Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue.

Vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF), is a potent microvascular permeability enhancing cytokine and a selective mitogen for endothelial cells. It has been implicated in tumor angiogenesis and ascites fluid accumulation. Since development of the destructive synovial pannus in rheumatoid arthritis (RA) is associated with changes in vascular permeability (synovial fluid accumulation), synovial cell hyperplasia, and angiogenesis, we examined synovial fluids (SFs) and joint tissue for the expression and local accumulation of VPF/VEGF. VPF/VEGF was detected in all of 21 synovial fluids examined and when measured by an immunofluorimetric assay, ranged from 6.9 to 180.5 pM. These levels are biologically significant, since < 1 pM VPF/VEGF can elicit responses from its target cells, endothelial cells. Levels of VPF/VEGF were highest in rheumatoid arthritis fluids (n = 10), with a mean value (+/- SEM) of 59.1 +/- 18.0 pM, vs. 21.4 +/- 2.3 pM for 11 SFs from patients with other forms of arthritis (p = 0.042). In situ hybridization studies that were performed on joint tissues from patients with active RA revealed that synovial lining macrophages strongly expressed VPF/VEGF mRNA, and that microvascular endothelial cells of nearby blood vessels strongly expressed mRNA for the VPF/VEGF receptors, flt-1 and KDR. Immunohistochemistry performed on inflamed rheumatoid synovial tissue revealed that the VPF/VEGF peptide was localized to macrophages within inflamed synovium, as well as to microvascular endothelium, its putative target in the tissue. Together, these findings indicate that VPF/VEGF may have an important role in the pathogenesis of RA.

Outcomes in primary Raynaud phenomenon: a meta-analysis of the frequency, rates, and predictors of transition to secondary diseases.

OBJECTIVE: To summarize the current literature on the frequency, rates, types, and outcome predictors of secondary diseases that develop in patients with primary Raynaud phenomenon. METHODS: A structured MEDLINE literature search with the MeSH heading "Raynaud's disease," which was crossed with (1) systemic sclerosis, (2) prognosis, (3) prospective studies, (4) follow-up studies, and (5) retrospective studies, was used to identify 910 articles for possible inclusion. Articles that identified patients with primary Raynaud phenomenon who were followed up and re-evaluated at the end of the study, and which used published classification criteria to assess the presence or absence of secondary disease were included. Patient-years of Raynaud disease, patient-years of follow-up, and rates and predictors of transition to secondary disease were calculated from the articles selected. The summary odds ratio and positive predictive value for evaluation criteria at entry were calculated from 2 x 2 tables generated for each variable. RESULTS: Ten articles identified a total of 639 patients with primary Raynaud phenomenon who were followed up for 2531 patient-years. Eighty-one patients (12.6%) developed a secondary disorder, 80 of which were connective-tissue diseases. Transitions occurred at a mean rate of 3.2 per 100 patient-years of observation. The mean time to develop a secondary disorder was 2.8 years from study entry and 10.4 years from the onset of Raynaud phenomenon. At entry, the best predictor of transition was an abnormal nailfold capillary pattern (positive predictive value, 47%). Antinuclear antibodies in these patients had a positive predictive value of only 30%. CONCLUSION: Although a variety of clinical and serological abnormalities can be found in patients with primary Raynaud phenomenon, only a small percentage of them develop a connective-tissue disease.

Test performance in systemic sclerosis: anti-centromere and anti-Scl-70 antibodies.

PURPOSE: To determine the sensitivity and specificity of anti-centromere (ACA) and anti-Scl-70 antibodies in systemic sclerosis (SSc). METHODS: Four-hundred ninety-seven English language articles published from 1966 to 1994 were identified by structured MEDLINE search. Articles in which either ACA or anti-Scl-70 antibodies were measured in both SSc patients and a non-SSc control group were reviewed and rated using a previously published diagnostic testing scale. Reported sensitivity and specificity from each study was converted into a 2 x 2 table, and combined across studies to calculate summary rates for each antibody. Author's clinical classification criteria for SSc served as the gold standard for disease diagnosis. RESULTS: In 30 articles that fulfilled inclusion criteria, ACA were found in 441 of 1,379 SSc patients (sensitivity 32%, range 17% to 56%). This increased to 57% (332 of 585) in patients with the limited cutaneous, or CREST, subset of SSc (IcSSc). Anti-Scl-70 antibodies were found in 366 of 1,074 SSc patients (sensitivity 34%, range 3% to 75%), and this increased slightly to 40% in patients with the diffuse cutaneous form of SSc (dcSSc). Both antibodies were measured in 670 patients, and either test was positive in 58% (range 29% to 86%), but in only 3 patients were both antibodies present. The specificity of each antibody was high, but varied by control group. ACA were present in 5% and anti-Scl-70 antibodies were present in 2% of patients with other connective tissue diseases, but fewer than 1% of disease free controls had either antibody present. CONCLUSIONS: As individual diagnostic tests in SSc, both ACA and anti-Scl-70 antibodies are highly specific. Each performs somewhat better as discriminators of clinical subsets for patients in whom a diagnosis of SSc has already been established. Clinicians can rely on a positive test result as being specific in the detection of disease, but 40% of SSc patients are likely to have neither antibody present, and a negative result does not exclude the diagnosis. Measurement of these antibodies should be considered secondary to the clinical features when making a diagnosis of SSc.

Skin capillary abnormalities as indicators of organ involvement in scleroderma (systemic sclerosis), Raynaud's syndrome and dermatomyositis.

Forty-four study patients with scleroderma (systemic sclerosis) (28 patients), Raynaud's syndrome (13 patients) or dermatomyositis (three patients) were observed for skin capillary abnormalities by widefield microscopy and compared with three control groups of 20 subjects each: (1) patients with other rheumatic disease, (2) hospitalized patients with nonrheumatic conditions, and (3) healthy volunteers. The distinctive microvascular pattern (dilated and distorted capillary loops alternating with avascular areas) previously reported in scleroderma and dermatomyositis was observed almost exclusively in the study patients. The severity of capillary abnormalities varied among the diagnostic subgroups, and a positive correlation was found between the degree and extent of abnormal microvascular patterns and multisystem involvement. On this basis, widefield nailfold capillary observations are proposed as a simple, inexpensive, reproducible technic for making an improved early diagnosis and predicting multisystem involvement in scleroderma, Raynaud's syndrome and dermatomyositis, presently a group of loosely associated and overlapping connective tissue disorders which often defy early and precise diagnosis.

Prospective study of the evolution of Raynaud's phenomenon.

Seventy-four patients with Raynaud's phenomenon and no associated illness were followed prospectively to determine whether a secondary disease would develop, and clinical and laboratory assessments were performed at study entry to determine their association with the subsequent development of disease. After an average of 2.7 years of follow-up (range 0.5 to 5.7 years), outcome information was available on 58 persons (78.4 percent). A connective tissue disease developed in 11 (19.0 percent): three systemic sclerosis and eight CREST syndrome. The two variables at entry most strongly associated with the subsequent development of a connective tissue disease were an abnormal nailfold capillary pattern (adjusted odds ratio = 26.82, 95 percent confidence interval = 4.69, 153.2) and an abnormal pulmonary function test result (odds ratio = 4.78, 95 percent confidence interval = 1.02, 22.41). The positive association of an abnormal barium esophagram, presence of antinuclear antibodies, and cutaneous abnormalities did not reach statistical significance. The development of connective tissue diseases in this group of patients is not rare. An abnormal nailfold capillary pattern is strongly associated with the subsequent development of systemic sclerosis or CREST syndrome in patients with Raynaud's phenomenon.

Drug treatment of arthritis. Update on conventional and less conventional methods.

Nonsteroidal anti-inflammatory drugs comprise an important class of medications that reduce the signs and symptoms of osteoarthritis and rheumatoid arthritis. They bring relief to millions of people but do not eliminate underlying disease. Disease-modifying antirheumatic drugs also bring relief, but these drugs are often ineffective and not well tolerated. Failure to provide long-term benefits combined with the high toxicity of most of the disease-modifying agents has prompted a search for more effective treatments. New methods using modern technologies have generated much enthusiasm and hold promise for the future. In the meantime, administration of nonsteroidal anti-inflammatory drugs and judicious use of disease-modifying agents remain the cornerstone of therapy for arthritis.

Diagnosis and management of vascular disease in systemic sclerosis.

Vascular disease is seen in virtually all patients with systemic sclerosis and presents several challenges to physicians caring for them. Early recognition of isolated pulmonary hypertension and scleroderma renal crisis may be keys to successful outcomes. Although complete reversal of vascular disease is usually not possible, the availability of calcium channel blocking agents for RP and isolated pulmonary hypertension and ACE inhibitors for hypertensive renal disease has improved the morbidity and mortality of these patients. Optimal management of the vascular events in systemic sclerosis will ultimately depend on a clearer understanding of their pathogenesis. Treatment may ultimately be directed at preventing the development of these vascular syndromes. This may occur through combined therapy directed at both the abnormal immune response and disregulated fibroblast function seen in the disease, as well at the abnormal vascular responses. Such therapies have yet to be identified.

Low dose etodolac in rheumatoid arthritis: a review of early studies.

Short and longterm safety and efficacy of etodolac in a wide range of dosages in patients with rheumatoid arthritis (RA) are summarized. Data from 8 studies, one longterm (1 year) and 7 short term (< 10 weeks) were analyzed. All studies were double blind and randomized; 6 had a placebo control group and 7 had an active comparator (aspirin, piroxicam, or sulindac) group. In the 1 year study, doses of etodolac were titrated up from 50 mg bid until clinical efficacy was achieved and maintained; the highest dose for > 80% of patients was 150 mg bid. In 6 of the 7 short term studies, dosages were fixed and ranged from 50 to 300 mg bid. Continuation rates and 4 efficacy measures (patients' and physicians' global assessments and numbers of painful and swollen joints) were assessed. The 1 year study enrolled 475 patients. Overall continuation rates for etodolac and aspirin were comparable, but more patients taking aspirin discontinued the study because of adverse events. Most patients given etodolac who discontinued treatment for lack of efficacy did so during the titration phase. Four of 236 patients received aspirin and none received etodolac developed ulcers. For patients continuing to take the study medication, improvement in efficacy variables in the etodolac group was comparable to that in the aspirin group. In the 7 short term studies, dose related improvement in patients' and physicians' global assessments and number of swollen joints was noted in the etodolac group compared with the placebo group; this improvement was statistically significant at dosages of > or = 200 mg bid. Pooled analysis showed the efficacy of etodolac at dosages of 300 mg bid to be similar to that of comparator drugs. These short and longterm studies show that etodolac in a wide range of dosages, starting at 200 mg bid, has clinical efficacy in the treatment of RA. It is significantly better tolerated than aspirin, and at doses of 300 mg bid, it is as effective as sulindac, aspirin, and piroxicam.

Retinoic acid effects on endothelial cell function: interaction with interleukin 1.

Blood vessel angiogenesis is an important component of chronic synovitis, and its regulation may be mediated through local production and effects of certain inflammatory cytokines, including interleukin-1 (IL-1). Retinoic acid (RA) can alter the progression of some inflammatory arthritic diseases, presumably through effects on fibroblast collagenase and PGE2 production. To explore alternate hypotheses, we examined the interaction of retinoic acid and IL-1 on endothelial cell (EC) function and found that RA directly affects and modifies the effects of IL-1 on EC proliferation, prostacyclin production, and plasminogen activator inhibitor capacity (PAI-1). With respect to EC proliferation, cis- and trans-retinoic acid and retinol induced a dose-dependent increase of [3H]TdR uptake by cultured ECs, independent of the effects of serum or eicosanoid production. This effect was blocked by IL-1. With respect to EC prostacyclin production, although retinoic acid alone had no effect, cis and trans-retinoic acid and retinol all induced a dose-dependent increase in IL-1-mediated prostacyclin production, which was most marked at higher concentrations (20 U/ml) of IL-1. This effect was mediated through effects independent of cyclooxygenase (COX) production. With respect to plasminogen activator inhibitor capacity, both IL-1 and retinoic acid stimulated EC PAI-1 synthesis, but the individual effects were additive, with RA augmenting the known IL-1 effects on EC PAI-1 production. The interaction between RA and IL-1 on the endothelium, described in this study, may play a role in the fashion through which retinoic acid alters the expression of synovitis in certain types of experimental inflammatory arthritis.

Etanercept (Enbrel): update on therapeutic use.

Tumour necrosis factor (TNF) is an important inflammatory disease mediator in a wide spectrum of articular diseases, including adult and juvenile rheumatoid arthritis (RA, JRA). Etanercept (Enbrel), approved in the United States and in Europe for use in patients with RA and JRA, is an effective inhibitor of TNF that has been shown to provide rapid and sustained improvement in both of these diseases. Long term studies continue to show that etanercept controls signs and symptoms of RA and JRA with no change in rate or type of adverse event over time. To demonstrate that etanercept is effective as first line treatment for patients with early active RA who have not been previously treated with methotrexate, and to examine the effect of etanercept on radiographic progression, a double blind, placebo controlled study was recently conducted, comparing etanercept with methotrexate (median dose 20 mg per week). Both etanercept 25 mg twice weekly and rapidly escalated methotrexate were effective in reducing the signs and symptoms of RA, and etanercept was significantly better than methotrexate in slowing the rate of radiographic erosions. In patients with severe psoriatic arthritis (PsA), a double blind, placebo controlled study demonstrated that etanercept was also effective in reducing disease activity in PsA. Etanercept has been well tolerated in all of these clinical trials and offers an important new treatment option to patients with inflammatory articular diseases.

Augmentation of interleukin-1 induced prostacyclin production by endothelial cell growth factor: implications for chronic synovitis.

Interleukin-1 (IL-1) is a key inflammatory cytokine that has important effects both on endothelial cell (EC) growth and synthetic function. Fibroblast growth factors (FGF's), including endothelial cell growth factor (ECGF), are important regulators of EC growth, and their role in the pannus formation and synovial proliferation seen in chronic arthritis has been emphasized recently. While ECGF mediated EC proliferation is inhibited by IL-1, potential interaction of these peptides on other aspects of EC function has not been described. As both IL-1 and FGF may be important disease mediators in rheumatoid arthritis, we studied their combined effects on EC prostacyclin production. While ECGF alone had no measurable effects, it enhanced rIL-1 alpha induced prostacyclin production in a dose and time dependent fashion. Both pertussis and cholera toxins blocked the augmentation, suggesting a role for G proteins in mediating the synergism. These studies demonstrate that ECGF can alter certain effects of IL-1 on the endothelium, and point to an additional role that this family of growth factors may play in some inflammatory disorders.

Nonsteroidal therapy of rheumatoid arthritis and osteoarthritis: how physicians manage treatment failures.

OBJECTIVE: Few studies have examined the practice patterns of primary care physicians who treat patients with rheumatoid (RA) or osteoarthritis (OA), and the strategies used when nonsteroidal antiinflammatory drugs (NSAID) are ineffective or cause side effects. Our purpose was to study practice patterns of physicians who initiate treatment of RA and OA, and their management approaches when NSAID are ineffective or cause dyspepsia. METHODS: Using a structured questionnaire simulating management of patients with RA or OA we surveyed treatment preferences of primary care physicians. RESULTS: Responses from 176 physicians were analyzed. For RA 98% used NSAID as initial therapy. For those patients who did not respond, most (over 60%) would either change or increase the initial NSAID and try a mean of 2.2 different NSAID over a period of 3.3 months before initiating second-line therapy or referring to a rheumatologist. For OA 67% of physicians surveyed initially used NSAID to treat these patients, and changing or increasing the NSAID was the most common strategy used to manage patients not responding to initial therapy. For patients who developed dyspepsia taking NSAID there was wide divergence of management approaches in both diseases: stopping the NSAID and starting an analgesic (OA) or second-line agent (RA) were common choices, but continuing the NSAID and adding an "antidyspeptic" regimen was chosen by over half of physicians selecting a single regimen. Most initial management approaches did not differ significantly between RA and OA. CONCLUSION: NSAID are used frequently as initial therapy in patients with OA, and in RA the initiation of second-line therapy is often deferred for months and is only prescribed after patients have failed several NSAID. Opportunities exist to better standardize the approaches physicians use in the initial management of RA and OA, and to delineate what role NSAID should have in the management program of these disorders.

Vascular steal mimicking compression myelopathy in Paget's disease of bone: rapid reversal with calcitonin and systemic steroids.

Neurologic manifestations of Paget's disease of bone are primarily a result of mechanical compression on cranial nerves, spinal cord and roots. Less recognized is a myelopathy from "vascular steal" to highly vascularized and hypermetabolic pagetic bone. We describe a case of presumed ischemic myelitis in a patient with Paget's disease and aortic stenosis that was rapidly reversed with subcutaneous calcitonin and intravenous dexamethasone.

Nailfold capillaroscopy in type I diabetics with vasculopathy and limited joint mobility.

The nailfold capillary pattern of 48 Type I diabetic patients with longstanding disease and of 15 normal controls was studied using the technique of widefield nailfold capillaroscopy. Twenty-six diabetic patients had documented vascular disease (retinopathy) and 27 had flexion contractures of the hand. No distinctive morphologic capillary lesions were observed in any diabetic patient, nor were any differences in capillary loop number or density found between the diabetic and control groups. While vascular disease is a prominent feature of diabetes, it is not reflected in the appearance of the nailfold capillary pattern.

Nailfold capillary abnormalities and clinical outcome in childhood dermatomyositis.

The nailfold capillary pattern was observed in a population of patients with childhood dermatomyositis. Distinctive nailfold capillary loop abnormalities were found in 11 of 19 childhood dermatomyositis patients and in none of 2 control populations (P less than 0.001). By a retrospective analysis of the childhood dermatomyositis patients, we found that the presence of nailfold capillary abnormalities correlates with more severe forms of the disease (ulcerative and chronic types), as opposed to limited type of disease. These changes occurred independently of disease activity or of cutaneous abnormalities.

Polynucleotide antibodies in connective tissue disease: viral markers or disease mediators?

Antibodies to polynucleotides are seen primarily in systemic lupus erythematosus (SLE), but also occur in a variety of other connective tissue diseases. We looked at the prevalence of antinucleotide antibodies (double- and single-stranded RNA and DNA [dRNA, sRNA, dDNA, and sDNA]) in the sera of patients with SLE (70), rheumatoid arthritis (RA) (31), juvenile rheumatoid arthritis (JRA) (68), osteoarthritis (12), and of 22 patients with a preceding viral illness. In comparison with sera from a control population, elevated mean antibody levels to sRNA were found in the sera of all the patients with connective tissue disease, as well as in the sera of patients with preceding RNA, but not DNA, viral infections. Elevated mean levels of antibodies to dRNA were seen in all groups with the exception of RA. Elevated mean antibody titers to sDNA were not seen in patients with JRA nor were they present in the sera of patients with preceding RNA viral infections. Elevated mean anti-dDNA titers were seen only in sera from patients with SLE. High correlation coefficients between the levels of antibodies to sRNA and dRNA in sera from SLE and RA, and between sDNA and dDNA in sera from SLE suggest cross-reactivity of the antibodies in these diseases. Immunization of an elderly population with influenza (RNA) viral vaccine induced antibodies to sRNA only. These studies further document the prevalence of antipolynucleotide antibodies in the sera of patients with connective tissue diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothenar hammer syndrome: an occupational cause of Raynaud's phenomenon.

Hypothenar hammer syndrome is an uncommonly recognized, occupationally associated cause of Raynaud's phenomenon, induced by traumatic compromise of the vascular supply to the hand. Two patients are presented, one with preexisting Raynaud's phenomenon who sought attention after the development of cutaneous ulcers. The features of the syndrome are reviewed, and the importance of its recognition in the appropriate occupational setting as a potentially curable form of Raynaud's phenomenon is emphasized.

The evolution of Raynaud's phenomenon: a longterm prospective study.

OBJECTIVE: To evaluate prospectively a cohort of patients with Raynaud's phenomenon (RP) and signs, symptoms, or laboratory abnormalities suggestive of a connective tissue disease (CTD) to determine prognosis and to identify predictors of evolution. METHODS: Patients with suspected secondary RP were evaluated at baseline, 2.7 years, and 8.4 years after entry by history and examination, chest radiograph and barium esophagram, pulmonary function tests, antinuclear and anticentromere antibodies (ACA), cryoglobulins, and nailfold capillary microscopy (NCM). Logistic regression was used to identify predictors of evolution and to develop a risk factor model. RESULTS: Sixty-four patients were entered and all were subsequently evaluated. Thirty-two (50%) progressed to a definite CTD. Abnormalities of nailfold capillaries [odds ratio (OR) = 21.8] and hand swelling (OR = 18.5) at baseline were independent predictors of the development of systemic sclerosis. A positive ACA was the only risk factor identified for evolution into CREST syndrome (calcinosis, RP, esophageal dysmotility, sclerodactyly, telangiectasias) (OR = 22.5). Finally, nailfold capillary abnormalities were the only baseline feature associated with the development of any definite CTD (OR = 8.3). CONCLUSION: Fifty percent of patients with suspected secondary RP will develop a CTD over a period of 8.4 years. NCM predicts development of systemic sclerosis or any definite CTD and should be included in the evaluation of all such patients.