Biomedical subjects

J S Coblyn

Publications and source records attributed to J S Coblyn.

At least 19 recordsLinked to original sources

PubMed2001

Leflunomide-associated weight loss in rheumatoid arthritis.

OBJECTIVE: To determine the frequency of weight loss in patients treated with leflunomide for rheumatoid arthritis at an arthritis referral center. METHODS: We queried 35 rheumatologists at the Robert Breck Brigham Arthritis Center to determine if weight loss had occurred as an adverse event in patients treated with leflunomide between November 1998 and January 2000. Five such patients were identified and their clinical course was reviewed. RESULTS: Five of 70 patients who had begun leflunomide therapy had significant weight loss that could not be linked to other identifiable etiologies. The amount of weight loss was substantial in this group of patients, ranging from 19 pounds to 53 pounds. All patients had normal levels of thyroid-stimulating hormone and no other gastrointestinal complaints; evaluation revealed no other cause for the weight loss. Despite the significant weight loss, 4 of the 5 patients continued to take the drug due to its efficacy. CONCLUSION: Significant weight loss is a potential adverse event in patients with rheumatoid arthritis treated with leflunomide. Awareness of this may obviate the need for extensive medical evaluations.

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PubMed2000

Hydroxychloroquine retinopathy despite regular ophthalmologic evaluation: a consecutive series.

We describe a consecutive series of patients with hydroxychloroquine (HCQ) retinopathy. Their clinical features illustrate that with normal renal function there is no threshold for total dosage for HCQ toxicity; that color vision testing is important; that almost all patients complain of altered central vision as their first symptom; and that a normal optic fundus does not exclude the diagnosis. Finally, HCQ retinopathy may progress even when the agent is stopped.

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PubMed1999

Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis.

OBJECTIVE: To examine the safety and pharmacokinetics of and clinical response to leflunomide, a de novo pyrimidine synthesis inhibitor, when administered to patients with active rheumatoid arthritis (RA) who have been receiving long-term methotrexate therapy. METHODS: This was an open-label, 52-week study in which 30 patients with RA that remained active despite therapy with methotrexate at 17+/-4 mg/week (mean +/- SD) for > or =6 months were given leflunomide, 10-20 mg/day. Patients were assessed for adverse effects, pharmacokinetic measurements of leflunomide and methotrexate, and clinical response by American College of Rheumatology (ACR) 20% response criteria. RESULTS: Twenty-three patients completed 1 year of treatment. No significant pharmacokinetic interactions between leflunomide and methotrexate were noted. This combination therapy was generally well tolerated clinically, with the exception of elevations of liver enzyme levels. Seven patients withdrew from the treatment regimen: 2 withdrawals were voluntary, 3 were due to persistent elevation of plasma transaminase levels, and 2 were due to lack of efficacy. Of the patients, 16 (53%) met ACR 20% response criteria. Two met ACR criteria for remission after 1 year. CONCLUSION: The combination of methotrexate and leflunomide has therapeutic potential in RA.

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PubMed1998

Longterm prospective study of methotrexate in rheumatoid arthritis: conclusion after 132 months of therapy.

OBJECTIVE: To conclude observations of efficacy of longterm methotrexate (MTX) treatment of rheumatoid arthritis (RA). METHODS: Twenty-six patients with RA entered a prospective study of MTX in 1983. The study was completed after 132 months of therapy. RESULTS: Significant improvement (p < 0.001) was noted in the number of painful joints, swollen joints, and physician and patient global assessments. There was 50% improvement in the joint pain index and joint swelling index in > 65% of the patients. A significant reduction in prednisone dose was achieved. Sixteen patients withdrew from the study. Toxicity led to 3 drug related withdrawals of study patients (alopecia 1; pneumonitis 2). At 132 months, 10 patients (38%) had completed the study; 3 patients (11%) discontinued due to MTX toxicity. CONCLUSION: MTX was an effective treatment for RA in this 132 month prospective study.

Arthritis, Rheumatoid↗

PubMed1995

CAMPATH-1H, a humanized monoclonal antibody, in refractory rheumatoid arthritis. An intravenous dose-escalation study.

OBJECTIVE: To evaluate the biologic response, tolerability, and potential clinical effect of a humanized antilymphocyte monoclonal antibody, CAMPATH-1H, in patients with rheumatoid arthritis (RA). METHODS: Forty adult patients with active, refractory RA were treated with CAMPATH-1H, given intravenously, in a multicenter, open, single-dose-escalation study. Patients were assigned to dose groups of 1, 3, 10, 30, 60, and 100 mg CAMPATH-1H. RESULTS: There was a profound, immediate, and sustained reduction of the peripheral lymphocyte count; the most susceptible were the levels of CD4+ and CD8+ cells, which remained depressed during the study period. Sixty-three percent of patients developed antibodies to CAMPATH-1H. Side effects occurred frequently throughout the first 24 hours following infusion, and included fever, headache, nausea, vomiting, and hypotension. All of the immediate drug toxicities resolved within the initial 24-hour postdosing period. One patient developed a reactivation of Mycobacterium xenopi infection 10 weeks following infusion. Sixty-five percent of patients developed a clinical response; the mean duration of response was 2 weeks. CONCLUSION: CAMPATH-1H is a lymphocyte-depleting antibody that is biologically potent even after single-dose therapy. There was no correlation between biologic effect and clinical response. Sustained lymphocyte suppression was observed. Acute infusion toxicities were observed in most patients. The role of depleting monoclonal antibodies in the treatment of RA should be reevaluated.

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PubMed1994

Lack of a renal-protective effect of misoprostol in rheumatoid arthritis patients receiving cyclosporin A. Results of a randomized, placebo-controlled trial.

OBJECTIVE: To assess whether the synthetic prostaglandin misoprostol is renal protective in rheumatoid arthritis (RA) patients who are beginning cyclosporin A (CSA) therapy. METHODS: In this randomized, placebo-controlled, multicenter trial, 50 patients with active RA were randomized to receive either misoprostol (800 micrograms/day) or placebo for 16 weeks. After 2 weeks of pretreatment with misoprostol or placebo, all patients concomitantly received CSA at an initial and maximum dosage of 5 mg/kg/day for 12 weeks. RESULTS: A significant increase in the serum creatinine level was observed in both treatment groups, with no difference noted between groups. There was a high withdrawal rate in both groups, primarily due to adverse events. CONCLUSION: A renal-protective effect was not demonstrated for misoprostol compared with placebo in RA patients who are beginning CSA therapy.

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PubMed1994

Bronchiectasis. A late feature of severe rheumatoid arthritis.

Bronchiectasis as a feature of rheumatoid arthritis is considered rare and, in most series, has preceded rheumatoid arthritis. We identified 23 patients with rheumatoid arthritis and bronchiectasis at the Brigham and Women's Hospital followed between 1984 and 1991, 18 of whom had arthritis preceding lung disease. The 18 patients with rheumatoid arthritis and subsequent bronchiectasis had a mean age of 63.8 years. Fourteen were women and 4 were men, with a mean arthritis duration of 24.7 years before bronchiectasis developed. Most patients had seropositive and nodular disease. All but 1 had advanced radiographic changes of rheumatoid arthritis, and many had received joint replacement surgery. In addition to standard treatment regimens, 17 patients had received corticosteroids. Productive cough, hemoptysis, and dyspnea were the most common respiratory symptoms and were present for an average of 4.3 years prior to bronchiectasis diagnosis. The most common radiographic abnormalities were bibasilar diffusely increased interstitial markings and focal infiltrates, although nodules, bullae, cysts, and air-fluid levels were found. Common pulmonary-function abnormalities were obstructive and/or restrictive abnormalities. Three patients died of complications relating to bronchiectasis. Five patients with rheumatoid arthritis had antecedent bronchiectasis. Compared with patients with rheumatoid arthritis and subsequent bronchiectasis, those with antecedent lung disease had milder arthritis (stage I or II radiographic changes, p < 0.001), a lower frequency of rheumatoid nodules (p < 0.05) and a lower comorbidity score (5.8 versus 9.4, p < 0.01). They also had received fewer disease-modifying agents for the treatment of their rheumatoid arthritis. Bronchiectasis can be a feature of rheumatoid arthritis and is often found in patients with severe, long-standing nodular disease. Recurrent pulmonary infections and respiratory failure occur and may be fatal.

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PubMed1993

Low dose leucovorin does not interfere with the efficacy of methotrexate in rheumatoid arthritis: an 8 week randomized placebo controlled trial.

OBJECTIVE: To determine if simultaneously administered low dose leucovorin interferes with the efficacy of methotrexate (MTX). METHODS: An 8-week double blind placebo controlled study of leucovorin (1 mg) in 16 patients with rheumatoid arthritis receiving chronic MTX was performed at a single academic center. RESULTS: A flare of disease activity was not observed. Clinical variables of arthritis activity did not change in the leucovorin treated population. CONCLUSIONS: Low dose leucovorin when taken simultaneously with MTX did not interfere with the efficacy of MTX in a short term 8 week trial.

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PubMed1992

Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. 84-month update.

OBJECTIVE: To determine the long-term efficacy and safety of low-dose methotrexate (MTX) in rheumatoid arthritis (RA). METHODS: Eighty-four-month open prospective trial at a single academic rheumatology center. RESULTS: Twenty-six patients were enrolled in a prospective study of the long-term efficacy of MTX in RA; a significant improvement had been demonstrated after 36 months of therapy. Twelve patients remained in the study at the 84-month visit; the mean weekly dosage of MTX was 10.2 mg. A significant improvement was still noted at 84 months in the number of painful joints, number of swollen joints, joint pain index, joint swelling index, and physician and patient global assessments. A 50% improvement in the joint pain index and joint swelling index was observed in more than 80% of the 12 patients still enrolled. A significant reduction in prednisone dosage was achieved; of 14 patients taking prednisone at entry, 7 had discontinued prednisone completely. Fourteen patients withdrew from the study: 10 between 0 and 36 months, and 4 between 36 and 84 months. Toxicity in 3 patients and visit noncompliance in 1 patient were the reasons for withdrawal between 36 and 84 months. At 84 months, 46% of the patients remained in the study; 11.5% had discontinued due to MTX toxicity. CONCLUSION: The effectiveness of MTX in the treatment of RA continues to be demonstrated in this prospective study, after 84 months of treatment.

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PubMed1992

Acute and chronic suppression of leukotriene B4 synthesis ex vivo in neutrophils from patients with rheumatoid arthritis beginning treatment with methotrexate.

OBJECTIVE: To compare the cumulative effects of oral methotrexate (MTX) therapy (after 6-8 weeks) with the acute effects (24 hours after a dose) on arachidonic acid metabolism by the 5-lipoxygenase (5-LO) pathway in neutrophils from patients with active rheumatoid arthritis (RA) who were beginning therapy with MTX. METHODS: Neutrophils and monocytes were isolated from whole blood from 7 patients with RA, immediately before and 24 hours after their first weekly dose of 7.5 mg of MTX, and again after their dose at 6-8 weeks. RESULTS: Total immunoreactive leukotriene B4 (LTB4) formation in neutrophils activated ex vivo with calcium ionophore A23187 was significantly suppressed (by 33%) before the 6-8-week dose, compared with the level before the first dose (mean +/- SEM 8.29 +/- 1.24 ng/10(6) cells at predose 6-8 weeks versus 12.29 +/- 2.13 ng/10(6) cells at predose 1; P = 0.03). Reductions were also observed after the first dose (27%; P = 0.07) and after the 6-8-week dose (43%; P = 0.05) compared with the respective predose levels. MTX treatment produced significant reductions in the total generation of 5-LO pathway products (5-hydroxyeicosatetraenoic acid + 6-trans-LTB4 + LTB4 + omega-oxidation products of LTB4) by calcium ionophore-activated neutrophils, as quantitated by integrated optical density after resolution on reverse-phase high-performance liquid chromatography. Decreases were observed after the first dose (26%; P = 0.025), immediately before the 6-8-week dose (23%; P = 0.05), and after the 6-8-week dose (47%; P = 0.0033) compared with levels before the first dose, and after the 6-8-week dose compared with the level before it (32%; P = 0.04). The generation of LTB4 by calcium ionophore-activated monocytes was not significantly affected by MTX therapy. CONCLUSION: The significant decreases in the formation of omega-oxidation products of LTB4 and in the total generation of neutrophil 5-LO pathway products in the absence of a significant change in the release of 3H-arachidonic acid or the generation of platelet-activating factor suggest that the activity of the 5-LO enzyme in neutrophils is inhibited. We conclude that weekly oral MTX therapy in patients with active RA inhibits neutrophil 5-LO pathway product generation in a pattern consistent with inhibition of the activity of the 5-LO enzyme; an effect is observed after the first dose. The inhibition of 5-LO is cell-selective and cumulative, with a superimposed incremental inhibition observed after the weekly MTX dose.

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PubMed1992

Zileuton, a 5-lipoxygenase inhibitor in rheumatoid arthritis.

The effects of zileuton, a new 5-lipoxygenase inhibitor, on leukotriene generation and clinical response in rheumatoid arthritis (RA) was studied in a 4-week randomized double blind placebo controlled study at 2 academic rheumatology centers. Zileuton decreased the mean (+/- SEM) ionophore induced synthesis of leukotriene B4 at Week 1 by 70% from 191.2 +/- 28.5 to 57.5 +/- 17.0 ng/ml. A parallel suppression of all major 5-lipoxygenase pathway products was observed. An improvement in clinical variables was observed in the zileuton and placebo treated population. No unique toxicity was identified in this study. Zileuton inhibited 5-lipoxygenase in RA with a suggestion of clinical response with limited toxicity.

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PubMed1990

Inhibition of leukotriene B4 synthesis in neutrophils from patients with rheumatoid arthritis by a single oral dose of methotrexate.

We studied the effects of a single, oral dose of methotrexate (MTX) on arachidonic acid metabolism in neutrophils from 6 patients with rheumatoid arthritis, which were obtained 1 day before and 1 day after their usual weekly MTX dose. The 6 patients had received a mean weekly MTX dose of 9.6 mg (range 5-15) for a mean of 61.7 months (range 58-64), and none received concomitant corticosteroids. Total generation of leukotriene B4 (LTB4) in neutrophils stimulated ex vivo with 10 microM calcium ionophore A23187 for 20 minutes was significantly suppressed, by a mean of 53%, after the MTX dose compared with the predose levels (mean +/- SEM 13.0 +/- 1.4 ng/10(6) cells versus 6.0 +/- 0.9 ng/10(6) cells; P = 0.0019), reflecting a comparable suppression of both released and cell-retained LTB4. A 49% decrease in omega-oxidation products of LTB4 demonstrates that decreased LTB4 synthesis, rather than increased degradation, is responsible for the decrease in LTB4 generation. The absence of a significant change in either 3H-labeled arachidonic acid release or platelet-activating factor generation indicates that the observed decrease in LTB4 synthesis was apparently not caused by diminished phospholipase A2 activity. A 28% decrease in the total formation of the 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid and the 6-trans-LTB4 diastereoisomers, and a 48% suppression of production of LTB4 plus its omega-oxidation metabolites after the MTX dose suggest inhibition of 5-lipoxygenase activity and possible suppression of leukotriene A4 epoxide hydrolase activity.

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PubMed1989

The effect of cyclosporine on urinary kallikrein excretion in patients with rheumatoid arthritis.

The effect of cyclosporine (6 to 8 mg/kg/24 hr) on urinary kallikrein excretion is summarized for 9 patients with rheumatoid arthritis using a specific kallikrein radioimmunoassay. Baseline serum creatinine and BUN values were within the normal range for all patients, and baseline kallikrein excretion rates were either normal (n = 5) or more than two S.D. below the mean of the normal group (n = 4). The patients with normal baseline values excreted significantly less urinary kallikrein three and six months after cyclosporine therapy was started, but all of them completed the six-month protocol. Patients in the subgroup with low baseline values also decreased their kallikrein excretion in response to cyclosporine therapy, and two of the four in this group experienced elevations of BUN such that therapy was terminated. In a low-dose (3 mg/kg/24 hr) open extension that followed the initial trial, kallikrein excretion decreased by almost 50% at least one month before any change in serum creatinine was observed. The data suggest that changes in urinary kallikrein excretion rates may be an indicator or predictor of cyclosporine nephrotoxicity. Decreased kallikrein excretion rates could also be a factor in the diminished renal blood flow reported in patients treated with cyclosporine.

Arthritis, Rheumatoid↗

PubMed1989

Rheumatoid aortitis: a rarely recognized but clinically significant entity.

Aortitis as a feature of rheumatoid arthritis is considered rare. We have, however, identified 10 patients with aortitis from among 188 consecutive autopsy cases of rheumatoid arthritis. There were 5 men and 5 women with a mean duration of rheumatoid arthritis of 9.6 years. Nine were rheumatoid factor positive and had associated nodules. In addition to standard treatment regimens, 9 patients received corticosteroids. Although involvement of the thoracic aorta was most common, involvement of both the thoracic and abdominal aorta was present in 4 cases. Two patients had aneurysmal dilatation of the thoracic aorta and 1 of the abdominal aorta. Microscopic features of aortitis included necrosis of medial smooth muscle and elastica, with an inflammatory infiltrate comprising primarily lymphocytes and plasma cells. A panmural aortitis was seen in 3 cases. Rheumatoid granulomas were noted in the aortic wall in 5. The diagnosis of aortitis was not made until autopsy in any case. Aortitis was hemodynamically significant in 3 patients. Two had congestive heart failure secondary to thoracic aortitis and aortic valvulitis, and 1 had rupture of an abdominal aortic aneurysm at a site involved by aortitis. Seven patients had rheumatoid vasculitis with a mean of 10 organs involved. Six of these died of complications directly related to vasculitis, including 4 patients with coronary arteritis and associated myocardial infarction. Aortitis can be a feature of severe rheumatoid arthritis and is often associated with rheumatoid vasculitis. Hemodynamic compromise does occur and may be fatal.

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PubMed1988

Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis.

Twenty-six patients with severe rheumatoid arthritis who had completed a randomized crossover trial of methotrexate elected to continue to receive the drug in a long-term prospective study. At 36 months, 16 patients remained in the study. Over this period of time, significant improvement was noted in the number of painful and swollen joints, physician and patient global assessments, erythrocyte sedimentation rate, and prednisone dose. Adverse reactions occurred in 16 patients (62%), including nausea, alopecia, headache, stomatitis, herpes zoster, and diarrhea. Mild leukopenia (3 patients), thrombocytopenia (3 patients), and elevated transaminase levels (8 patients) resolved with temporary drug discontinuation. No patient withdrew due to drug toxicity. Liver biopsy specimens in 17 patients after 24 months of treatment showed no evidence of fibrosis or cirrhosis. A significant increase in the percentage of T3 and T4 blood cells and increases in lymphocyte proliferation to concanavalin A and purified protein derivative of tuberculin were found after 2 years of therapy. Our findings indicate that methotrexate has remained effective over 36 months of therapy, with acceptable toxicity levels and no evidence of systemic immunosuppression.

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PubMed1988

Immunogenetic and racial determinants of gold toxicity in rheumatoid arthritis.

Typing for antigens HLA-A,B,C and DR was performed on 165 rheumatoid arthritis patients (14 black, 151 white) who had received gold therapy to determine the relationship between HLA antigens and gold dermatitis, stomatitis, thrombocytopenia, and proteinuria. Dermatitis and stomatitis occurred in both black and white patients. Thrombocytopenia and proteinuria occurred only among the white patients studied. The absence of thrombocytopenia and proteinuria among the black patients was not statistically significant. Antigen HLA-DR7 was uncommon among black and white subjects with dermatitis (0 of 6 blacks, 4 of 48 whites), but this decrease in frequency was not statistically significant. Antigen HLA-DR3 was an important risk factor for thrombocytopenia (relative risk = 11.8, P = .0043) and proteinuria (RR = 5.8, P = .032). These results are consistent with previous studies of HLA-DR3 and gold toxicity. The only black patient with stomatitis possessed the A1B8DR3 phenotype. Future studies should examine whether the same HLA antigen confers risk of different gold toxicities in different racial groups, and whether there are HLA antigens that provide a protective effect.

Arthritis, Rheumatoid↗

PubMed1987

Cyclosporin A treatment of refractory rheumatoid arthritis.

Ten patients with rheumatoid arthritis were entered into a 24-week pilot study of oral cyclosporin A at a starting dosage of 6 mg/kg/day, followed by a 12-week washout period. Significant improvement in clinical parameters was observed at 12 weeks and 24 weeks (P less than 0.02 versus baseline for joint pain and joint swelling indexes and patient and physician assessments; P less than 0.04 versus baseline in the numbers of painful/tender joints and swollen joints). Adverse reactions were varied: renal impairment occurred in all patients and hypertension occurred in 7. All patients demonstrated an increase in defined disease activity at cessation of treatment and through the washout period. Cyclosporin A is clinically effective in the treatment of patients with refractory rheumatoid arthritis, but its value as an intervention therapy is limited by its toxicity.

Arthritis, Rheumatoid↗

PubMed1987

Effects of dietary supplementation with marine fish oil on leukocyte lipid mediator generation and function in rheumatoid arthritis.

Twelve patients with active rheumatoid arthritis supplemented their usual diet with 20 gm of Max-EPA fish oil, daily, for 6 weeks. Following this supplementation, the ratio of arachidonic acid to eicosapentaenoic acid in the patients' neutrophil cellular lipids decreased from 81:1 to 2.7:1, and the mean generation of leukotriene B4 (with calcium ionophore stimulation) significantly declined by 33%. The mean neutrophil chemotaxis to both leukotriene B4 and FMLP significantly increased toward the normal range at week 6. The generation of 5-lipoxygenase products by calcium ionophore-stimulated monocytes was not significantly suppressed, but a significant decline (37%) in platelet-activating factor generation was noted at week 6. The modulation of these measures of leukocyte inflammatory potential suggests that fish oil supplementation may have an antiinflammatory effect.

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