Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study.

OBJECTIVES: Everolimus, a proliferation signal inhibitor with disease-modifying properties, may be useful in treating rheumatoid arthritis (RA). This proof-of-concept study assessed efficacy and safety of everolimus in combination with methotrexate (MTX) in patients with refractory RA. METHODS: A multi-centre, randomised, double-blind, placebo-controlled trial was performed in 121 patients with active RA receiving MTX. Patients were randomised to receive everolimus (6 mg/day) or placebo. The primary endpoint was the American College of Rheumatology criteria for a 20% improvement in measures of disease activity (ACR20) at 12 weeks. RESULTS: There was a rapid onset of action and at 12 weeks the ACR20 response rate was significantly higher in the everolimus group (36.1%) than in the placebo group (16.7%; p = 0.022). Improvements from baseline in tender and swollen joint counts, patient's assessment of pain, and patient's and physician's global assessment of disease activity were significantly greater after treatment with everolimus. The most common adverse events (AEs) in the everolimus group were gastrointestinal (52.5% vs 31.7% in the placebo group), skin (29.5% vs 8.3%), and nervous system disorders (21.3% vs 10.0%); AEs leading to treatment discontinuation were reported for 16.4% and 10.0% of patients, respectively. Changes in haematological parameters, liver function tests, and lipid levels occurred more frequently with everolimus compared to placebo, but were mild and reversible. CONCLUSIONS: The study indicates that everolimus plus MTX provides clinical benefit with an acceptable safety and tolerability profile. It may offer a new treatment option in RA patients with inadequate response to MTX.

Human-human hybridoma autoantibodies with both anti-DNA and rheumatoid factor activities.

Human hybridomas have been produced by fusing peripheral blood lymphocytes from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) with the GM 4672 human cell line. 262 hybridoma clones from the fusions of four RA and five SLE patients were screened for binding to denatured DNA (dDNA), native DNA, and the Fc fragment of human IgG (HIgG). Of the 17 hybridoma antibodies (nine RA, eight SLE) selected for strong binding to denatured DNA, Fc, or both, five reacted with dDNA only, one with Fc only, and eight with both dDNA and Fc. Hybridoma supernatants exhibiting dual reactivity were absorbed over HIgG and bovine serum albumin (BSA)-Sepharose immunoabsorbent columns. The reactivities to both DNA and HIgG were completely removed by the HIgG column but unaffected by passage over the BSA column, and both DNA binding and rheumatoid factor activities were recovered in the acid eluates from the Sepharose-IgG column. The binding of dual reactive hybridoma autoantibodies to the Fc fragment of HIgG was specifically competed by dDNA and HIgG, providing additional evidence that one antibody may be capable of reacting both as a rheumatoid factor and as an anti-DNA antibody.

Immunologic abnormalities in patients with malignant lymphoproliferative diseases.

The B- and T-lymphocyte distribution was studied in 45 patients with malignant lymphoproliferative diseases. Eight patients with untreated Hodgkin's disease had normal mean percentages of complement receptor lymphocyte (CRL) cells and T-cells; however, the mean absolute number of T-cells was decreased. T-lymphocytes were also decreased in 3 patients with Hodgkin's disease treated 7-24 months previously. The number of T-lymphocytes increased markedly in all patients after treatment. Lymphocyte surface markers in non-Hodgkin's lymphoma showed distinctive patterns. Patients with leukemic reticuloendotheliosis or "hairy cell leukemia" characteristically had low percentages of CRL but normal or increased percentages of surface immunoglobulin-positive lymphocytes. The mean percentage and number of T-lymphocytes in this group were normal. Eight patients with nodular lymphocytic lymphoma and 2 patients with nodular lymphocytic-histiocytic lymphoma had normal mean numbers of CRL but decreased numbers of T-lymphocytes. Of 6 patients with diffuse lymphocytic lymphoma, 4 had elevated percentages and numbers of CRL. Despite low percentages, normal numbers of T-lymphocytes were found in 3 of these patients.

Wegener's granulomatosis. Clinical features and outcome in 13 patients.

Thirteen patients with Wegener's granulomatosis were seen over 10.5 years. The clinical features resembled those in previously reported series, except for the increased frequency of inflammatory arthritis, which was a prominent early feature in ten patients (77%). Four (31%) of the 13 had fulminant vasculitis and died before receiving an adequate course of cytotoxic drug therapy. Two of these four had a pulmonary-renal syndrome that mimicked Goodpasture's syndrome. All of the remaining nine patients (69%) achieved an initial remission with cytotoxic agents (azathioprine or cyclophosphamide), but four died in less than one year with no evidence of vasculitis at autopsy. The 56% survival rate to one year in these nine patients contrasts with an 86% to 100% survival in other series. Chronic renal failure was a prominent sequela in those who survived one year.

Lactic acidosis in diabetic patients.

Plasma lactate and beta-hydroxybutyrate concentrations were measured during episodes of ketoacidosis and lactic acidosis in diabetics. In 39 patients with ketoacidosis, with a mean plasma beta-hydroxybutyrate concentration of 12.4 millimols/liter, the plasma lactate concentration was less than 3.6 millimols/liter in 28 and moderately elevated in 11. In seven of the latter, coexisting lactic acidosis had been suspected clinically. In these 39 patients, there was no correlation between plasma lactate and beta-hydroxybutyrate concentrations. In six of ten episodes of presumed and later proved lactic acidosis, despite negative or weakly positive serum reactions with sodium nitroprusside, the plasma beta-hydroxybutyrate concentration was elevated. Although positive, the serum reaction with nitroprusside was also misleadingly weak in five of 39 patients with ketoacidosis, including three with plasma lactate concentrations less than 3 millimols/liter.

Adult Still's disease.

The clinical and laboratory features in six patients with adult Still's disease are presented and compared with those in 52 other cases gathered from the literature. Although there is no pathognomonic abnormality, the condition can be readily recognized by the striking constellation of clinical and laboratory abnormalities. The typical rash occurs in 90 per cent of the cases, arthritis in 88 per cent, a fever with temperatures of 40 degrees C or more in 83 per cent and leukocytosis of 18,000 cells/mm3 or more in 67 per cent. One or more ot the following are frequently found: lymphadenopathy (48 per cent), splenomegaly (45 per cent), pleuritis or pneumonitis (31 per cent) and pericarditis (26 per cent). The initial therapy of choice is high doses of nonsteroidal anti-inflammatory drugs. This is not an uncommon disease, as was once thought, and awareness of it will avoid unnecessary diagnostic procedures and delay in initiating therapy.

The centralized prenatal genetics screening program of New York City III: The first 7,000 cases.

The Prenatal Diagnosis Laboratory of New York City (PDL) is a regional program for the prevention of genetic diseases. The administrative aspects of the establishment of the laboratory were described in papers I [Hsu, 1981] and II [Hsu and Benn, 1981] in this series. We now report our experience of the first 7,000 referrals to the laboratory. The laboratory achieved a success rate of 99.5% in obtaining a diagnosis. The frequency with which a repeat amniocentesis was required was 1.9%, usually attributable to inadequate initial amniotic fluid volume or condition. Cases were completed in an average time of 20.82 days. A total of 149 (2.13%) cytogenetic abnormalities were detected. There were 59 nonmosaic autosomal trisomies and 29 sex chromosome abnormalities. The incidence of unbalanced structural abnormalities (0.186%) was much higher than that reported in surveys of newborn infants largely because of the prenatal detection of cases with supernumerary chromosomes. The incidence of balanced structural abnormalities was also considerably higher than that found in surveys of the newborn population, in part because of the detection of subtle familial pericentric inversions of common chromosome regions (inv(Y)(p11q11), inv(2) (p11q13), and inv(1)(p11q13)). The incidence of cases with multiple independent chromosome abnormalities was no higher than expected by chance. A high incidence of mosaicism, pseudomosaicism, and maternal cell contamination was found. Screening for neural tube defects accounted for the detection of a further 16 abnormalities. Nearly all women with severely abnormal fetuses (trisomy 13, 18, 21) elected to terminate their pregnancy whereas only 62% of patients with a prenatally diagnosed sex chromosome abnormality elected to terminate their pregnancies. Full details of follow-up and confirmatory studies for unusual diagnoses are reported. Utilization of prenatal diagnosis in the New York City area has increased sharply since PDL became operational. The laboratory's success illustrates the role of a prenatal diagnosis laboratory that provides a service independent of the patient's financial status. The experience further shows the high degree of acceptance of prenatal diagnosis by individuals at high risk for a child with a genetic disorder.

Chromosomal polymorphisms of 1, 9, 16, and Y in 4 major ethnic groups: a large prenatal study.

Using trypsin Giemsa banding (GTG), major polymorphisms of the constitutive heterochromatin regions of chromosome 1, 9, 16, and Y were recorded in a New York City population. Polymorphisms were recorded from amniotic fluid specimens received from 6,250 patients from 4 major population groups, ie, White (European)-2,334 cases, American Black-1,795 cases, Hispanic descent-1,737 cases, and Asian (Oriental and Indian)-384 cases. The major chromosomal polymorphisms were classified as follows: obvious pericentric inversion of the constitutive heterochromatin of the long arm of the chromosome (inv qh); significantly enlarged heterochromatic region of the long arm (qh + is greater than, or equal to, twice the size of the short arm of chromosome 16 [16p]); very small or deficient heterochromatic region in the long arm (qh-); large Y (Yq + greater than size of chromosome 18), small Y (Yq- less than size of a G-group chromosome), and pericentric inversion of Y. Our prenatal study confirmed that the incidence of specific chromosomal variants is different in each population group. The most striking examples of this are the pericentric inversion of chromosome 9 and the different polymorphisms of the Y chromosome. The incidence of inv (9) is highest in the Black population (3.57%); slightly above average in Hispanics (2.42%); and relatively low in Whites (0.73%) and Asians (0.26%). The Y appears to be more variable in Asian (3.37%) and Hispanic (1.82%) than in White or Black groups. The 9qh+ is seen more frequently than 1qh+, or 16qh+. Inv (1), 9qh-, and 16qh- are rare. There were no cases of either 1qh- or inv (16).(ABSTRACT TRUNCATED AT 250 WORDS)

Osteopenia in rheumatology practice: pathogenesis and therapy.

Postmenopausal osteoporosis has a multifactorial pathogenesis related to decreases in bone mass, calcium intake, and circulating estrogen levels. Therapy with supplemental calcium, estrogen, fluoride, anabolic steroids, and calcitonin is discussed. Corticosteroid-induced osteopenia is in part related to a decrease in intestinal calcium absorption and therapy with supplemental vitamin D and calcium may favorably alter the outcome. The osteopenia of rheumatoid arthritis appears to be a diffuse process, with increased metabolic bone activity at sites that are remote from the areas of active synovitis.

Immunological identification of subpopulations of mononuclear cells in sarcoid granulomas.

The quantity of both circulating B and T lymphocytes in patients with sarcoidosis is diminished, although the relative percentage of each cell type appears normal. Immunocompetent cells comprising B and T lymphocytes, plasma cells, and histiocytes have been recognized in the sarcoid granuloma and the implications of these findings have been discussed.

A comparison of flurbiprofen and naproxen in the treatment of rheumatoid arthritis: a Canadian multi-centre study.

A 6-week double-blind, parallel controlled, randomized study was carried out to compare the efficacy and tolerability of 100 mg flurbiprofen twice daily with 375 mg naproxen twice daily in patients with rheumatoid arthritis. One hundred and six patients from five centres were evaluable; 52 from the flurbiprofen group and 54 from the naproxen group. Evaluation of the primary efficacy parameters demonstrated no difference in efficacy between the treatment groups. In general, the results of evaluation of the secondary efficacy parameters also supported similar improvement for both treatment groups. The overall incidence of adverse clinical/laboratory experiences was similar between the treatment groups. Five patients, 3 flurbiprofen and 2 naproxen-treated, discontinued the study, all because of gastro-intestinal intolerance.

Efficacy and tolerability of enteric-coated naproxen in the treatment of osteoarthritis and rheumatoid arthritis: a double-blind comparison with standard naproxen followed by an open-label trial.

One hundred and twenty-three patients with osteoarthritis (n = 50) or rheumatoid arthritis (n = 73) were enrolled in a 6-week, double-blind, randomized, controlled, parallel trial comparing enteric-coated naproxen with standard naproxen. Ninety-eight patients subsequently entered a 20-week, open-label trial of enteric-coated naproxen. The study demonstrated that naproxen in both its standard formulation and its new enteric-coated formulation is a highly effective form of therapy for osteoarthritis and rheumatoid arthritis. The tolerability profiles of the two formulations were similar in terms of the types of complaints reported. It is concluded that enteric-coated naproxen is an efficacious and well-tolerated formulation for the treatment of osteoarthritis and rheumatoid arthritis.

A prospective study comparing the clinical examination of peripheral joints with radionuclide scintigraphy in patients with rheumatoid arthritis.

Fifteen patients with classical rheumatoid arthritis were evaluated prospectively on 3 occasions to determine if any additional data could be obtained by joint scintigraphy which was not found by physical examination. Clinical and scan examinations were performed simultaneously and the scans were interpreted qualitatively by a radiologist without knowledge of the clinical findings. Simultaneous evaluations of 86 shoulder, elbow, knee, ankle, 84 wrist, 420 MCP and PIP, and 430 MTP joints were recorded. Concordance was noted in 67% of the evaluations and this was significant for the MCP, PIP, elbow, shoulder, knee, MTP, ankle, but not wrist joints. In 10% of instances the clinical examination was positive when the joint scan was negative. On average, the scan was positive 23% of the time (range 5-44%), when the clinical findings were normal. However, most of these scan abnormalities were due to minimal radionuclide uptake. The scan was most useful in the detection of MTP and ankle abnormalities which had been scored clinically negative, suggesting that greater attention be devoted to the clinical examination of the RA foot by the rheumatologist.

Quantitative scintigraphy using radiophosphate and radiogallium in patients with rheumatoid arthritis.

Quantitative scintigraphy of the wrist, MCP, and knee joints in patients with RA was performed using Tc-99m-MDP and Ga-67 citrate. Radiopharmaceutical uptake in affected joints was compared with uptake at 2 control reference sites (juxta-articular bone and soft tissue). Following a 6-week course of therapy with Sulindac, the patients' overall assessment of disease was improved, but the results of joint/bone and joint/soft tissue ratios were variable. Improvement using Tc-99m-MDP during the first 2 weeks of NSAID therapy was noted in the minimally inflamed wrist by joint/soft tissue measurement and in the maximally affected MCP joint by joint/bone ratio. There was no change in the joint ratios employing the Ga-67 citrate radiopharmaceutical. The initial qualitative score assigned to a joint using Tc-99m-MDP was in agreement with the calculated quantitative ratio except for the knee joint. Our results suggest that quantitative scintigraphy in its present format cannot be used as a reliable indicator to monitor the course of rheumatoid arthritis during NSAID therapy and subjective measurements are still the best judge of effective treatment.

An evidence-based approach to prescribing NSAIDs in the treatment of osteoarthritis and rheumatoid arthritis: The Second Canadian Consensus Conference.

The Second Canadian Consensus Conference was convened to discuss the latest developments in the management of osteoarthritis (OA) and rheumatoid arthritis (RA), and to make evidence-based recommendations, specifically regarding the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for these indications in primary care practice. The recent availability of cyclo-oxygenase-2-specific inhibitors has raised questions as to their role in the pharmacological management of OA and RA, particularly in relation to conventional treatments such as acetaminophen and nonspecific NSAIDs (with or without misoprostol or proton pump inhibitors). The recommendations in this document, which were arrived at through critical review of data from published randomized, clinical trials, deal with treatments of choice, information to discuss with patients, use of NSAIDs in patients at risk for serious upper gastrointestinal complications, renal or hepatic impairment or congestive heart failure, appropriate follow-up, and the use of NSAIDs with anti- hypertensives, warfarin, low dose acetylsalicylic acid and other medications. The goal of these recommendations is to improve patient outcomes in the primary care setting by maximizing treatment efficacy and minimizing rates of adverse events.

Influence of fusion cell ratio and cell plating density on production of human-human hybridomas secreting anti-DNA autoantibodies from patients with systemic lupus erythematosus.

The utilization of one human lymphoblastoid cell line in fusion experiments with peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE) has made it possible to define efficient and reproducible conditions for the production of anti-DNA-secreting human-human hybridomas. This investigation, using the human lymphoblastoid cell line GM 4672 fused in the presence of 44% polyethylene glycol with lymphocytes from SLE patients, demonstrated a maximal yield of 22.8% hybridomas, 17% of which produced anti-DNA antibodies. We were able to define, in two independent laboratories, that the maximal yield of hybridomas occurred when the lymphocyte to GM 4672 cell ratio was 1:1 and cells were seeded in 2.0 ml wells at a concentration of 4 X 10(5) cells/well. This report demonstrates the reproducibility of human-human hybridoma production with the GM 4672 cell line and the establishment of efficient conditions for the production of anti-DNA autoantibodies from SLE patients.

Radiophosphate imaging of regional migratory osteoporosis.

A patient with regional migratory osteoporosis had somewhat unusual features in that there was involvement of the small joints of the foot demonstrable by 99mTc-methylene diphosphonate joint imaging.

Presence of "rheumatoid neoantigen-like material" in urine of patients with RA, demonstrated by use of leukocyte adherence inhibition assay.

Peripheral blood leukocytes (PBL) from patients with rheumatoid arthritis (RA) when used in the leukocyte adherence inhibition (LAI) assay were capable of distinguishing antigenic differences between rheumatoid and osteoarthritic synovial membrane extracts. The positive LAI response of RA patients was negated by preincubating the cells with sera or urine proteins obtained from LAI nonreactive RA patients. This study suggests that LAI nonreactive RA subjects have in their serum a material cross reactive with rheumatoid synovium which we have called "rheumatoid neoantigen-like material" which is excreted in their urine, and is capable of being recognized by PBL of reactive, LAI positive RA patients.

Polyfunctional properties of hybridoma lupus anticoagulant antibodies.

Lupus anticoagulant antibodies are antiphospholipid antibodies which are characterized by their ability to prolong the clotting time in in vitro coagulation assays measuring the partial thromboplastin time (PTT). In our study, we have analyzed 11 hybridoma lupus anticoagulant antibodies and studied their reactivity with hexagonal and lamellar phospholipids, DNA, IgG, cytoskeletal components, and intact platelets. Our results demonstrate that hexagonal phase phospholipids but not lamellar phospholipids were able to neutralize the lupus anticoagulant activity of all 11 hybridoma antibodies. However, the lupus anticoagulant antibodies differed from one another in their reactivity with DNA, the Fc fragment of IgG, cytoskeletal proteins and platelets. Some of the lupus anticoagulant antibodies reacted with all of these structures, while others reacted with only some or none of the antigens tested. Isoelectric focusing gel analysis confirmed that this polyreactivity was due to a single antibody. Direct binding of lupus anticoagulant antibodies to intact platelets was shown to correlate with the DNA binding activity of the antibodies. Lupus anticoagulant antibodies were also capable of inducing a morphological shape change in platelets. Our data suggest that hybridoma lupus anticoagulant antibodies may react as lupus anticoagulant antibodies only, anti-DNA antibodies, rheumatoid factors, anticytoskeletal antibodies, and antiplatelet antibodies. The degree of overlap in these subgroups and the epitopes responsible for these multiple reactivities remain to be determined.

The leukocyte adherence inhibition assay in rheumatoid arthritis.

Peripheral blood leukocytes (PBL) from patients with rheumatoid arthritis (RA) and from control subjects were exposed to rheumatoid and osteoarthritic synovial membrane extracts. The number of nonadherent PBL in the presence of each extract was monitored in a test tube leukocyte adherence inhibition (LAI) assay. Six of 7 rheumatoid synovial extracts produced significantly greater nonadherence values when RA leukocytes were used as the test cell (36 +/- 5) compared with values obtained when control leukocytes were used (-5 +/- 3). Preincubation of LAI reactive leukocytes from RA patients with the RA synovial extracts abrogated the positive response, whereas preincubation with the OA extract had no effect. These studies indicate that leukocytes from RA subjects respond to a greater degree to extracts derived from rheumatoid synovium than to extracts derived from osteoarthritic synovium and add further support to the concept that unique substances (putative neoantigens?) are present in RA synovium.