopathy (LN) or nephrotic syndrome (NS). On the contrary, the serum levels of TNF were elevated from most patients with SLE associated with thrombocytopenia (TP). However, serum levels of TNF were in the normal range from patients with SLE associated with NS, LN, or central nervous system disease. Of interest, patients with SLE associated with humoral immunodeficiency disorder, hypogammaglobulinemia, had highly elevated levels of serum IL-6. The concanavalin A-stimulated mononuclear cells (MNC) of patients with SLE associated with TP secreted highly elevated levels of TNF compared to other patient groups. We suggest that abnormal production of various cytokines in SLE is an intrinsic defect of MNC and the immune system that may be the key element for a variety of clinical manifestations of this disease.     

Mediators of joint swelling and damage in rheumatoid arthritis and pristane induced arthritis.

Joint swelling and tenderness in rheumatoid arthritis (RA) probably result from IgG aggregates activating complement with the consequent attraction of polymorphonuclear leucocytes (PMNs) and the liberation of their granule enzymes such as kininogenases. By contrast IL-1 and TNF are the major stimulants of cartilage and bone loss although other agents contribute. The fundamental drive for the production of these mediators is unknown but a role for heat shock proteins is suggested from work on pristane induced arthritis.     

Muscle changes in rheumatoid arthritis

Summary Muscle changes were studied in biopsy material obtained from 100 patients suffering from classical rheumatoid arthritis. The abnormalities consisted of denervation atrophy of type II muscle fibres, degenerative changes in the sarcoplasm including presence of nemaline rods, and changes within the interstitium: namely perivascular nodular myositis, lymphocytic accumulations, different stages of vasculitis and abnormalities within the intramuscular nerves and muscle spindles. The muscles examined were always severely affected. It is considered that the simultaneous presence of these abnormalities is suggestive of rheumatoid arthritis. The importance of histochemical studies is emphasized. The literature concerning muscle changes in rheumatoid arthritis is reviewed.Temporary Research Fellow the Rotterdam Centre for Rheumatic Disease     

Stretch reflexes and joint dynamics in rheumatoid arthritis

In clinically diagnosed rheumatoid arthritis (RA), studies were conducted to investigate the reflex and passive tissue contribution to measured increases in joint stiffness in the resting upper limb and during constant contractions of an attached muscle. The tonic stretch reflex was induced by a servo-controlled sinusoidal stretch perturbation of the metacarpophalangeal joint of RA patients, and age- and sex-matched controls. The resulting reflexes and mechanical changes in the RA affected joint were explored. Surface electromyographic (EMG) measurements were obtained from first dorsal interosseus muscle. Reflex gain (EMG/joint angle amplitude ratio), phase difference (reflex delay after stretch), coherence square (proportion of EMG variance accounted for by joint angle changes), joint mechanical gain (torque–joint angle amplitude ratio) and mechanical phase difference (torque response delay after stretch) were determined. RA patients showed decreased reflex gain that was partly due to coexistent severe muscle weakness, as determined from maximum voluntary contraction and grip pressure estimates. The decreased reflex gain was most evident at high stretch frequency suggesting a disproportionate loss of the large diameter afferent response and also increased reflex delay in the patients. These changes ensemble suggest significant loss of neural drive to the motor unit population. Patients also showed increased joint stiffness (measured as torque gain) in the contracting muscle, but there was no evidence of reflex activity or increased stiffness at rest. This suggests that the increased joint stiffness in RA was due to changes in the mechanical properties of the active muscle–joint system rather than changes in reflex properties.     

Morphological changes in the joint tissues and synovial fluid in rheumatoid arthritis and arthrosis deformans]

A simultaneous morphological investigation of bioptic material of the synovial sheath, articular cartilage, and synovial fluid from patients with various forms of rheumatoid arthritis (100 patients with a typical articular form, 10 with benign evolution, and 20 with lesions of visceral organs) was carried out. It was noted that in the usual articular form of rheumatoid arthritis the most common morphological component in the synovial sheath was lympho-plasmo-cellular infiltration. In the "benign" form of rheumatoid arthritis immunomorphological shifts were manifested but slightly, in the articular-visceral form in the immunocompetent cells there were observed karyopycnosis and plasmorrhexis. Cells and the main matter of the cartilage apparently underwent an enzymatic lysis, the intensity of which correlated with the degree of phagocytosis of the synovial fluid. In the deforming osteo-arthrosis (150 observations) in the synovial sheath there were usually noted drastic sclerosis and atrophy of organ-specific structures, impairmement of the production of the synovial fluid, and dystrophic falling into fibers of the articular cartilage with intensive proliferation of the cartilage cells. It is probable that distructiion of the cartilage in arthrosis depends upon an impairment of the function of the synovial sheath to produce synovial fluid.     

Arthritis and other proliferative joint diseases

Arthritis is a leading cause of disability in the Western world. As clinical outcomes and treatment options vary depending on the type of arthritis present, it is important for practicing histopathologists to be aware of the various disease manifestations. Although inflammatory phenomena pertain in all forms of arthritis, it is classically characterised as non-inflammatory (osteoarthritis being the most common example) or inflammatory (seropositive and seronegative arthritis, crystal deposition disease, or sepsis). Other proliferative joint diseases including tenosynovial giant cell tumour and primary synovial chondromatosis are also discussed.     

Obstructive lung diseases and risk of rheumatoid arthritis

ABSTRACT

Introduction: Smoking is an established risk factor for both lung diseases and rheumatoid arthritis (RA). Chronic mucosal airway inflammation may result in immune tolerance loss, neoantigen formation, and production of RA-related autoantibodies that increase the subsequent risk of RA. In this review, we aimed to summarize the current evidence supporting the role of obstructive lung diseases and subsequent risk of RA.

Areas covered: We identified scientific articles discussing the biologic mechanisms linking mucosal airway inflammation and RA risk. We also identified studies investigating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, chronic tuberculous and nontuberculous mycobacterial infections, and interstitial lung disease with subsequent risk for RA.

Expert opinion: The current evidence supports the hypothesis that mucosal airway inflammation may increase the risk of developing RA. However, most studies investigating this relationship have been retrospective and may not have adequately addressed the role of smoking. Larger prospective studies may provide stronger evidence for obstructive lung disease and RA risk. Determining the role of obstructive lung disease in RA pathogenesis may provide opportunity for RA prevention and screening strategies, while identifying novel biologic mechanisms that could offer targets to improve treatment and outcomes.