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Biomedical subjects

D E Furst

Publications and source records attributed to D E Furst.

At least 91 records · Page 5Linked to original sources
PubMed1997

The evolving role of blood and marrow transplantation for the treatment of autoimmune diseases.

With over 4 decades of seminal contributions to the development and application of BMT, Dr. Thomas stresses the importance of collaboration between rheumatologists and transplant clinicians in developing this evolving area of treatment. While the debate concerning the value of TBI in the conditioning regimen and the use of autologous or allogeneic stem cells will continue, he states there is simply no other way to answer these questions than to begin well designed clinical studies. As pointed out by Dr. Hahn, unexpected post-transplant complications may arise in patients with SSc and SLE and possibly require modifications to the transplant procedure similar to the experience in patients with other specific diseases. Other difficulties may be encountered, including restricted funding of the transplant procedure by insurance carriers. The emergence of managed care contracts and payer limitations in the United States described by Dr. Appelbaum could hinder the development of innovative, curative therapies. As initial clinical data are being collected, it is vital to actively support patient referral and participation in clinical studies that will ultimately establish the indications, risks, costs, and benefits of hematopoietic stem cell transplantation for autoimmune disease.

Autoimmune Diseases↗
PubMed1997

Hypothesis for the pathogenesis of systemic sclerosis.

An hypothesis for the pathogenesis of systemic sclerosis is introduced. It posits a genetic background with environmental stimuli that activate immune cells. The immune cells, in turn, may damage vascular endothelium, cause proliferation of fibroblasts, or stimulate fibroblasts to produce collagen. Endothelial cell damage can also activate the immune system or induce fibroblast proliferation. Associated with fibroblast proliferation may be immune activation or collagen production. Finally, collagen production and end organ damage can induce immune activation thus perpetuating the cycle. Raynaud's phenomenon, an early finding in systemic sclerosis can cause vascular damage, thus entering the cycle at a different point than other environmental stimuli. This hypothesis will undoubtedly require change as data emerge, but it presents a conceptual model for testing and modification.

Animals↗
PubMed1997

Development of a protocol for allogeneic marrow transplantation for severe systemic sclerosis: paradigm for autoimmune disease.

Some types of severe autoimmune disease are associated with significant morbidity and a high mortality rate. Many of these cases occur in young adults who, even if they survive, become severely debilitated. Systemic sclerosis (SSc) is a paradigm for other severe autoimmune diseases in which patients with poor prognostic features can be identified early in the course of the disease. Allogeneic marrow transplantation may be effective for the control of autoimmune diseases like SSc because the preparative regimen will significantly suppress the host immune system and the antihost effects of the donor immune system in the engrafted marrow will help maintain the suppression of the host immune system. Considering the morbidity and poor prognosis associated with severe SSc and the favorable outcome now associated with allogeneic marrow transplantation from HLA identical siblings for other nonmalignant diseases, Phase I and II studies are warranted. These will evaluate the safety of allogeneic marrow transplantation and explore its role in the management and control of a severe autoimmune disease. We review issues important in the development of an allogeneic marrow transplant protocol for severe SSc, including patient selection, plan of treatment, prevention of graft versus host disease, supportive care, and evaluation after transplant.

Adolescent↗
PubMed1997

Autologous stem cell transplantation for autoimmune diseases: issues in protocol development.

For patients with autoimmune disease resistant to conventional therapy, aggressive strategies employing high dose chemoradiotherapy and autologous stem cell transplant appear to be warranted. Support for this approach comes from animal studies employing marrow transplantation, which have shown promising results. Likewise, longterm control of autoimmune disease has been demonstrated in some survivors of allogeneic transplants for malignancy who incidentally had preexisting autoimmune disease. Initial strategies for autografting will use intensive transplant regimens incorporating cyclophosphamide with or without total body irradiation. Peripheral blood stem cell grafts purified by CD34 selection will be depleted of lymphocytes, and lead to rapid hematologic reconstitution after treatment. Close monitoring for disease responses, adverse effects of intensive immunosuppression, and longterm sequelae of high dose therapies will be required. Initial studies are best performed as close collaborations between rheumatologists and transplant specialists in appropriate research centers.

Animals↗
PubMed1997

Choosing appropriate patients with systemic sclerosis for treatment by autologous stem cell transplantation.

Systemic sclerosis (SSc) with diffuse cutaneous scleroderma and visceral organ involvement is associated with considerable morbidity and mortality almost from its inception. Since the risk of accrual and progression of skin and organ complications is greatest in the first few years of SSc, the best opportunity for significantly modifying the course of SSc (prolonging survival and/or preventing or lessening the progressivity of organ involvement) is probably limited to the first 3 to 4 years. Transplantation of autologous stem cells (ASCT), after immune ablation of the host, has the potential to modify the disease course. Even though the mortality risk of ASCT is low (< 2% mortality in the first year), the mortality risk of the disease being treated must justify that risk. We suggest that patients with diffuse Sc of short duration (< 3 years from the first non-Raynaud sign/symptom) with evidence of at least mild involvement of heart, lung, or kidney, have sufficiently severe disease to warrant ASCT. In contrast, we suggest that patients with severe/end stage organ involvement have progressed to the point where ASCT will not be helpful in improving that degree of organ involvement.

Adult↗
PubMed1996

Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases.

Hydroxychloroquine (HCQ) and chloroquine (CQ) are well absorbed (0.7-0.8 bioavailability) when given orally. Severe malnutrition (such as kwashiorkor) effects absorption but diahrrea does not. Both HCQ and CQ have prolonged half-lives, between 40 and 50 days, and low blood clearance (e.g. hydroxychloroquine's blood clearance is 96 ml/min). There is great variability of blood concentrations with an eleven-fold range of drug concentrations found after similar doses in RA patients. Protein binding ranges between 30 and 40% with binding to both albumin and alpha, glycoprotein. There is differential binding and metabolism of the (R) and (S) stereoisomers. Both drugs bind strongly to pigmented tissues but also bind to mononuclear cells, muscles, etc. There is stereo-selective excretion of both drugs and 40-50% of the drug is excreted renally. Between 21 and 47% is excreted unchanged. There is a suggestion of concentration response and concentration toxicity relationships with decreased morning stiffness as HCQ concentrations increase and increased EKG abnormalities as CQ concentrations become higher, but further testing is required. Pharmacokinetic interaction studies are limited. Potentially important kinetic interactions have been documented for d-penicillamine and cimetidine but have not been found for aspirin, ranitidine or imipramine.

Antirheumatic Agents↗
PubMed1996

Significant changes in serum AST across hepatic histological biopsy grades: prospective analysis of 3 cohorts receiving methotrexate therapy for rheumatoid arthritis.

OBJECTIVE: To describe the statistical association between serum AST and liver biopsy grade in patients with rheumatoid arthritis. METHODS: 94 patients from 3 prospectively followed cohorts underwent a total of 354 biopsies graded according to Roenigk. Blood samples for serum aminotransferase (AST) were obtained every 37.7 + or - 32.7 days (mean + or - SD) and 15.2 + or - 7.1 samples were obtained before each biopsy. For each prebiopsy interval, 4 AST functions were calculated: (1) mean, (2) maximum, (3) percentage abnormal, and (4) the presence or absence of at least one abnormality. Analysis of variance was performed to determine the effect of each of these variables on liver biopsy score. RESULTS: AST increased across biopsy grades: 26.5 IU + or - 10.7 IU (mean + or - SD) in Grade I biopsies, 28.4 + or - 10.9 in Grade II, and 35.4 + or - 21.1 in Grade IIIA (p = 0.0006, overall difference between classes). The percentage of abnormal prebiopsy AST values increased across biopsy grades: 8.7 + or - 13.9 (mean + or - SD) in Grade I biopsies, 12.3 + or - 17.5 in Grade II, and 18.6 + or - 27.1 in Grade IIIA samples [(p = 0.0014) overall difference between classes.] A mean prebiopsy AST in the abnormal range was more likely to be associated with a more abnormal liver biopsy grade (p = 0.01, Wilcoxon's rank sum test). AST values abnormal <49% of the time had a 97% specificity for a normal biopsy grade. CONCLUSION: Regular AST measurements are useful markers of hepatic histologic outcome, within the range of mostly normal histology reported here, in patients with RA receiving longterm weekly MTX.

Adult↗
PubMed1996

Clinical pharmacology of combination DMARD therapy in rheumatoid arthritis.

Knowledge about disease modifying antirheumatic drug (DMARD) mechanism(s) of action, kinetics and toxicities can be used to help develop rational DMARD combinations. While limited by the present lack of knowledge in these areas, the present DMARD characteristics will be used to develop rational DMARD combinations. Combinations of methotrexate (MTX) plus azathioprine, and MTX plus gold might be expected to be poor DMARD combinations, a prediction borne out by experimental studies. MTX plus cyclosporine, on the other hand, should be an effective combination, again demonstrated by a recently published clinical study. Also, hydroxychloroquine plus MTX should be a good combination, and an observational study seems to support this. However, not all predictions are accurate (probably due to inadequate data about mechanisms, kinetics, and toxicities). For example, hydroxychloroquine plus D-penicillamine had a negative interaction when tested, a result not predicted by the suggested approach. In addition, predictions are inevitably oversimplified so that what appears to be a negative interaction between MTX and sulfasalazine is not actually one when the details of the potential negative interaction between these 2 drugs are examined. Ultimately, use of a construct such as the one suggested should improve the chances of success and decrease the costs of testing DMARD drug concentrations.

Antirheumatic Agents↗
PubMed1995

Innovative treatment approaches for rheumatoid arthritis. Cyclosporin, leflunomide and nitrogen mustard.

Cyclosporin A (CSA) Cyclosporin inhibits IL-2 release and T-cell activation and, secondarily, affects B-cell function. It also inhibits bone resorption, at least in vitro. This drug's bio-availability averages 25-35% but is highly variable. Food and grapefruit juice enhance bio-availability and newer formulations may make its absorption more reliable. It is highly concentrated in fatty tissues and red blood cells but does not cross the blood-brain barrier. CSA is metabolized to numerous metabolites by the liver and its elimination half-life is 6-12 hours in the absence of severe liver disease. Biliary excretion accounts for 94% of CSAs elimination. Because it is highly metabolized, its metabolism can be inhibited by other drugs (e.g. ketoconazole and erythromycin) or its metabolism can be induced (e.g. anticonvulsants). Cyclosporin is more effective than placebo for the treatment of rheumatoid arthritis and as effective as other antirheumatics. There is potential for the use of CSAs in DMARD combinations. The principal toxicities of cyclosporin are gastro-intestinal and renal, with the latter being of more concern. Leflunomide (LF). Leflunomide may be a pyrimidine synthesis inhibitor, although tyrosine kinase inhibitor may also be part of its mechanism of action. Its active metabolite is excreted renally to a large degree, with a prolonged elimination half-life of about 11 days. Since LF is activated by liver metabolism, renal failure may have less effect on kinetics than severe liver disease. Early data on efficacy indicate efficacy at 10-25 mg/day, although more well-controlled data is necessary. Toxicity relates to the skin, liver and GI tract, although some degree of weight loss was also found. Nitrogen mustard (NM). Nitrogen mustard is an alkylating agent whose pharmacokinetics are poorly understood. Small, open studies in RA indicate that NM has a potential for relatively rapid response (1-2 weeks) but, clearly, much work remains to be done. As an alkylating agent, GI and hematological toxicities are of greatest concern.

Absorption↗
PubMed1995

Low-dose methotrexate may cause air trapping in patients with rheumatoid arthritis.

Both rheumatoid arthritis (RA) and methotrexate (MTX) are reported to be associated with the development of pulmonary disease. To determine whether MTX enhanced the risk of developing abnormalities in pulmonary function in patients with RA, we prospectively studied 31 subjects (12 male, 19 female) with the diagnosis of classic RA for an average period of 4.4 yr (range, 1 to 5 yr). Each subject was placed on low-dose weekly MTX (mean 17 mg, range 2.5 to 40) for control of RA symptoms. Other medications included non-steroidal anti-inflammatory agents and prednisone if required for control of arthritis symptoms. No other immunosuppressive therapy was used. Each subject was evaluated by pulmonary function tests (PFT) and chest X-ray initially, and at 1, 2, 3.5, and 5 yr. Chest X-rays obtained initially and at the end of the study period were found to be normal. The percent predicted values for initial PFTs in the study group were within the normal range. From the beginning to the end of the observation period, the following mean changes in lung function were observed: 1.9% increase in TLC, 5.1% increase in residual volume (RV), 1.8% increase in FVC, 0.71% decrease in FEV1, 14.7% improvement in alveolar-arterial oxygen (A-aO2) difference, and a 12.7% increase in single-breath diffusing capacity (DLCO). To determine whether MTX (average dose, weekly dose, or cumulative dose) was significantly related to changes in pulmonary function, we used multivariate techniques to control for the initial measure of lung function while assessing the relationship between MTX and the subsequent measures of lung function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Disease-modifying antirheumatic drugs. Potential effects in older patients.

Disease-modifying antirheumatic drugs (DMARDs) are frequently used in rheumatoid arthritis. A number of physiological changes occur in the elderly which may modify the use of these medications. The most commonly used DMARDs are antimalarial drugs (particularly hydroxychloroquine), sulfasalazine and methotrexate. The principal mechanism of action of the antimalarials relates to the fact that they change intracellular pH, which downregulates numerous immune functions. Hydroxychloroquine is metabolised to 3 metabolites and has a very low clearance. It is moderately effective in dosages up to 6.4 mg/kg/day. While it is not the most effective of the DMARDs, it is the least toxic. Sulfasalazine is a prodrug which is enzymatically split in the bowel to form sulfapyridine (the principal active metabolite) and 5-aminosalicylic acid. The metabolism of sulfasalazine is complex and, to some extent, genetically determined. The mechanism of action of the drug is not well understood, but involves decreased production of cytokines and decreased proliferative response of lymphocytes. It may slow the rate of bony damage associated with rheumatoid arthritis. Nearly 50% of the patients who are prescribed sulfasalazine continue to receive the drug for up to 4 years. Sulfasalazine is not as well tolerated as hydroxychloroquine. Gastrointestinal toxicity, in particular, seems to be a problem in elderly patients taking this medication. Methotrexate is presently the most popular of the DMARDs for the treatment of rheumatoid arthritis. Methotrexate inhibits dihydrofolate reductase and adenosine release and has a secondary effect on cytokines and polymorphonuclear chemotaxis. It is highly metabolised within cells and remains there for prolonged periods. Up to 70% of patients who are prescribed methotrexate continue treatment for 5 years. Methotrexate treatment is associated with gastrointestinal, hepatic, cutaneous and, possibly, pulmonary adverse effects. The use of azathioprine, penicillamine and gold compounds is briefly reviewed in this article. Elderly patients have an increased incidence of rashes when using penicillamine, relative to young patients. There are no age-related differences in the efficacy and tolerability of azathioprine or gold therapy. The poor absorption and renal toxicity associated with cyclosporin, the new 'salvage' therapy in rheumatoid arthritis, make it generally unsuitable for use in the elderly, except under specialists' supervision.

Aged↗
PubMed1995

Practical clinical pharmacology and drug interactions of low-dose methotrexate therapy in rheumatoid arthritis.

The clinical pharmacology and clinically important drug interactions of methotrexate (MTX) are reviewed. The points discussed are as follows. (a) The bioavailability of oral preparations of MTX is approximately 15-20% lower than that of intramuscular or intravenous MTX, although there is great variability in relative bioavailability. (b) Protein-binding displacements are unlikely to be of importance with this low-to-medium protein-binding drug. Because MTX is polyglutamated and remains within cells, dialysis is unlikely to be an effective mode of elimination. The principal excretory pathway of MTX is via the kidneys, although some is also excreted through the bile. These facts imply that: (i) MTX needs to be used with extreme caution, if at all, in the face of renal insufficiency; (ii) cholestyramine may be used to enhance the biliary excretion of MTX; and (iii) probenecid may be a cost-effective way to increase the efficacy of MTX. (c) Although aspirin inhibits MTX clearance more than other non-steroidal anti-inflammatory drugs (NSAIDs), clinical toxicity of aspirin is not significantly greater than that of other NSAIDs. In all cases this negative interaction is very rare (although, of course, it needs to be considered at all times). (d) It is possible that corticosteroids inhibit MTX metabolism, although this requires significant research. (e) Trimethoprim-sulphamethoxazole (TS) toxicity is well documented and may be related to synergistic anti-folate effects of MTX and TS. (f) Folic acid decreases MTX toxicity, possibly through an effect on dihydrofolate reductase.

Antirheumatic Agents↗
PubMed1994

Abnormalities of renal physiology in systemic sclerosis. A prospective study with 10-year followup.

OBJECTIVE: To evaluate the prognostic value of measurements of renal plasma flow and circulating vasoactive hormones in patients with systemic sclerosis (SSc). METHODS: Renal plasma flow (para-aminohippurate [PAH] clearance) and levels of selected circulating hormones (plasma renin activity [PRA] and serum aldosterone and catecholamines) were assessed in 57 SSc patients under the following conditions: at rest, in response to cold, while in upright position, and in response to sodium depletion. Survival was assessed 10.7 years after testing (20 patients had died). RESULTS: Both unstimulated and stimulated PRA clearance rates were frequently elevated. Resting PAH clearances were usually abnormally low. PAH clearances and levels of aldosterone and catecholamines did not change during cold stimulation. Supine PRA levels following acute sodium depletion correlated with survival (P < 0.008). CONCLUSION: The frequent finding of elevated PRA and reduced PAH values reflects clinically the high frequency of renovascular disease noted histopathologically in SSc. Isolated decreases in PAH and elevations in PRA, however, did not predict renal crisis. Changes in PAH clearances were not demonstrable during cold stimulation. An abnormally high supine PRA after sodium depletion correlated with improved survival.

Adolescent↗
PubMed1994

Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology.

Methotrexate (MTX) has become an important drug in the treatment of rheumatoid arthritis (RA). The American College of Rheumatology convened a committee to assess the risks of development of clinically significant liver disease (CSLD) during MTX treatment, to evaluate the risk and role of surveillance liver biopsies, and to provide recommendations about monitoring patients for liver toxicity. The committee recommends obtaining liver blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies, and other standard tests including complete blood cell count and serum creatinine tests prior to starting treatment with MTX. A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection. At intervals of every 4-8 weeks the AST, ALT, and albumin levels should be monitored. Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX. However, a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests. These are defined as elevations (above the upper limit of laboratory normal) in the AST in 5 of 9 determinations within a given 12-month interval (6 of 12 if tests are performed monthly) or a decrease in serum albumin below the normal range. The recommendations for monitoring and selection of patients for liver biopsy identify patients at potential risk for CSLD, and thus significantly reduce the number or patients who would be exposed to this procedure. Close monitoring is essential to reduce the risk of unrecognized serious liver disease. These recommendations should be revised as necessary to reflect new and compelling information.

Arthritis, Rheumatoid↗