Genetics of HLA-associated disease; rheumatoid arthritis

An association between rheumatoid arthritis (RA) and the HLA antigen DR4 supports the view that genes in the HLA region are important in susceptibility to this disease. To further define the basis for genetic susceptibility to RA, we analyzed HLA haplotype sharing among affected and unaffected individuals in 29 multiple-case families with definite or classic RA. We have observed a non-random distribution of HLA haplotypes to unaffected as compared with affected offspring in sibships containing two or more affected individuals having 3 of 4 parental haplotypes. These data support the view that susceptibility to RA is determined, at least in part, by genes in the HLA region of chromosome 6.     

Genetics of rheumatoid arthritis: Underlying evidence of ethnic differences

A new age has begun in the genetics of rheumatoid arthritis (RA), as genome-wide association studies scanning the human genome have been put into practical use. Among the RA-susceptibility genes identified by genetic studies, HLA-DRB1 gene appears to represent the most major determinant of genetic predisposition to RA. However, inconsistent results of the contributions of non-HLA susceptibility genes have been described, with the exception of a few genes repeatedly associated with RA-susceptibility, such as PTPN22 gene in populations of European ancestry and PADI4 gene in populations of Asian ancestry, revealing the presence of genetic heterogeneity in RA. We review herein recent advances in the genetics of RA and discuss the underlying differences among populations of European and Asian ancestries, taking as examples our previous findings for RA-susceptibility genes in the Japanese population: PADI4; FCRL3; and CD244.     

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.     

Spotlight on etanercept in rheumatoid arthritis,psoriatic arthritis and juvenile rheumatoid arthritis

Etanercept (Enbrel) is a subcutaneously administered biological response modifier that binds and inactivates tumour necrosis factor-alpha, a proinflammatory cytokine. In patients with early active rheumatoid arthritis, etanercept 25mg twice weekly was associated with a more rapid improvement in disease activity and a significantly greater cumulative response than methotrexate over 12 months of treatment in a randomised, double-blind trial. In addition, etanercept recipients showed a slower rate of radiographic progression and a more rapid improvement in quality of life than methotrexate recipients. The efficacy of etanercept was maintained at 3 years' follow-up. Etanercept was also significantly better than placebo at reducing disease activity in patients who had an inadequate response to previous treatment with disease-modifying antirheumatic drugs (DMARDs) in several well controlled trials. At study end (after 3 or 6 months' treatment), the percentage of patients achieving an American College of Rheumatology 20% (ACR20) response with etanercept (25mg or 16 mg/m(2) twice weekly) was 59-75% as monotherapy and 71% in combination with methotrexate; corresponding placebo response rates were 11-14% and 27%, respectively. Response has been maintained in patients who continued treatment for up to 5 years. In patients with psoriatic arthritis, etanercept 25mg twice weekly significantly reduced disease activity and improved skin lesions in two double-blind, placebo-controlled, 12- to 24-week trials. In the 24-week study, ACR20 response rates (50 vs 13%), psoriatic arthritis response rates (70 vs 23%) and the median improvement in skin lesions (33 vs 0%) were significantly greater in etanercept than in placebo recipients. In patients with polyarticular-course juvenile rheumatoid arthritis, etanercept resulted in improvements in all measures of disease activity and was significantly more effective than placebo at reducing disease flare. Eighty percent of patients receiving etanercept achieved a > or =30% reduction in disease activity over 7 months of treatment, and this was maintained for up to 2 years in a trial extension. Etanercept was generally well tolerated in children and adults in clinical trials; the most commonly occurring adverse effects included injection site reactions, infection, headache, rhinitis and dizziness. In conclusion, etanercept has emerged as an important new treatment option in inflammatory arthritis. Etanercept provides rapid and sustained improvements in disease activity in patients with early and DMARD-refractory rheumatoid arthritis and has been shown to inhibit radiographic progression in those with early disease. Well controlled studies have also demonstrated the efficacy of etanercept in patients with psoriatic arthritis or polyarticular-course juvenile rheumatoid arthritis.     

From reactive arthritis to rheumatoid arthritis

Reactive arthritis was initially described as a sterile synovitis, without microbial components present in the joint tissue. It has, however, become evident that bacterial degradation products, and even bacterial DNA, are present in the synovium of patients with this disease. Since intestinal pathogens are important causes of reactive arthritis, and since cellular homing allows transport of bacterial products from the gut to synovium, we have approached the etiology of rheumatoid arthritis from this point of view. A series of observations has led to a hypothesis that patients with rheumatoid arthritis might favour, for genetic reasons, intestinal bacteria which are capable of inducing arthritis. In the long-run, with continuous seeding of bacterial products from the gut, the synovial inflammation is followed by erosion, exposition of cartilage antigens, and autoimmunity.     

Etiology of rheumatoid arthritis

The major thesis of the proposed hypothesis is that in the absence of microbial material synovial macrophages in rheumatoid arthritis patients continue to release interleukin 1, which perpetuates the inflammation so characteristic of the disease. Its release is suggested to result from an altered synovial macrophage glutathione metabolism brought about by the action of interleukin 1 on host copper metabolism. Three anti-rheumatic drugs are suggested to act at different points in this pathogenic chain reaction. Alclofenac on interleukin 1, gold thiolates on copper-inhibited macrophage glutathione reductase, and D-penicillamine on IgG catabolism. Drawing upon the hypothesis some suggestions are made for drug design.     

Pathogenesis of rheumatoid arthritis

This report gives a review on recent results of investigations of cellular aspects of inflammation. The role of macrophages and T-helper-cells with particular focus to the effects of the various mediators on their target cells will be discussed. Interleukin 1, Tumor Necrosis Factor, Interleukin 2, and Interferon as well as arachidonic acid metabolites contribute to the clinical findings of inflammation. We have to admit that the whole process of inflammation in rheumatic arthritis (RA) is not yet clear. For example we do not know in detail why RA is self perpetuating, why and when rheumatoid pannus occurs or under which circumstances immune complexes may cause the various organ manifestations. Recent findings are discussed.     

Cyclosporine and rheumatoid arthritis

Conclusions All the studies so far performed indicate that CS treatment in RA is effective. But it is also clear that CS-induced nephrotoxicity is so far the main problem. However, nephrotoxicity can be minimized by lowering the CS dosage and by ensuring that RA patients subjected to CS therapy have a normal kidney function and no history of hypertension. Hypertrichosis due to CS therapy is also a considerable problem, since the majority of patients with autoimmune diseases are women. Malignant lymphomas are a minor problem as so far there have only been two reported cases among 2500 CS-treated patients with autoimmune diseases.We believe that CS alone or in combination with other drugs will find its place in the treatment of RA and other autoimmune diseases in the future.     

Depression in rheumatoid arthritis

We have examined 144 patients with rheumatoid arthritis and found a high prevalence of depression, which has not previously been reported.

It is probable that good practitioners who see patients at home acquire a better understanding of the social and psychological aspects of such an illness. The presence of depression was statistically significant when associated with the articular index, the degree of functional impairment, and with dependence on others, but not with many other medical and social factors.

     

Nephropathy in rheumatoid arthritis

Occurrence of renal involvement in Rheumatoid arthritis is uncommon; when present it has been attributed to amyloid or secondary effects of drugs. Nevertheless, recent observations seem to indicate the existence of primary renal lesions associated with the disease. The purpose of this paper is to review the data suggesting that the kidney can be directly involved in Rheumatoid arthritis. The main points of interest are the occurrence of glomerulonephritis and/or amyloidosis, the presence of vasculitis and other arterial changes, the existence of chronic interstitial nephritis and papillary necrosis and lesions associated with gold and penicillamine therapy.     

Atopy and rheumatoid arthritis

The prevalence of rheumatoid arthritis (RA) was studied among 266 atopic patients attending an allergy clinic. Two patients had definite RA, a prevalence similar to that seen in the general population. We also studied the prevalence of atopy (positive skin-prick tests) and diseases associated with atopy among forty patients with RA and forty age- and sex-matched controls. The two groups had a similar prevalence of atopy (5 RA patients, nine controls) and atopic diseases (fourteen RA patients, fourteen controls) and they did not differ with respect to blood eosinophil counts or total serum IgE. Positive RAST tests to inhaled allergens were found in three RA patients and five controls and all patients had negative RAST tests to milk and egg. It was concluded that patients with rheumatoid arthritis have a normal prevalence of atopy and atopic diseases and we found no evidence that allergic factors contributed to the arthritis of the forty RA patients in the study.     

Apheresis in rheumatoid arthritis

Plasmapheresis was first introduced as a means of treating the rheumatic diseases in 1976. The rationale of its use was the removal of circulating immune complexes, thus preventing their deposition in the tissue. In rheumatoid arthritis circulating immune complexes do indeed occur and are responsible for some of the serious complications such as vasculitis. Since the T cells are implicated in tissue damage, lymphapheresis and lymphoplasmapheresis were introduced with various success rates. Controlled trials in rheumatoid arthritis have found no value for intensive plasmapheresis, limited value for lymphapheresis and possible, though suspect, value for lymphoplasmapheresis.