Current Rheumatology Reviews - Volume 2, Issue 4, 2006

Scleroderma Associated Inflammatory Arthritis: Common and Painful, but Ignored by Researchers Although the correct term is limited scleroderma, the acronym CREST is still widely used for two reasons. First, CREST is a descriptive and understandable name for five features of scleroderma which are relatively common and frequently concurrent. Secondly, limited scleroderma is associated with pulmonary hypertension and significant nutritional problems which render it hardly “limited”. Whatever the case, while CREST is frequently also associated with inflammatory arthritis, the literature reviewing the nature of this manifestation is scanty. In the report by Restrpo et al., Current Rheumatology Reviews explores this process in CREST in a detail not previously undertaken. First, the widespread association of inflammatory, rheumatoid-like arthritis with CREST is probably greater than appreciated. Secondly, since the process is often erosive and deforming, there is a compelling need to examine this in greater detail. Interestingly, there have been no studies or clinical trials evaluating the best way to manage CREST arthritis. Restropo et al. have performed a service to rheumatology by providing a compelling rationale and précis which clearly demonstrates the need to further elucidate this under investigated process and lure researchers into testing the effectiveness of existing and experimental therapies into managing CREST arthritis.

Osteoarthritis is generally thought to be a disease of articular cartilage characterised by the formation of defects. A number of diagnostic and treatment options have been developed to identify and treat these large lesions. There has been evidence of early cartilage changes consisting of ‘splits’ or ‘cracks’ which have not received much attention or research in the literature. The structure of articular cartilage and the way in which it responds to physiological loading by sometimes acting as a brittle substance may explain how these ‘cracks’ form. Particular types of ‘cracks’ may cause the formation of larger defects. In particular, those at 45° to the bone-cartilage interface may progress and ultimately lead to large areas of cartilage lifting off subchondral bone. Surface ‘cracks’ can also become unsafe if joint congruity changes. The clinical relevance of these ‘cracks’ remains uncertain. Further research is needed to determine if these ‘cracks’ do progress, whether they lead to pain, whether it is possible to accurately diagnose them, whether it is possible or necessary to treat them and whether current grading systems of articular cartilage lesions should include these ‘crack’s in their classification systems. This may be particularly relevant in the asymptomatic individual to retard or prevent progression to established osteoarthritis.

Pentosidine is one of the advanced glycation end-products (AGEs). Its significant elevation was firstly observed in diabetes mellitus, and later found in patients with end-stage renal failure. In addition, during the aging process, pentosidine accumulates in the extracellular matrix and causes insolubility and protease resistance of extracellular matrix proteins. In cartilage, pentosidine is crosslinked in collagen and proteoglycan, and thus increases the stiffness of the cartilage. Carbonyl stress, oxidative stress and aging progress the formation and accumulation of pentosidine. In arthritis, a significant elevation of pentosidine was found in rheumatoid arthritis and moreover in osteoarthritis. This review will discuss the relationship between pentosidine and arthritis, and its role as a potential marker for arthritis.

Annxine-1 (Anx-1), a member of the annexin superfamily of calcium- and phospholipid- binding proteins, is induced by glucocorticoids (GC) and functions as a mediator of their anti-inflammatory effects. The wide range of effects of Anx-1 includes inhibition of leukocyte recruitment, suppression of the production of inflammatory mediators and cytokines, and induction of apoptosis in inflammatory cells. This profile of activity suggests that the inhibitory effects of Anx- 1 would be beneficial in the pathological context of rheumatoid arthritis (RA). Anx-1 is expressed in human RA synovial tissue and cells, and has recently been identified as an important endogenous anti-inflammatory mediator in multiple animal models of RA. Emerging data on the mechanisms of action of Anx-1 suggest it acts to inhibit mitogen activated protein (MAP) kinases, through as yet unidentified mechanisms, thereby inhibiting pro-inflammatory pathways known to be important in RA. Anx-1 treatment strategies, especially as an alternative to GC therapy, may be valuable in RA and other inflammatory diseases.

Since 1992 extracorporeal shock wave therapy (ESWT) has been used in the treatment of pain, in various tendinopathies, including plantar fascitis, heel spur, epicondylitis, calcific and non-calcific tendonitis of the rotator cuff. The exact mechanism by which ESWT relieves tendon-associated pain is not known; however, numerous controlled and noncontrolled studies have demonstrated the efficacy of ESWT in the treatment of various tendinopathies, including plantar fascitis, heel spur and epicondylitis. Based on personal experiences and analysis of the literature, this review confirmed that ESWT is an effective therapeutic procedure with no side-effects in the treatment of calcific rotator cuff tendonitis, and which can be considered a valuable alternative to conventional treatments.

Autoimmune thyroid disease is among the most common autoimmune disorders affecting 10% of the population. It is characterized by diffuse lymphocytic infiltration of the thyroid gland, the presence of antithyroid antibodies and diffuse hypoechogenicity on thyroid ultrasound. Despite the fact that autoimmune thyroid disease is classically considered a localized disease of the thyroid gland, systemic features, such as musculoskeletal complaints, sicca symptomatology, pregnancy loss and even neurological manifestations are not uncommon. Although thyroid dysfunction could account for some of these features, concomitant autoimmune disorders or even thyroid autoimmunity itself could be involved. In the current report new clinical and laboratory data from our department are presented and the existing literature regarding the systemic/rheumatic features of autoimmune thyroid disease is reviewed.

Spirochetes are gram-negative bacteria, which include the Treponema, Borrelia and Leptospira and cause different diseases such as syphilis, Lyme borreliosis and leptospirosis, respectively. Antiphospholipid antibodies as a consequence of the infection with Treponema pallidum subsp. pallidum have been extensively studied. There have also been a few reports of antiphospholipid antibodies in leptospirosis. On the other hand, there are very few data on the presence of antiphospholipid antibodies in Lyme borreliosis and to our knowledge, there is no information about antibodies against β2-glycoprotein I. In this study, we report the frequency of anticardiolipin antibodies and for the first time, the frequency of antibodies against β2-glycoprotein I in patients with acute and chronic Lyme borreliosis. The frequency of anticardiolipin antibodies and IgG antibodies against β2-glycoprotein I was similar in both groups, but antibodies against β2- glycoprotein I of the IgM isotype were surprisingly higher in the late stage of the disease. The frequency of IgM class antibodies against β2-glycoprotein I was 10% in chronic Lyme borreliosis versus none in acute Lyme borreliosis.

In addition to their action on a decrease in blood pressure levels and a reduction of mortality in individuals with vascular disease, β-blockers can have beneficial effects on osteoporosis. The relationship between the sympathetic nervous system and bone metabolism is well known. There have been reports of adrenergic receptors in osteoblasts and of the presence of sympathetic nerve fibers in bone. The central infusion of leptin inhibits osteoblast activity through hypothalamic sympathetic activation resulting in decreased bone mass. This leads to the consideration of the use of β-blockers in the treatment of osteoporosis. Retrospective studies (case-control, cohort studies) followed, which showed a beneficial effect of the β-blockers on the reduction of fractures, although not all the results are consistent. In 9 published studies, a protective effect was shown in 7. The reduction of risk fracture was over 30 %. The aim of this article is to review the available evidence, experimental and clinical, of the effect of β-blockers on bone mass and the reduction of fractures. These drugs may be useful for the treatment of osteoporosis in patients with vascular disease

Thrombocytopenia in Systemic Lupus Erythematosus (SLE) is a common clinical manifestation affecting up to one third of patients in published cohorts. Anti-platelet antibodies have been implicated in its pathogenesis, as sensitized platelets interact with macrophages through the Fc receptor eliminating them from circulation. Non-specific, immunecomplex mediated platelet destruction is also implicated as are antiphospholipid syndrome, thrombotic microangiopathies and hemophagocytic syndrome. A few cases of thrombocytopenia with amegakaryocytic hypoplasia due to antibodies against c-mpl receptor have recently been identified. Pathophysiology has recently been intrigued by frequent findings of anti-thrombopoietin antibodies and faulty hemopoiesis in SLE patients with cytopenias. More specifically, histologic data has shown dysplastic changes and stromal alteration suggesting that bone marrow is a target organ in SLE. Although thrombocytopenia, per se, is a benign complication, with hemorrhagic manifestations being infrequent, it is associated with a more active disease and worse outcome: it marks a subgroup of SLE patients, having a higher risk of irreversible end-organ events throughout their disease course. These patients exhibit a predilection to a distinct pattern of damage, rendering thrombocytopenia a quantitive and qualitative marker of impending damage. Immunosuppressive therapy is required to restore normal platelet counts and treat concomitant organ involvement of other systems. Common therapeutic modalities include corticosteroids, intravenous immunoglobulin (IVIG), cytotoxic agents (mainly cyclophosphamide), immunomodulators (azathioprine) and androgens (Danazol). More recently, B-lymphocyte depletion (anti- CD20 immunotherapy) and mycofenolate mofetil have been successfully used in refractory cases with splenectomy as a last resort should other options fail.

Systemic sclerosis (SSc) is characterized by vascular abnormalities, fibrosis, inflammatory changes, and late stage atrophy/obliterative vasculopathy. Localized scleroderma forms show a longitudinal or circumscribed skin involvement. In scleroderma-like disorders the distribution/characteristics of skin involvement seem to be ‘atypical’ as compared to classic SSc, and the acral skin involvement is usually missing. Exposure to certain chemicals or drugs may also suggest the presence of a scleroderma-like disease. Lack of Raynaud's phenomenon, scleroderma-specific antinuclear antibodies, scleroderma capillary pattern on nailfold capillaroscopy, and typical internal organ manifestations may also indicate the presence of a scleroderma-like disorder. For differential diagnosis skin biopsy is almost always required. Scleroderma-like disorders include diseases with mucin deposition (scleromyxedema, scleredema, etc.). Some disorders show papular-nodular skin changes with or without dermal deposition of materials (amyloid, mucin deposition; fibroblastic rheumatism, etc.). Diseases with monoclonal gammopathy (scleromyxedema, POEMS syndrome, myeloma with scleroderma-like skin changes) also belong to the large group of scleroderma-like diseases. Some disorders are characterized by eosinophilia (diffuse fasciitis with eosinophilia, eosinophilia-myalgia syndrome, toxic oil syndrome), metabolic/ biochemical abnormalities (IDDM, nephrogenic fibrosing dermopathy), and endocrine abnormalities (POEMS syndrome, hypo/hyperthyroidism with mucin deposition, diabetes). Chronic graft-versus host disease (cGVHD) may also show scleroderma-like skin changes. Scleroderma-like disorders can be induced by drugs or chemicals (eosinophilia-myalgia syndrome, toxic oil syndrome, vinyl-chloride disease; cytostatic/appetite suppressant, etc), and also by physical injury (trauma, vibration stress, radiation injury). Inherited progeroid syndromes with early ageing (Werner's syndrome, etc.), and a large heterogeneous group of hereditary disorders with either skin thickening (porphyria, phenylketonuria) or skin atrophy/tightening (restrictive dermopathy, scleroatrophic and keratotic dermatosis of the limbs, etc.) should also be taken in consideration in the differential diagnosis of scleroderma-like disorders. These categories are not mutually exclusive, because the remarkably different scleroderma-like diseases show overlapping features.

Background: Systemic sclerosis is a disease characterized by sclerosis of the skin, internal organs and vasculopathy. Articular manifestations are common, and include arthralgias, arthritis, and morning stiffness, which in some cases can be confused with rheumatoid arthritis (RA). Patients develop functional impairment and thickening of the skin including around the joints, with inflammation and fibrosis of tendon sheaths. However, articular inflammation is rare clinically, as is the development of articular erosions. Objective: To define the presence and characteristics of arthropathy in patients with scleroderma and distinguish it from RA. Methods: Case series of 106 Colombian patients with scleroderma evaluated between January 1998 and December 2004, of whom 5 had significant articular involvement and are the subject of this report. Results: All patients had the CREST variant of scleroderma. Their average age was 48.6 years (range 35-56). All had arthropathy affecting mainly the hands and feet. In the majority of cases the clinical picture resembled that of RA, with inflammation and subluxation of the metacarpophalangeal joints, and involvement of the feet with subluxation of the toes. Radiographs revealed joint space narrowing, subluxation, juxtaarticular osteopenia, carpal ankylosis and erosions. Rheumatoid factor was negative and antinuclear antibody (ANA) was positive with anticentromere antibodies in all patients. Conclusions: We conclude that there is a unique arthropathy of scleroderma which is due to inflammation and mechanical factors related to skin and periarticular involvement from the underlying disease. It is not due to coexisting RA. All of our cases had CREST variant scleroderma with erosive arthritis, negative rheumatoid factor, and positive ANA with centromere antibody. None fulfilled classification criteria for RA. This is a distinct subtype of scleroderma. Patients should be identified and treated promptly to avoid development of serious articular disease. The tendency to develop severe articular disease is likely immunogenetically linked.

The antiphospholipid syndrome (APS) is characterised by arterial and/or venous thrombosis and pregnancy morbidity in the presence of anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA). APS can occur either as a primary disorder (PAPS) or secondary to a connective tissue disease, more frequently systemic lupus erythematosus (SLE). Any organ and any size of vessel can be affected in this disorder. In 1983 Hughes, in his original description of the syndrome, also reported thrombocytopenia, neurological disease, livedo reticularis and labile hypertension. The range of clinical features that has been associated with the presence of antiphospholipid antibodies (aPL) is extremely wide and has broadened over the last 20 years.