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Biomedical subjects

D E Trentham

Publications and source records attributed to D E Trentham.

At least 37 records · Page 2Linked to original sources
PubMed1993

Association between bovine collagen dermal implants and a dermatomyositis or a polymyositis-like syndrome.

OBJECTIVE: To determine whether an excess incidence of dermatomyositis or polymyositis or both exist in patients treated with injectable bovine collagen implants and to characterize the clinical picture. DESIGN: Historical cohort study (July 1980 through June 1988). PATIENTS: Patients were identified from personal experience or adverse reaction reports received by the manufacturer. SETTING: An 8-year period in the United States during which approximately 345,000 patients received implants. RESULTS: Eight patients with dermatomyositis and an additional patient with polymyositis were identified from approximately 345,000 patients receiving injectable bovine collagen implants from July 1980 through June 1988. The nine patients with dermatomyositis or polymyositis were diagnosed an average of 6.4 months (range, 0.7 to 24.9 months) after collagen implant or skin test exposure or both. Eight of the nine patients had a delayed-type hypersensitivity response at the test or treatment sites or both, and five of six patients tested were found to have increased serum antibodies to collagen. Compared with the general population, the incidence of dermatomyositis or polymyositis among collagen-treated patients was statistically increased (standardized incidence ratio, 5.05; 95% CI, 2.31 to 9.59; P < 0.0001). A similar analysis of the eight dermatomyositis case patients produced a standardized incidence ratio of 18.8 (CI, 8.1 to 37.0; P < 0.0001). Using a Monte Carlo simulation, an interval of 6.4 months or less from exposure to onset of disease was found to be an extremely rare event, occurring less than 72 times per one million simulation trials (CI, 57 to 91). CONCLUSIONS: Because these data suggest that an immunologic response to bovine type I or type III collagen or both caused this dermatomyositis or polymyositis-like syndrome, the risks versus benefits for the cosmetic use of collagen implants should be reassessed.

Adult↗
PubMed1993

DAB486IL-2 fusion toxin in refractory rheumatoid arthritis.

OBJECTIVE: To evaluate the safety and antiarthritic effects of DAB486IL-2. This agent is a fusion toxin and the product of a synthetic gene, engineered by replacing the codons for the receptor-binding domain of diphtheria toxin (DT) with the codons for human interleukin-2 (IL-2). DAB486IL-2 targets cells expressing the 2-chain, high-affinity form of the IL-2 receptor (IL-2R), and achieves selective diphtheria toxin-mediated cytotoxicity of activated T cells by inhibition of protein synthesis. METHODS: Nineteen patients with rheumatoid arthritis (RA) that had been refractory to methotrexate participated in an open-label, phase I/II trial evaluating 3 dose levels of intravenous DAB486IL-2 given for 5 or 7 consecutive days. Thirteen patients received additional courses, at higher doses if the original response had been inadequate or at an equivalent dose if the original course produced a response, for a total of 38 courses. Arthritis response was assessed at 28 days, with biweekly followup of patients with substantial response (> or = 50% improved) or meaningful response (> or = 25% improved). Laboratory monitoring included measurement of CD4+ cells and circulating shed IL-2R. RESULTS: Nine of 19 patients treated with high- or medium-dose DAB486IL-2 had a substantial or meaningful response after 1 or 2 treatment courses. No significant responses occurred with the low-dose regimen. Clinical benefit was rapid, with full effect noted by 14 days following completion of infusions. Antibodies to DT developed in all patients, or levels of preexisting antibodies were boosted. Adverse effects included transient elevation of transaminase levels (55% of the patients), fever (40%), nausea or anorexia (30%), hypersensitivity (6%), and thrombocytopenia (5%). Repeat courses were associated with less transaminase elevation and were clinically effective despite induction of anti-DT antibodies. CONCLUSION: The results of this open trial provide preliminary evidence for a potential therapeutic effect of DAB486IL-2 in RA, with an acceptable safety profile. Reversible transaminase elevations limit escalation of the dosage beyond 0.1 mg/kg/day. A controlled study of DAB486IL-2 is required to determine the efficacy of this high-affinity IL-2R-targeted fusion toxin in the treatment of RA.

Adult↗
PubMed1993

New focus on treatment for rheumatoid arthritis.

Although the pathogenesis of rheumatoid arthritis increasingly continues to be well understood, therapeutic approaches to the disease remain relatively unsophisticated and based more on anecdote than scientific reasoning. During the past year, additional supportive data regarding the usefulness of front-line agents such as methotrexate and hydroxychloroquine were acquired, and novel potential interventions, such as pulse gammaglobulin and OM-8980 were identified. Animal model studies still support the prospect that genuine remission-inducing strategies will be realized in the future.

Animals↗
PubMed1992

Anti-arthritic effects demonstrated by an interleukin-2 receptor-targeted cytotoxin (DAB486IL-2) in rat adjuvant arthritis.

DAB486IL-2 is an interleukin-2 receptor-specific cytotoxin which selectively targets and kills cells which bear the high-affinity form of the IL-2 receptor. Since elimination of activated T lymphocytes may be useful in the treatment of rheumatoid arthritis, the effect of DAB486IL-2 treatment in an animal model of arthritis was investigated. We demonstrated that rats treated with DAB486IL-2 during the induction phase of disease have delayed onset of symptoms and significantly reduced severity of inflammation as well as a depressed proliferative response to mycobacterial stimulation in vitro. In addition, the presence of preexisting antibodies to the molecule had no impact on the anti-arthritic effects observed in this model. These data suggest that DAB486IL-2 may have therapeutic potential in the treatment of rheumatoid arthritis.

Animals↗
PubMed1992

POEMS syndrome with myocardial infarction: observations concerning pathogenesis and review of the literature.

A 27-year-old white man with no significant risk factors for coronary artery disease presented with a 9-month history of progressive impotence, gynecomastia, lower extremity paresthesias, and extensive myocardial infarction and subsequently developed ulcerative proctitis. A diagnosis of POEMS syndrome was made based on the clinical presentation; additional physical findings of papilledema, clubbing, and hyperpigmentation; and laboratory findings of an immunoglobulin G M component of the lambda subtype, elevated cerebrospinal fluid protein, and typical sclerotic bone lesions. Abnormal in vitro binding of the patient's serum immunoglobulin to testicular tissue was also seen. Cardiac catheterization showed evidence of diffuse coronary artery narrowing and left ventricular wall motion abnormalities. Diffuse coronary involvement and ulcerative proctitis have not been previously described in POEMS syndrome. It is hypothesized that an abnormal immunoglobin (or fragment) is responsible for both findings. Furthermore, the detection of antitesticular autoantibodies suggests the possibility of an interaction between the antibody and Leydig cells, leading to an alteration in the synthesis and release of sex steroids and thereby explaining the gonadal failure seen in this syndrome. Long-term glucocorticoid therapy for the past 5 years has resulted in marked subjective and objective improvement.

Adult↗
PubMed1992

Novel immunomodulating and immunotherapies, and novel therapies and strategies for inflammatory arthropathy.

During the past year, another disease possibly influenced by intravenous gammaglobulin was identified as dermatomyositis/polymyositis. Additional studies provided further information regarding the use of monoclonal anti-CD4 antibody and combination therapy in rheumatoid arthritis, antithymocyte globulin in scleroderma, and intravenous gammaglobulin in juvenile rheumatoid arthritis. New therapeutic horizons also emerged including the novel immunosuppressant FK-506, the removal of disease incitants by medical arthroscopy, antiarthritic T-cell receptor V beta-specific antibodies, and the potential of achieving tolerance via peroral administration of autoantigens.

Adjuvants, Immunologic↗
PubMed1991

Correlation between antibodies to type II collagen and treatment outcome in bilateral progressive sensorineural hearing loss.

Our aim was to assess whether "idiopathic" bilateral progressive sensorineural hearing loss (BPSHL) has an immunological cause in some patients; antibodies to native type II collagen were sought by an ELISA in eighteen patients with BPSHL, before and after corticosteroid treatment, and in twelve patients with Menière's disease, fifteen with otosclerosis, eighteen with rheumatoid arthritis, nine with fibrositis, and nine healthy controls. A positive result was defined as a mean dilution titre of 2 or more. Eight of eighteen BPSHL patients had positive titres--significantly (p less than 0.005) more than in any other group (one Menière's disease, two otosclerosis, and no others). The mean antibody titre was higher in the BPSHL group than in any other group (2.02 [SEM 0.62] vs 0.17 [0.17]) Menière's disease, 0.44 [0.32] otosclerosis, 0 all others; p less than 0.005). The nine BPSHL patients who showed a clinical response to corticosteroids (improvement in at least one tone by audiogram or 25 db in speech discrimination score) had the highest mean antibody titre (3.46 [0.88] vs 0.59 [0.59] for the nine non-responsive patients; p less than 0.04). We suggest that in some patients with BPSHL, immunity to type II collagen, a major constituent of the inner ear, may be important in the pathogenesis of the disorder.

Antibodies↗
PubMed1991

Intractable vasculitis, resorptive osteolysis, and immunity to type I collagen in type VIII Ehlers-Danlos syndrome.

A unique patient with type VIII Ehlers-Danlos syndrome and cutaneous vasculitis, resorptive osteolysis, and cardiac valvular disease is described. Collagen analyses identified morphologic and physical abnormalities of type I collagen. The patient's T lymphocytes could be propagated in vitro with type I collagen and produced a 60-kd lymphokine that bound this protein. Cellular autoimmunity to type I collagen may be responsible for this patient's intractable clinical condition.

Autoimmunity↗
PubMed1991

Immunotherapy and other novel therapies.

Although no true breakthroughs occurred, publications during the 12-month period of this review added substantial definition to certain novel immunotherapies potentially applicable to the treatment of rheumatoid arthritis. Overall, this period witnessed maturation in the field of biologic interventions. Clinical trials provided further data needed to assess the efficacy of high-dose intravenous gamma-globulin therapy in patients with systemic juvenile rheumatoid arthritis, and extended uncontrolled experience with interferon-gamma in adult rheumatoid arthritis was obtained. An intriguing immunostimulant and antiviral drug, isoprinosine (inosine pranobex), failed in a scientifically rigorous trial in rheumatoid arthritis. Provocative insights into totally new approaches surfaced in additional reports from a variety of immunologic areas. Although seemingly distal to rheumatoid arthritis, these papers are cited because their further development or adaptations could reach a stage where clinical trials in rheumatoid arthritis are warranted.

Alprostadil↗
PubMed1990

Novel therapies.

Extremely preliminary results from uncontrolled feasibility studies hint that minocycline and T-cell cytolitic strategies deserve further evaluation in RA, as does the use of high-dose intravenous gammaglobulin in chronic cutaneous vasculitis.

Arthritis, Rheumatoid↗
PubMed1990

Measurement of joint inflammation in rheumatoid arthritis with indium-111 chloride.

Studies in the collagen and rabbit models of arthritis have indicated that indium-111 chloride (111InCl3) scintigraphy objectively measures synovial inflammation. Indium-111 chloride scans, with imaging three days after 19 MBq intravenous injection, were performed on 21 patients with definite or classical rheumatoid arthritis (RA), all of whom were functional class II. Standard clinical indices of disease activity were recorded at the time of imaging by the same investigator, who was unaware of the results of joint scans. In addition, eight patients with severe osteoarthritis, four of whom were considered to need hip or knee joint replacement, were similarly scanned. In each patient 16 joints were graded as 0 to 5, based on increasing degrees of 111InCl3 uptake, by a single investigator blinded to the patient's diagnosis and clinical status. In the group with RA significant correlations were observed between individual joint uptake on scan and peripheral joints with swelling, joints reported to be painful, and joints with any abnormality on physical examination. In the group with osteoarthritis joints positive on scan correlated with the presence of pain. A total scan score (sum of individual joint scores) was calculated for each patient. In the patients with RA values ranged from 0 to 42 with a mean (SEM) of 20.7 (2.7) and correlated with the number of swollen joints and decreasing grip strength. In the group with osteoarthritis the mean total scan score (9.2 (1.5), range 3-14) was significantly lower than in the patients with RA. These data show that 111InCl3 scanning can measure joint involvement by RA.

Adult↗
PubMed1989

Collagen arthritis in the rat is initiated by CD4+ T cells and can be amplified by iron.

The role of iron in arthritis was studied by administering ferric citrate (Fe-cit) to age-matched, female Sprague-Dawley rats immunized with chick type II collagen on Day 0. Rats received intravenously (iv) either Fe-cit (7.7 mg/kg body wt) or an identical concentration of sodium citrate on varying days after immunization. Transferrin saturation peaked (88-95%) 1 hr post-Fe-cit and returned to baseline values within 24 hr. Injection of Fe-cit on either Day 3 or Day 5, but not on Day 7 or Day 9, significantly (P less than 0.03) increased the incidence of arthritis. Synovium from the infrapatellar fat pad was harvested on Days 0-10 for analysis by immunocytochemistry. The inceptual morphologic change in the synovium following collagen immunization in rats not injected iv was an increase in the number of CD4+ and transferrin receptor+ mononuclear cells in perivascular regions; compared to Day 0 both cell types had increased two- to threefold by Day 3. On Day 7, an increase in CD8+ mononuclear cells occurred and the first polymorphonuclear leukocytes were noted. These alterations resulted in a peak in the CD4-CD8 ratio on Day 3, with a gradual decline thereafter. Although Fe-cit administration promoted the ingress of these mononuclear cells, it did not change the CD4-CD8 ratio significantly or recruit polymorphonuclear leukocytes into the joint tissue. Serum antibody titers to type II collagen, measured 20 days after immunization by an enzyme-linked immunosorbent assay, and delayed-type hypersensitivity to collagen, measured by a radiometric ear assay on Day 23, did not differ significantly between the groups. As well as showing that the initial intrasynovial event in collagen arthritis is perivascular infiltration by members of the CD4+ T cell subset displaying a phenotypic sign of activation, these findings demonstrate that iron administered at a critical time after immunization enhances the induction of collagen arthritis. The coincidence of this brief period of susceptibility with maximum CD4-CD8 ratios within the synovium and its occurrence prior to the stage of neutrophil infiltration are consistent with the possibility that the augmenting effect of iron is mediated by the inducer T cell subset.

Animals↗
PubMed1989

Experimental synovitis induced by collagen-specific T cell lines.

Type II collagen (CII) and ovalbumin (OV) reactive T cell lines were developed from the lymph node cells of Louvain rats previously immunized with the respective antigen. Histologic sections of rat knees injected intraarticularly (ia) with 10(6) cells from line CII (VA) or CII (VII) were graded blindly. Significant synovitis (P less than 0.000001 and 0.004, respectively) was evident compared to OV line recipients. Pannus developed within 48 hr, persisted for at least 4 to 6 weeks, was inducible with fewer than 10(3) CII cells, and required viable lymphocytes. The process was independent of anticollagen antibodies and was associated with the lines' capacity to elaborate a previously described 65-kDa CII-binding arthritogenic lymphokine. Line CII (VIII), which could not elicit a synovitis, did not produce detectable quantities of this factor. A line- and antigen-specific synovitis, comparable to the ia injection protocol, was also induced by intravenous administration of 2 x 10(7) CII (VA) cells and ia challenge with soluble collagen. These studies demonstrate that CII lines bearing the T helper phenotype can evoke a sustained synovitis and suggest that this experimental process is associated with the release of an arthritogenic lymphokine and not dependent on the formation of antibodies to CII.

Animals↗
PubMed1989

Evaluation of a modified hexose sugar, amiprilose hydrochloride, in experimental models of synovitis.

Amiprilose HC1 (SM-1213), a nontoxic modified hexose sugar, was evaluated in in vivo and in vitro models of synovitis. In 8 sequential trials, 90 Louvain (LOU) rats and 91 Sprague-Dawley (SD) rats were immunized with chick type II collagen and given amiprilose HC1 in water (1 mg/ml) or water alone. In the LOU rats, the arthritis incidence was 7/46 (15%) in the amiprilose HC1 group vs 16/44 (36%) in the water group (p less than 0.01). In the SD rats, the incidence was 28/46 (60%) in the experimental vs 33/45 (73%) in the control group (p greater than NS), although the prevalence of arthritis on Days 16 and 21 was significantly (p less than 0.03) lower in the experimental group. Amiprilose HC1 did not affect the antibody titers or delayed-type hypersensitivity to collagen, or T cell subset distribution in the LOU experiments. Two analogues, SM-1211 and SM-1212, did not alter this disease. No toxicity was noted. At a nontoxic concentration of 1 mg/ml, amiprilose HC1 suppressed 3H thymidine incorporation in cultured rabbit synovial fibroblasts by 78% and resulted in the appearance of numerous intracytoplasmic granules/vacuoles. These effects were partially antagonized by indomethacin or dexamethasone at 10(-7) M. SM-1211 was inert in this system. Amiprilose HC1 system also reduced rabbit synoviocyte supernatant prostaglandin E2 levels up to 73% in a dose related fashion, but did not affect collagenase activity. These morphologic changes in synoviocytes, combined with anti-inflammatory and antiproliferative effects, provide evidence that amiprilose HC1 possesses modest and nontoxic antirheumatic properties. A search for analogues of this sugar with more substantial clinical activities is warranted.

Adjuvants, Immunologic↗
PubMed1989

Rheumatologic therapy for the 1990s. Evolution or revolution?

The 1980s was a decade of immunologic, biochemical, and pharmaceutical advances in the treatment of patients with rheumatic diseases. The therapeutic revolution will continue into the 1990s, and this article reviews several areas of change and controversy that have developed.

Anti-Inflammatory Agents, Non-Steroidal↗