Current Rheumatology Reviews - Volume 2, Issue 3, 2006

In this issue of Current Rheumaology Reviews, Farhey and Hess review the concepts of mixed connective tissue disease (MCTD) and undifferentiated connective tissue disease (UCTD) [1]. It is now widely agreed upon the MCTD has a reproducible set of serologic findings, clinical manifestations and statistically validated defined criteria. Once thought to be a benign process, nearly 20% develop pulmonary hypertension, which is its major cause of death. The review succinctly summarizes the literature with regards to management and prognosis. Less well understood is UCTD. In 1982, an American College of Rheumatology endorsed collaborative effort evolved a working definition for UCTD [2]. It included isolated Raynaud's phenomenon, unexplained polyarthritis, or isolated keratoconjunctivitis sicca. Those who had one of these 3 manifestations also had to have at least three additional findings among the following: Raynaud's, polyarthritis, sicca symptoms, myalgias, rash, pleurisy, pericarditis, central nervous symptoms, pulmonary symptoms, peripheral neuropathy, false-positive test for syphilis, and elevated sedimentation rate. Over 20 years of observations, the outcomes of 410 patients originally enrolled were consistent with one third having no disorder at follow up, one third still manifesting UCTD, and one third evolving accepted criteria for rheumatoid arthritis, primary Sjogren's, scleroderma, systemic lupus erythematosus or inflammatory myositis [3]. UCTD is the "tip of the iceberg". It does not overlap with MCTD and is different from early inflammatory arthritis that will declare itself as rheumatoid arthritis or another process within 12 months. The number of UCTD patients in my practice exceeds the number with scleroderma and polymyositis that I see, and other than the United States and a couple of European cohorts, very little is known about these individuals. We tend to manage UCTD patients with nonsteroidal anti-inflammatory agents, hydroxychloroquine, methotrexate and occasional corticosteroids. Since the disorder is rarely, if ever, organ threatening, aggressive management is uncommon. However, there are no controlled studies relating to the treatment or clinical outcomes of the disorder. The prevalence of UCTD is not known, but it is probably the second or third most common autoimmune disorder seen in clinical practice. This editorial makes the following suggestions: 1. A committee should be constituted to derive an updated consensus definition for UCTD and work to have it validated. 2. Patients with UCTD should be considered a distinct entity in existing rheumatic disease cohorts and thus be available for observational studies and clinical trials. REFERENCES [1] Farhey Y, Hess EV. Mixed connective tissue disease (MCTD) and undifferentiated conncective tissue disease (ICTD), Curr Rheumatol Rev 2006; 2: 261-267. [2] Alarcon GS, Williams GV, Singer JV, et al. Early undifferentiated connective tissue disease. 1. Early clinical manifestations in a large cohort of patients with undifferentiated connective tissue disease compared with cohorts of well established connective tissue disease, J Rheumatol 1991; 18: 1332-1339. [3] Williams HG, Alarcon GS, Joks R, et al. Early undifferentiated connective tissue disease (CTD): VI: An inception cohort after 10 years: disease remissions and changes in diagnoses in well established and undifferentiated CTD, J Rheumatol 1999; 26: 816-825.

In the last few years there has been an explosion of research into epigenetics and, in particular, the roles of DNA methylation in the normal functioning of the mammalian organism as well as whether changes in methylation status contribute to or cause aberrant gene expression in diseases. While abnormal patterns of DNA methylation in cancer cells have been intensively investigated, little attention has so far been paid to the role of DNA methylation in cartilage and cartilage degeneration. This review summarizes the current knowledge of the mechanism of methylation, its association with transcriptional silencing, possible mechanisms of hyper- and hypomethylation as well as age- and disease related changes in methylation pattern. We discuss the possible involvement of DNA methylation in chondrogenesis as well as its potential importance for cartilage degradation. Overall, epigenetic gene regulation has largely been neglected in cartilage research, but is likely to be an important issue in future. There is increasing evidence that besides cytokines, growth factors and changes in matrix composition, variations in the genetic methylation pattern might also be important determinators of the complex gene expression pattern pathognomically observed in osteoarthritic cartilage tissue.

Systemic lupus erythematosus (SLE) is a complex disease involving many different immune mechanisms, whose pathogenesis is not fully understood. In the past therapeutic interventions have employed medications with multiple immunological targets, making their use as probes of disease mechanisms difficult. For example, prednisone and cyclophosphamide, the most widely used therapies for severe disease until recently, affect such a broad array of immune mechanisms that they do not help identify the most important immunological SLE pathways. While examining the efficacy and toxicity of some of the new targeted therapies, this review will address what specific agents tell us about the pathogenesis of SLE. These include anti-CD20 and BlyS antibody, B and T cell co-stimulatory blockade such as anti- CD40L antibody and CTLA4Ig, therapies aimed at decreasing dsDNA specifically, as well as cytokine modulation with TNF alpha inhibitor, anti IL-10 ab, etc.

Systemic sclerosis (SSc) is a connective tissue disease characterised by widespread vascular lesions and fibrosis of the skin and internal organs. Cardiac involvement is recognised as a poor prognostic factor when clinically evident. Primary myocardial involvement is common in SSc. Increasing evidence strongly suggests that myocardial involvement is related to repeated focal ischaemia leading to myocardial fibrosis with irreversible lesions. This results from microcirculation impairment with abnormal vasoreactivity, with or without associated structural vascular abnormalities. Myocardial perfusion impairment, abnormal systolic and diastolic left ventricular dysfunction and right ventricular dysfunction have been reported in SSc, using conventional methods. Recent methods such as tissue Doppler echocardiography and magnetic resonance imaging have underlined these results. These sensitive and quantitative methods have demonstrated the ability of vasodilators, including calcium channel blockers and angiotensin converting enzyme inhibitors, to improve both perfusion and function abnormalities.

Rheumatoid arthritis (RA) is a common inflammatory rheumatic disease affecting 2-3 times more women as compared to men. The peak incidence of RA in women coincides with the years around menopause when the production of estradiol (E2) and progesterone diminishes. The course of RA is also influenced by hormonal changes. The condition often ameliorates during pregnancy followed by flares after delivery. Animal studies have revealed distinct beneficial effects on arthritis by E2. Studies of hormone replacement therapy (HRT) in postmenopausal RA have disclosed improvement in bone mineral density (BMD) and recently also beneficial effects on disease activity was found. However, in view of side effects by conventional HRT, its use has to be individualized for any given patient and there is a need for new therapeutic agents selectively inducing potent anti-arthritic and anti-inflammatory effects, but without the adverse effects associated with HRT. This review will discuss: - Hormonal factors and gender associated with RA. - Sex hormones and the influence on the immune system and bone. - The effects of treatment with sex hormones on disease activity in RA. - The effects of HRT on BMD and bone and cartilage turnover in RA.

In Mixed Connective Tissue Disease (MCTD), features of various connective tissue disorders such as systemic lupus erythematosus (SLE), systemic sclerosis (PSSc), dermatomyositis/polymyositis (DM/PM), and occasionally Sjogren's syndrome and rheumatoid arthritis (RA) can coexist and overlap. The picture is marked by the presence of high titer anti-U1 ribonucleoprotein (RNP) antibodies. Over the last 30 years since first described a lot of controversial studies have been published regarding the nature, the severity or the very existence of the condition. We review here the various aspects and the characteristics which make it a distinctive autoimmune condition. We discuss the new understanding of the prognosis of this connective tissue disorder. We give an update on the management of MCTD. Some aspects of the Undifferentiated Connective Tissue Disease (UCTD) are approached as a class apart.

Vascular disease is integral to the pathogenesis of connective tissue diseases. Small vessel vasculitis underlies many clinical manifestations of systemic lupus erythematosus and complicates rheumatoid arthritis and other connective tissue diseases. In contrast, in systemic sclerosis, abnormal vasomotor activity and a proliferative arterial vasculopathy are prominent. Disorders of angiogenesis have been implicated in many connective tissue diseases, thromboembolic disease is common in antiphospholipid antibody syndrome and Behçet's disease, and the association between chronic systemic inflammatory diseases and accelerated atherosclerosis is now well-recognised. Emerging evidence suggests that agents prescribed as either immunomodulators or cardiovascular risk modifiers may be effective in both capacities. The clinical significance of vascular disease in connective tissue disease is emphasized by the observation that excess mortality is predominantly cardiovascular. We re-evaluate the paradigm of disease-modifying therapy in connective tissue disease with attention to the mechanisms of vascular disease and review therapeutic strategies by which these may be inhibited.

Cardiovascular disease remains the leading cause of mortality in the United States. The increased prevalence of atherosclerotic cardiovascular disease is well established in rheumatoid arthritis and systemic lupus erythematosus. Recently, studies of other rheumatic diseases, such as the systemic vasculidities, have also demonstrated accelerated atherosclerotic disease. The detection and delineation of the inflammatory pathways that contribute to atherogenesis in the general population are important in deriving insight into how disease-associated factors may initiate and participate in accelerated atherogenesis in patients with rheumatic diseases.

Osteoporosis, is a clinical syndrome in which a bone mass decrement greater than that normally expected in an individual of a given age, race, and gender prevails, thus causing bones to thin, become brittle, and liable to fracture. While estrogen therapy (ET) has been applied to postmenopausal women to assist them to maintain or increase their bone density levels, or to slow down the rate at which they lose bone mass, and is effective in increasing this, ET causes more side-effects. Since ET is still being recommended in some contexts of postmenopausal health care, we presently elected to examine the body of literature detailing the effects of exercise for preventing postmenopausal bone loss to better identify whether this non-pharmacological approach can be recommended as a substitute for ET. We specifically focused on examining a less well documented body of this voluminous literature, namely the efficacy of aerobic exercises for preventing osteoporosis among postmenopausal women. This body of research indicated, that unlike ET, the effects of moderate, prolonged aerobic exercise on bone, health status, and muscle strength are generally quite positive with few side-effects. Furthermore, due to their positive effects on cognitive and muscle neurophysiology, moderate aerobic exercises may have the additional benefit of preventing falls that lead to fractures. Pending further research to substantiate these findings, we conclude clinicians can safely recommend moderate intensity aerobic exercises to their premenopausal or perimenopausal patients in order to help prevent or retard the anticipated rate of bone loss and osteoporotic fractures commonly experienced by postmenopausal women if ET is not advisable.

Reactive arthritis is triggered by an infection. Much of evidence has been accumulated to prove that the causative microbes or their components may persist in the organism for extended periods, maintaining an active immune response. Therefore, the question about the value of antibiotics has been entertained by several research groups. A number of studies have demonstrated that antibiotics may be useful only if applied very early, before the pathogenetic process has started. In established reactive arthritis short-term treatment is apparently not effective. Also a three-month course of ciprofloxacin has been demonstrated to be without clinical effect as observed during a one-year follow-up. The same findings were made in a large multicenter EULAR study regarding azithromycin. However, when patients were re-examined four to seven years after an initial 3-month course of the antibiotics in the Finnish ciprofloxacin study, it turned out that patients in the placebo group had significantly more often developed chronic joint symptoms and objective findings of rheumatic disease than those treated with the antibiotic. In addition, a recent study suggests that intensive treatment with a combination of doxycycline and rifampin may have a beneficial effect even in chronic reactive arthritis. The question must be raised whether antibiotics, after all, should be considered especially in HLA-B27 positive patients.