Seropositive polyarthritis and skin manifestations in T-prolymphocytic leukemia/Sezary cell leukemia variant.

Sezary cell leukemia (SCL) is a rare T cell neoplasia that has been suggested to be a variant of T-prolymphocytic leukemia (T-PLL). Both disorders have an aggressive clinical course, lymphocytosis with characteristic morphology, lymphadenopathy, hepatomegaly, characteristic cytogenetic abnormalities and mature T cell phenotypes. Skin lesions, however, are mainly found in T-PLL. We describe a patient with T-PLL/SCL, who atypically presented with severe seropositive polyarthritis and skin lesions, responding to treatment with human CD52 antibody, CAMPATH-1H and pentostatin. Meningeal leukemia and an assumed myocardial infiltration subsequently developed. Polyarthritis is common in T large granular lymphocyte leukemia and adult T cell lymphoma-leukemia, but both entities could be ruled out in the present case. In rheumatoid arthritis, an expansion of CD4+ and/or CD8+ T lymphocytes is well documented and this phenomenon is believed to be of pathogenetic importance. We speculate that the T cell clone in the present case had special homing properties or cytokine effects resulting in synovitis.

D-penicillamine in early rheumatoid arthritis: experience from a 2-year double blind placebo controlled study.

OBJECTIVE: To evaluate the usefulness of early treatment with D-Penicillamine (DPA) in rheumatoid arthritis. METHODS: The patients were recruited from a Swedish early RA cohort comprising 180 patients. All patients experiencing active and/or erosive disease 2 years from onset were asked to participate in a 2-year placebo-controlled DPA trial. Previous treatment with slow-acting anti-rheumatic drugs (SAARDs) or oral corticosteroids was not allowed. The main outcome variable was radiographic progression in the hands and feet evaluated according to Larsen. Clinical assessment including the Ritchie index, active joint count, and the HAQ-disability index was performed every 6th month. Patients were included in the analyses of efficacy until the endpoint of therapy. RESULTS: 111/180 patients were eligible for treatment, and 74 agreed to participate in the trial. 21/33 patients on DPA and 22/41 on placebo completed the study. More patients taking placebo stopped due to lack of response (p < 0.01). 27% of the patients on DPA were withdrawn due to side effects. Radiographic deterioration increased but most clinical variables improved in both trial arms. A large inter-individual variation was observed. The only significant difference in trend over 2 years between DPA and placebo was found for joint tenderness. However, the median trends for most clinical variables showed a more positive effect for DPA. The 37 patients who refused to participate in the trial in general fared somewhat worse than patients taking DPA and somewhat better than patients taking placebo. The remission rate was about the same in all 3 groups (12-13.5%). CONCLUSIONS: About two-thirds of all early definite RA patients were eligible for treatment using current criteria. Psychological readiness for early therapy was fairly modest with a high refusal rate. The difference in efficacy between DPA and placebo was small, but was in favour of DPA for most clinical variables. However, only joint tenderness showed a significantly better trend. No significant slowing of radiographic progression by DPA was found.

C1 inhibitor deficiency in a patient with rheumatoid arthritis--increased risk of adverse effects of penicillamine?

We report the coincidence of hereditary angioedema and rheumatoid arthritis in a male patient and in his father. During treatment with D-penicillamine the patient developed a transient lupus-like disorder with glomerulonephritis that resolved when D-penicillamine was discontinued. He later was diagnosed with malignant lymphoma. Impaired classical complement pathway function could have contributed to development of the drug reaction.

Randomized, placebo controlled trial of withdrawal of slow-acting antirheumatic drugs and of observer bias in rheumatoid arthritis.

Patients with rheumatoid arthritis, in stable treatment with methotrexate, penicillamine, or sulfasalazine, were randomized in a double-blind fashion either to continuation of their usual treatment or to placebo. 112 patients were included; 52 patients who refused participation had no more severe disease than the others. The patients felt worse on placebo than on active drug (p = 0.002). The mean differences in number of tender, painful and swollen joints after one month were 2.4 (p = 0.08), 3.0 (p = 0.12) and 2.2 (p = 0.03), respectively. Treatment failure occurred for 42 patients of whom 33 received placebo (p = 0.000,001). There was no difference in the severity of side effects (p = 0.91). The patients guessed their treatment correctly more often than expected (p = 0.02) because of the perceived effect. None of the two observers guessed better than chance, and there were no differences between the observers' evaluations of the joints. The effect of slow-acting antirheumatic drugs was unequivocal and no observer bias occurred.

The occurrence and significance of hand deformities in early rheumatoid arthritis.

One hundred rheumatoid arthritis patients (38 men, 62 women), with mean age of 53 years and mean disease duration of 11.5 months, were followed. Standardized clinical, biochemical, and radiographic evaluation was performed regularly. After 2 years the prevalence of ulnar deviation, buttonhole deformity, and swan neck deformity was 13%, 16%, and 8%, respectively. Altogether, 31 patients had developed one or more deformities. There was no difference in age or gender distribution and no predominance of the dominant hand. Each patient with a deformity was matched according to age, sex, and disease duration with another early RA patient without deformity. The deformity group had more active disease, less grip strength, more disability, and markedly more severe radiographic changes. When studied retrospectively at a time point 3 months prior to the detection of deformity, synovitis of relevant joints was as common in the group who developed deformities as in the control group. This suggests that joint inflammation may contribute to the genesis of deformity but additional factors are needed. Hand deformities were found to be common in early RA.

111Indium-labelled leukocytes for measurement of inflammatory activity in arthritis.

Mononuclear leukocytes and granulocytes have been separated and labelled with 111In-oxine (111In). We show that granulocytes as well as monocytes can be labelled with 111In without serious adverse effects on the viability of the cells. The separated and 111In-labelled cells from patients with rheumatoid arthritis and psoriatic arthritis were reinfused into the patients and detection was made with a gamma camera over the inflamed joints. The study shows that images and semi-quantitative indices of leukocyte accumulation in the joints could be obtained in these patients. We suggest that the method may be a sensitive indicator of non exsudative synovitis and allow assessment of inflammation in joints not amenable to physical examination. This method also opens new possibilities to measure the migration of different leukocytes over the synovial membrane.

Early rheumatoid arthritis--onset, course, and outcome over 2 years.

Eighty-nine patients, 33 men and 56 women, with early definite rheumatoid arthritis were followed for 2 years. Two-thirds were seropositive. About 1/3 were eventually treated with second line drugs. The disease mostly had an insidious onset initially involving the finger joints. Early remission occurred in 16%. Patient relevant measures such as pain, patient's overall assessment of disease activity and anxiety decreased significantly. Disability evaluated by the HAQ disability index remained at a low level. The joint damage score (JDS) in hands and feet increased steadily and only 18% were nonerosive after 2 years. One-third developed hand deformities which was associated with higher JDS. A joint function index (SOFI) correlated significantly with JDS. Twenty-eight percent had a slower rate of joint damage progression the second year. There was no significant correlation between JDS and disease duration. Six patients developed rapidly progressive damage in larger joints, five in the hip joints and one in the shoulder joint, all requiring joint replacement. The ability to predict outcomes with clinical and laboratory variable obtained at entry was of limited clinical usefulness. By applying discriminant analyses 67%-80% of the cases who fared worst regarding clinical, functional, and radiological features could be correctly classified.

Random locomotion and phagocytosis of monocytes in undiluted normal serum and in undiluted SLE serum.

Time-lapse filming was performed with normal monocytes in normal serum and in SLE serum, with and without yeast cell phagocytosis. Undiluted sera were used. After incubation of the monocytes with SLE serum we found a decreased velocity of random movement and a change of morphology to more condensed, rounded-up and un-spread cells with a decreased yeast cell phagocytosis. No obvious correlation was found between the SLE serum induced impairment of monocyte function and disease activity, complement levels or the presence of immune complexes. We conclude that monocyte in vitro membrane functions, such as random motility, spreading and yeast cell phagocytosis, are impaired in the presence of undiluted SLE serum.

Effects on bone marrow cells of oral treatment with podophyllotoxin derivatives in rheumatoid arthritis.

SPG 827, a mixture of podophyllotoxin derivatives, has been thought to alleviate the symptoms of rheumatoid arthritis (RA) by arresting cell division in metaphase (i.e. resulting in an increase of the mitotic index) of rapidly proliferating cells of the immune apparatus. In contrast, the present study produced evidence that peroral SPG treatment of RA patients reduced the mitotic index of bone marrow cells, mainly in erythropoiesis. At the same time, slight megaloblastic changes appeared in the erythroblasts. These observations suggest that SPG treatment induced an interphase block in the G2 phase of the cell cycle, analogous to the cell action of the newer podophyllotoxin derivatives teniposide and etoposide. It may be that part of the clinical effect of SPG in rheumatoid arthritis is due to the described interphase-blocking activity.

Yeast cell phagocytosis by mononuclear leucocytes from peripheral blood: significance of the substrate.

Lymphoprep-isolated mononuclear leucocytes (L-MNs) from peripheral blood of healthy donors were mixed with yeast cells and filmed by time-lapse microcinematography in glass chambers at +37 degrees C. The concentration of L-MNs and yeast cells was lowered so as to make directional L-MN movement (chemotaxis) a necessary condition of phagocytosis. 54 cases of phagocytosis were filmed. Only yeast cells lying immobile on the glass surface were engulfed. In addition, 11 collisions between free-floating yeast cells and glass-adherent L-MNs were noted. None of these collisions led to immediate engulfment. It is suggested that the process of phagocytosis requires prolonged leucocyte-prey contact, in the order of magnitude of 3 to 5 seconds.

The computer leucocyte. Analysis of the random movement of leucocytes in a visual field by means of computer simulation.

In vital preparations moving polymorphonuclear leucocytes (PMNs) disappear from the visual field. The present study provides evidence by means of geometrical analysis and computer simulation, that this disappearance is due to a heterogeneous distribution of the PMNs at the beginning of observation. The path of random-moving computer leucocytes is more tortuous than the path of comparable vital PMNs without obvious attractant, i.e. vital PMNs supposed to be random-moving. This finding is in agreement with the Allan-Wilkinson observation of 'persistent random walk' of vital cells.

Lymphocyte migration through the walls of the post-capillary venules.

The results of morphological analyses of the direction of the lymphocyte traffic through the walls of the HE-venules are conflicting. The aim of this paper is to provide a short analytical review of the evidence available for the bi-directional hypothesis and for the uni-directional hypothesis.

The phagocytosis-associated chemotaxis of human mononuclear leucocytes from peripheral blood is not antitubulin-sensitive.

Lymphoprep-isolated and glass-adherent mononuclear leucocytes (L-MNs) from the peripheral blood of healthy donors appeared to display directional locomotion towards sparsely distributed yeast cells during continuous observation in coverslip preparations and during observations by means of time-lapse filming in Rose chambers. The phagocytosis-associated L-MN chemotaxis was not inhibited by antitubulin concentrations which were antichemotactic thesis that a direct antitubulin-insensitive chemotaxis exists in L-MNs, besides the antitubulin-inhibited L-MN chemoataxis reported in a previous study.

Locomotion and phagocytosis of polymorphonuclear leukocytes (PMNs) in infected urine. Reversal of PMN polarity.

The appearance of polymorphonuclear leukocytes (PMNs), fixed during locomotion and phagocytosis in deposits of infected urine, is described. By comparison with previous observations on vital PMNs, it is inferred that the anterior lamellipodium is the direction-choosing and prey-catching cell organelle. During phagocytosis the lamellipodium may assume such proportions that a reversal of cell polarity is produced, i.e., the lamellipodium forms the handle of a hand-mirror cell.

Initiation and direction of polymorphonuclear leucocyte locomotion. The particle collision hypothesis.

A simple model of the initiation of locomotion, the random movement and the directional locomotion during chemotaxis is derived from observations on moving human polymorphonuclear leucocytes (PMNs). This model provides a unifying concept of initiation of PMN locomotion, PMN random movement and PMN chemotaxis. The lamellipodium is thought to be the direction-determining cell organelle.

Cytochalasin B partially inhibits the oxalate-induced radial segmentation of mononucleated blood cells.

Cytochalasin B (CB), 5 microgram/ml (= 1.0 x 10(-5) M), inhibited the oxalate-induced radial segmentation of the nuclei of lymphocytes and monocytes from peripheral blood. The median inhibition was 60%. The oxalate-induced radial segmentation (RS) is thought to be due to a microtubule-dependent contraction of the intermitotic residue of the mitotic apparatus around the nucleus. CB is thought to inhibit cell locomotion and cytokinesis by a centripetal contraction of the membrane-associated contractile cell layer without subsequent relaxation. It is thus suggested that the CB inhibition of the oxalate-induced RS was due to a spatial interference of the CB-induced contraction with the formation of RS nuclei.

Amoeboid movement in human leucocytes: basic mechanisms, cytobiological and clinical significance.

The present paper is an analytical review of the information available on amoeboid movement in human leucocytes. The reported evidence suggests that leucocyte locomotion is due to pressure developed in the cell cortex in the middle and posterior parts of the moving cell, that 4 nm fibrils may provide at least part of the ultrastructural basis of locomotion, that actin-like and myosin-like proteins may be involved in the mechanism of movement and that ATP may serve as an energy source. Leucocyte motility appears to be governed mainly by factors produced in the external medium. Neutrophil chemotaxis is the most antitubulin-susceptible cell mechanism known; from this observation an essential role of microtubule redistribution in chemotaxis is inferred. In contrast, the random movement of neutrophils is not appreciably affected by antimitotic concentrations of antitubulins. Amoeboid movement seems to be an important mechanism in the short-distance locomotion and immunological functions of leucocytes.

Amoeboid movement configuration in tumour cells of bone marrow smears from patients with leukaemia. Incidence and significance.

The incidence of amoeboid movement configuration (AMC), a cell shape suggestive of cell locomotion at the moment of fixation, has been studied in the tumour cells of bone marrow smears from leukaemia patients at the time of diagnosis. The groups of patients with CML (n = 8), ALL (n = 5) and CLL (n = 9) were small, and the incidences of AMC were close to those found in the corresponding cell lines from healthy probands. In 39 patients with AML, the incidence of AMC was higher than in the other cell lines investigated. A positive skew distribution of AMC values and a positive significant correlation between incidence of AMC were found at the time of diagnosis and subsequent survival of the patients with AML, in spite of differences in treatment. It is suggested that this positive correlation may be due to an immune reaction of the patients against their tumour cells.