Prevention of cardiovascular disease in rheumatoid arthritis.

The increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA) has been recognized for many years. However, although the characteristics of CVD and its burden resemble those in diabetes, the focus on cardiovascular (CV) prevention in RA has lagged behind, both in the clinical and research settings. Similar to diabetes, the clinical picture of CVD in RA may be atypical, even asymptomatic. Therefore, a proactive screening for subclinical CVD in RA is warranted. Because of the lack of clinical trials, the ideal CVD prevention (CVP) in RA has not yet been defined. In this article, we focus on challenges and controversies in the CVP in RA (such as thresholds for statin therapy), and propose recommendations based on the current evidence. Due to the significant contribution of non-traditional, RA-related CV risk factors, the CV risk calculators developed for the general population underestimate the true risk in RA. Thus, there is an enormous need to develop adequate CV risk stratification tools and to identify the optimal CVP strategies in RA. While awaiting results from randomized controlled trials in RA, clinicians are largely dependent on the use of common sense, and extrapolation of data from studies on other patient populations. The CVP in RA should be based on an individualized evaluation of a broad spectrum of risk factors, and include: 1) reduction of inflammation, preferably with drugs decreasing CV risk, 2) management of factors associated with increased CV risk (e.g., smoking, hypertension, hyperglycemia, dyslipidemia, kidney disease, depression, periodontitis, hypothyroidism, vitamin D deficiency and sleep apnea), and promotion of healthy life style (smoking cessation, healthy diet, adjusted physical activity, stress management, weight control), 3) aspirin and influenza and pneumococcus vaccines according to current guidelines, and 4) limiting use of drugs that increase CV risk. Rheumatologists should take responsibility for the education of health care providers and RA patients regarding CVP in RA. It is immensely important to incorporate CV outcomes in testing of anti-rheumatic drugs.

Fc gamma R expression on NK cells influences disease severity in rheumatoid arthritis.

Rheumatoid arthritis (RA) is associated with autoantibodies, the best known of which is rheumatoid factor (RF). RF/IgG complexes interact with FcgammaR on the surface of neutrophils, NK cells and monocyte/macrophages. We have analyzed the expression pattern and allelic polymorphisms of three FcgammaR genes (FcgammaRIIA, FcgammaRIIC and FcgammaRIIIA) in a large sample of RA patients and normal donors. We have found that the level of FcgammaR (CD16 and CD32) expression on NK cells is lower in RA patients than in normal individuals. Genotypic analysis demonstrated that the CD32 isoform expressed by the majority of RA patients was not the activating FcgammaRIIc1 isoform, commonly seen in normal individuals, but rather the inhibitory FcgammaRIIb isoform. The combination of the FcgammaRIIIA-176F allele with a lack of CD32 expression in NK cells appeared to be characteristic of RA subjects with aggressive disease. Since FcgammaRII and FcgammaRIIIA are predominantly expressed by NK cells, these data further suggest that FcgammaR-mediated activation of NK cells could be a disease-determining factor in RA patients.

Current concepts regarding pharmacologic treatment of rheumatoid and osteoarthritis.

Treating patients with osteoarthritis (OA) and rheumatoid arthritis (RA) remains challenging; however, new agents offer the chance for an improved quality of life. As an alternative to traditional nonsteroidal anti-inflammatories, cyclooxygenase-2 inhibitors provide pain relief for OA and RA patients with possible fewer side effects. Otherwise, OA patients may opt for topical agents, injections, or supplements. Rheumatoid arthritis research has led to an improved understanding of the inflammatory cascade and an appreciation of the early tissue destruction. A new treatment philosophy has thus emerged along with the development of new biologic agents; the latter, along with combination therapy and a new disease modifying antirheumatic drug, leflunomide, have greatly expanded the chances for disease control in RA patients.

A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

BACKGROUND: Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS: We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS: As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS: As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Clinical trials in the gene therapy of arthritis.

Gene therapy clinical trials raise important safety issues that complicate their design and require extensive preclinical testing. Human protocols for the treatment of arthritis and most other orthopaedic and rheumatologic indications are complicated additionally by the perception that they are largely acquired, nonlethal conditions. Taking these considerations into account, the first such human study used the local, ex vivo delivery of a gene whose product, the interleukin-1 receptor antagonist, has an outstanding safety profile. This gene was delivered to the metacarpophalangeal joints of postmenopausal women 1 week before these joints were removed during total joint replacement surgery. In addition to providing an additional safety cushion, the surgical removal of the genetically modified joints made available large amounts of tissue to examine for evidence of successful gene transfer and gene expression. This Phase I safety study was approved at the local and federal levels, and its funding was contingent on the establishment of an external monitoring board. This trial now has been completed and a Phase II, efficacy study is being planned. A similar study has begun in Dusseldorf, Germany and results from the first two patients are similar to the results of the American patients. Permission has been given for two additional human trials, one in the United States and one in the Netherlands, in which a gene encoding herpes thymidine kinase will be transferred to the joints of patients with rheumatoid arthritis who then will be administered gancyclovir. This procedure aims to treat the disease by producing a genetic synovectomy. Additional development of human gene therapies for arthritis and other orthopaedic and rheumatic conditions will be aided by the successful completion of these studies.

Dermatomyositis with erosive arthropathy: association with the anti-PL-7 antibody.

We describe a patient with dermatomyositis and inflammatory polyarthritis with erosive wrist arthropathy who was found to have the anti-PL-7 autoantibody directed against threonyl-tRNA synthetase.

Communicating hydrocephalus secondary to diffuse meningeal spread of Wegener's granulomatosis: case report and literature review.

OBJECTIVE AND IMPORTANCE: We present a very unusual case of diffuse spread of Wegener's granulomatosis causing hydrocephalus. CLINICAL PRESENTATION: A 53-year-old man presented in 1985 with bilateral middle ear infections requiring myringotomies. During the next 18 months, he went on to develop a left Bell's palsy. The patient then began to develop recurrent occipital headaches along with left sixth and seventh nerve palsies and a green nasal discharge requiring hospitalization. Workup included magnetic resonance imaging showing pronounced enhancement of the tentorium and meninges in the occipital region with normal ventricle size. An x-ray of the chest showed multiple pulmonary nodules. A regimen of prednisone and cyclophosphamide was initiated. The patient did well for 2 years until he again developed middle ear infections and headache. Serial lumbar punctures showed increased pressures. A circulating antineutrophil cytoplasmic antibody was positive. Cyclophosphamide was administered, with acetazolamide added for treatment of the elevated intracranial pressure. The patient stabilized for another 2 years but then presented in 1994 with recurrent headache, bilateral papilledema, and mild left arm and right leg weakness. A lumbar puncture was performed with an opening pressure of 52 cm H2O. Computed tomography of the head revealed moderate enlargement of the lateral third and fourth ventricles, consistent with communicating hydrocephalus. INTERVENTION: A right frontal ventriculoperitoneal shunt was placed. A leptomeningeal biopsy performed at the side of catheter placement (far away from any meningeal enhancement revealed by magnetic resonance imaging) showed chronic meningitis and multinucleated giant cells. Cyclophosphamide therapy was begun again. The patient has not experienced recurrence of headache, cranial nerve deficits, or papilledema for more than 3 years. CONCLUSION: This is the first reported case of diffuse involvement of the meninges from Wegener's granulomatosis. Fortunately, this patient responded well to shunting and sustained medical management. Although rare, Wegener's granulomatosis should be included in the differential diagnosis of chronic aseptic meningitis, communicating hydrocephalus, and papilledema.

Ulnar nerve compression following flexor digitorum superficialis tendon transfers around the ulnar border of the forearm to restore digital extension: case report.

This case report describes a complication that occurred following long and ring finger flexor digitorum superficialis tendon transfers routed around the ulnar border of the forearm to restore digital extension. An ulnar mononeuropathy developed in the early postoperative period that was characterized by decreased ring and small finger sensation and interosseous muscle weakness. Operative exploration demonstrated extrinsic compression of the ulnar nerve by the long and ring finger flexor digitorum superficialis tendons. When superficialis tendon transfers are chosen to restore digital extension, passage around the radial side of the forearm or through the interosseous space are recommended to avoid this potential complication.

Racial differences in scleroderma among women in Michigan.

OBJECTIVE: To examine racial differences in disease onset, extent, manifestations, and survival among women with scleroderma. METHODS: A retrospective cohort study of women with scleroderma, diagnosed in Michigan between 1980 and 1991, was conducted. Clinical, laboratory, and demographic data were abstracted from the patients' medical records. RESULTS: A total of 514 women with scleroderma were identified: 117 (23%) were black and 397 (77%) were white. Among black women, the mean age at diagnosis was lower (44.5 years versus 51.5 years; P < 0.001) and diffuse disease was more common (49.6% versus 24.9%; P < 0.001) than among white women. The overall incidence of scleroderma was 14.1 per million per year: 22.5 per million per year in black women versus 12.8 per million per year in white women (P < 0.001). Pericarditis (P = 0.009), pulmonary hypertension (P < 0.001), pleural effusions (P = 0.01), myositis (P = 0.02), and an erythrocyte sedimentation rate >40 mm/hour (P < 0.001) were more frequent among black women, while white women were more likely to have digital infarctions (P < 0.001). Survival at 7 years from diagnosis was 72.5% among black women and 77.6% among white women. Age-adjusted survival was significantly reduced among black women (P = 0.033), most likely because of increased diffuse involvement. Survival among those with renal or pulmonary involvement was also significantly reduced. CONCLUSION: Black women with scleroderma were significantly more likely than white women to develop diffuse disease, be diagnosed at a younger age, have a higher incidence of inflammatory features, and have a worse age-adjusted survival rate.

The epidemiology of scleroderma among women: assessment of risk from exposure to silicone and silica.

OBJECTIVE: To investigate the relationship between exposure to silicone (including breast implants) and silica and the development of scleroderma (systemic sclerosis, SSc) among women. METHODS: A population based case-control study was conducted among women in Michigan. 274 confirmed cases of SSc diagnosed between 1985 and 1991 were identified by contacting rheumatologists, hospitals, and a scleroderma support group. These cases and 1184 controls were interviewed by telephone to ascertain past exposures to silicone or silica. RESULTS: Silicone in the form of breast implants was not associated with significantly increased risk of SSc (adjusted odds ratio, 1.30; 95% confidence interval, 0.27 to 6.23). Among 20 other potential silicone exposure surveyed, self-reported exposure to silicone based glues, sealants, and caulks, manufacture or repair of windows or windshields, repairing or frequently using photocopy machines, consumption of simethicone-containing antacids, and implanted medication delivery pumps were significantly associated with SSc. However, blinded assessment of all job and hobby descriptions in terms of their potential for silicone exposure failed to support the first 3 associations, antacid consumption may have been confounded by esophageal dysmotility before the diagnosis of SSc, and other silicone containing device categories (pacemakers, central nervous system shunts, other shunts and catheters) were not significantly associated with SSc. Surgically implanted metallic fixation devices were associated with significantly reduced risk for SSc. No association was detected between SSc and silica dust exposure. CONCLUSION: Consistent with other studies, we found no increased risk of SSc among women with silicone breast implants, equivocal evidence of risk from other silicone exposures, and no evidence of risk from silica exposure.

Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study.

OBJECTIVE: To examine the effects of cyclophosphamide (CYC) on the development of malignancies and on the long-term survival of patients with rheumatoid arthritis (RA). METHODS: We used a longitudinal cohort design in which 119 patients (76 women and 43 men) with refractory RA who were treated with oral CYC between 1968 and 1973 were compared with 119 control patients with RA (matched for age, sex, disease duration, and functional class) who were evaluated during the same time period but did not receive CYC. RESULTS: There was increased risk of malignancy in the CYC-treated group, with 50 cancers found in 37 patients in the CYC group compared with 26 cancers in 25 of the control patients (P < 0.05). The relative risk of cancer for those treated with CYC was 1.5 (95% confidence interval 0.93-5.5). Nine of the malignancies in the CYC group were bladder cancers and 19 were skin cancers, compared with no bladder cancers and 6 skin cancers in the control group. The total dose of CYC was higher in those who developed cancer, particularly in those with bladder cancer. Three of the bladder cancers occurred 14, 16, and 17 years after CYC had been discontinued. CONCLUSION: The risk of malignancy, particularly bladder cancer, in RA patients treated with oral CYC continues even 17 years after discontinuation of the drug.