High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegener's granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide.

The objective of this study was to evaluate the feasibility and safety of high-dose azathioprine pulse (HAP) therapy in the induction of remission in patients with active Wegener's granulomatosis (WG) or progressive lupus nephritis (LN) refractory to or intolerant of cyclophosphamide. Four patients with antineutrophil cytoplasmic antibody (ANCA)-associated WG and two patients with progressive LN were treated with HAP (1200-1800 mg) applied monthly as continuous intravenous infusions at 50 mg/h. Patients received a total of 50 courses of intravenous azathioprine (AZA) therapy. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS) and the Systemic Lupus Erythematosus Activity Index (SLEDAI). As only partial remission was induced in patients with progressive LN on this regimen, an additional 18 cycles were applied in these patients in which oral AZA at 100 mg/day in weeks 2 and 3 was added between two intravenous courses. A hereditary defect in thiopurine methyltransferase activity was excluded before initiation of treatment. High-dose azathioprine pulse and the intensified HAP treatment were well tolerated. Complete remission was achieved in two patients with WG suffering from three relapses of disease on application of 2-6 courses of HAP. Remission was maintained for 16-24 months. The remaining two patients with WG were withdrawn after 2-3 courses due to unchanged disease activity. In two patients with LN, partial remission was noted on 6-9 courses of HAP; however, the patients relapsed despite therapy with methotrexate and mycophenolate mofetil. The intensified HAP regimen led to partial or complete remission in both LN patients which was confirmed by sequential renal biopsies. Our results suggest that HAP therapy represents a well-tolerated regimen in patients with active WG and LN intolerant of or refractory to cyclophosphamide. As partial or complete remission was observed in four of six patients, further studies seem warranted to assess clinical efficacy in these patients.

Cell fusion is not involved in the generation of giant cells in the Hodgkin-Reed Sternberg cell line L1236.

The mechanism of multinucleated cell formation in Hodgkin's disease has not yet been elucidated. We asked whether the giant multinucleated cells of the H-RS cell line L1236 develop via fusion of the predominant smaller cells. As a positive control for the fusion assay, human B cells from the B-cell lymphoma cell line BJA-B were split into two fractions, stained with the fluorochromes CMTMR and CMFDA, respectively, and fused using the polyethylene glycol 1500 cell hybridization protocol. Double-stained cells indicating fusion of BJA-B cells were detectable for up to 5 days. In parallel, L1236 cells were split into two fractions, stained with the fluorochromes, and mixed. No double-stained L1236 cells were detected. The same result was obtained when using FACS-sorted small mononuclear L1236 cells. It is thus concluded that the large multinucleated cells of the monoclonal H-RS cell line L1236 have emerged by endomitosis rather than by spontaneous cell fusion.

Lack of BCL10 mutations in Hodgkin's disease-derived cell lines.

The pathogenetic events leading to the malignant transformation of Hodgkin-Reed-Sternberg cells are unknown. As Hodgkin-Reed-Sternberg cells are resistant to CD95-mediated apoptosis and chromosomal aberrations involving the 1p22 region harbouring the proapoptotic BCL10 gene represent a recurrent event in Hodgkin's disease-derived cell lines, analysis of the BCL10 gene and its transcripts was performed. As transcription of wild-type BCL10 was detected in all Hodgkin's disease-derived cell lines analysed, alterations of the coding sequence of the BCL10 gene are unlikely to contribute to the malignant transformation of the Hodgkin-Reed-Sternberg cell.

[Pulse therapy with prospidin and methotrexate: comparative efficacy in rheumatoid arthritis (12-month controlled study)]. / Sravnitel'naia éffektivnost' pul's-terapii prospidinom i metotreksatom pri revmatoidnom artrite (12-mesiachnoe kontroliruemoe issledovanie).

Efficiency of pulse-therapy with prospidin (500 mg for 5 days in hospital, 500-1000 mg for a month as maintenance) and methotrexate (30 mg a week i.v. in hospital, 7-10 mg a week as maintenance) was investigated in 93 patients with severe RA. The response to prospidin and methotrexate arose quickly (within 10-14 and 4-5 weeks, respectively) and occurred in 73 and 70% of patients, respectively. Withdrawal of the drug was caused by side effects of methotrexate (19.3%) and resistance to prospidin (23.2%).

Prospidine versus methotrexate pulse in highly active rheumatoid arthritis: a controlled 6-month clinical trial.

Twenty-seven patients with highly active, refractory rheumatoid arthritis (RA) were treated with the new anti-rheumatic drug prospidine, in view of selecting the optimum pulse regimen and comparing its short-term use with methotrexate (MTX). Prospidine was administered intravenously 500 mg every 3-5 days in the hospital and then monthly. Fifteen patients received MTX (30 mg/week intravenously in hospital and then monthly. Fifteen patients received MTX (30 mg/week intravenously in hospital and then orally 7.5-15 mg/week). The randomisation code was 2:1. We assessed 7 clinical and 4 lab data. The clinical improvement was noticed statistically after 2-4 weeks in 85% prospidine-patients and sustained up to 6 months in 73% (cp. 40% and 57% by the MTX). Only in the prospidine patients were a significant reduction of the mean daily prednisolone dose and the levels of rheumatoid factor and immune complexes observed. Prospidine and MTX had a similar incidence of side effects (39% and 43%), but all drop-outs in prospidine pulse were due to lack of response (26%) and to initial intolerance (4%). Drop-outs in MTX pulse were connected both with drug toxicity (14%) and with lack of response (7%). Alternate prospidine pulse, as highly anti-inflammatory, rapidly acting and well-tolerated regimen, may be used in treating severe forms of RA.

A primary care nursing model in long-term care facilities: evaluation of impact on affect, behavior, and socialization.

A primary care model of delivery of nursing aide care was implemented and evaluated in one small, rural nursing home and one large, urban facility. Experimental unit residents received primary care consisting of permanent assignment of nursing aide, a team approach and enhanced communication. The urban experimental residents improved significantly in behavior and affect as measured across several sources, while the comparison group declined or remained the same. Significant improvements in behavior and social activities were observed among the experimental rural nursing home residents as contrasted with the comparison group after implementation of primary care nursing. It was concluded that primary care nursing as applied to nursing attendants in long-term care is beneficial to residents in terms of decreasing disturbed behavior and improved affect.

[A clinico-immunological analysis of the efficacy of prospidin and azathioprine in systemic lupus erythematosus (the results of a 12-month observation)]. / Kliniko-immunologicheskii analiz éffektivnosti prospidina i azatioprina pri sistemnoi krasnoi volchake (rezul'taty 12-mesiachnogo nabliudeniia).

Prospidin and azathioprine were given to 28 and 12 SLE patients, respectively, in a controlled trial which implied subsequent clinical and immunological surveillance for 12 months. The data obtained in the trial provided evidence for true antilupus activity of prospidin in a total dose 3.0-9.8 g. Prospidin brought about improvement with a complete or partial remission of the lupus nephritis in 71%, serious side effects in 21%, lethality in 17.8%, secondary resistance in 10% of the patients treated. The clinical and immunocorrective effects conformed. Compared to azathioprine, prospidin can produce more pronounced and rapid effect, induced more marked immunodepression. It is better tolerated, has no cytopenia effect. The drugs mechanisms of action and criteria of the treatment efficacy are discussed. It is hold valid to use prospidin in long-term maintenance of SLE patients.

[A study of the initial suppressor function of lymphocytes]. / Izuchenie iskhodnoi supressornoi funktsii limfotsitov.

The new method for analysis of initial suppressor lymphocyte function in newly isolated monocultures is based on quantitative cytofluorometric analysis of early mitogen-induced activation of B lymphocytes in the presence of prednisolone that switches off a T lymphocyte immunoregulatory effect. Suppressor lymphocytes monitor B lymphocyte exit into proliferative pool and early processes of nuclear chromatin activation. The levels of initial suppressor lymphocyte function and lymphocytic proliferative activity are in inverse correlation. Suppressor lymphocyte function has been essentially reduced in rheumatoid arthritis patients as against normal subjects. A reduction as low as 70 percent of the normal value (recorded in 1/3 of the patients) is compensated with unchanged regulatory control over B cells, and reduction as low as 40 percent of the normal value (in 2/3 of the patients) is characterized by loss of regulatory control and B cell hyperactivation.

[The rapid cytofluorometric indices of lymphocyte functional activity in rheumatoid arthritis and systemic lupus erythematosus]. / Tsitofliuorimetricheskie ékspress-pokazateli funktsional'noi aktivnosti limfotsitov pri revmatoidnym artrite i sistemnoi krasnoi volchanke.

As many as 49 patients with rheumatoid arthritis (RA), 16 with systemic lupus erythematosus (SLE) and 40 healthy persons were examined for functional parameters of freshly isolated peripheral lymphocytes with the aid of quantitative cytofluorimetry designed by the authors. Proliferative function was estimated according to the RNA/DNA ratio in nuclear chromatin, suppressor function to the early processes of mitogenin-induced activation of B cells in the presence of prednisolone, and immunoglobulin-synthesizing function was assessed by the mean level of Ig in B cells of the population. It has been established that lymphocytes from the healthy persons are primarily in a state of rest (G0), have low B activation and high suppressor function (SF). In RA, lymphocytes, mainly B cells, are in a state of spontaneous activation (G1--S--G2) related to the degree of SF decrease. In 1/3 of patients, moderately decreased SF (to 70% of normal) controls the early processes of mitogen-dependent B activation, whereas in 2/3 of patients, a more pronounced decrease of SF (to 40% of normal) combines with hyperactivation of B cells. SLE is characterized by higher, as compared with RA, proliferative and Ig-synthesizing activity of B cells combined with a decrease of SF (to 45% of normal). High correlations have been shown: a direct one between nuclear chromatin activation and Ig-synthesis in the B cell and a reverse one between these processes and SF. The conclusion has been made that the immune status in patients with RA and SLE is marked by hyperactivation of B cells and SF decrease.

[Immunoregulatory disorders and the proliferative activity of T- and B-lymphocytes in osteoarthrosis]. / Immunoreguliatornye narusheniia i proliferativnaia aktivnos't T- i B-limfotsitov pri osteoartroze.

The authors studied the activity of nuclear chromatin of the peripheral T- and B-lymphocytes in the polyclonal activation test using the method of quantitative cytofluorometry. A new experimental model in vitro has been proposed for the study of regulatory function of T-lymphocytes. It was found out that in approximately 50% of osteoarthrosis patients the greater part of the peripheral lymphoid population is in the state of initial activation and the activated B-lymphocytes occur more frequently than T-lymphocytes.

[Clinical effectiveness of prospidin in systemic lupus erythematosus (results of a 6-month follow-up)]. / Klinicheskaia éffektivnost' prospidina pri sistemnoi krasnoi volchanke (rezul'taty 6-mesiachnogo nabliudeniia).

The efficacy of the new Soviet antirheumatoid drug prospidin (the long-term treatment dose 1.4-6.0 g) was studied in 22 patients with significant lupus erythematosus (SLE). As a result of prospidin therapy administered for a month, 3 patients considerably improved and 19 patients improved. For 6 months the maintenance therapy was given to 15 patients. Considerable improvement was recorded in 4 and improvement in 9 patients. No effect was marked in one patient and one female patient died. The drug was tolerated well. No side effects requiring prospidin withdrawal were recorded. Prospidin exerted the most powerful effect with respect to lupoid nephritis, the articulation syndrome, and cytopenias. In accordance with the clinical improvement, the drug was established to return the immunological shifts common to SLE to normal. The drug may be viewed as a new basic agent for the treatment of SLE.

[Immunotropic therapy of rheumatoid arthritis (prerequisites, results and principles)]. / Immunotropnaia terapiia revmatoidnogo artrita (predposylki, rezul'taty, printsipy).

The author has summed up many-year investigation and literature data on immunological approaches to RA therapy including a study of the patients' immunological status, evaluation of the clinical efficacy and immunological effects of various therapeutic methods, and a study of the individual sensitivity of drugs in in vitro experiments. An indicator proposed by the author for the evaluation of clinicoimmunological therapeutic efficacy, expresses the true value of the method of RA therapy. Indices of the immune status necessary for a choice of patients and control of immunotropic therapy were defined; methods for the assessment of individual sensitivity to immunoreactive agents and principles of immunotropic therapy were presented.

[Assessment of the effect of prospidin and cyclophosphane on the indices of the T and B immune responses in vitro]. / Otsenka vliianiia prospidina i tsiklofosfana na pokazateli T- i B-immunnogo otveta in vitro.

Prospidin was shown to produce a decrease of receptors on T- and B-lymphocytes and T-subpopulations, to inhibit migration of leucocytes under the influence of the antigenic stimulus, to reduce the cytopathic activity of lymphocytes and the level of secreted immunoglobulins of the main classes. The degree of prospidin immunodepressive effect is compared with that of cyclophosphane.

[A new basic drug prospidin in the treatment of rheumatoid arthritis. III. Comparative analysis of prospidin and cyclophosphamide]. / Novoe bazisnoe sredstvo prospidin v terapii revmatoidnogo artrita. Soobshchenie III. Sravnitel'nyi analiz prospidina i tsiklofosfana.

A comparative study of the cytostatic drugs prospidin and cyclophosphamide used in equal doses for rheumatoid arthritis (RA) is reported. Clinical and immunologic effects were determined, and the nature and incidence of side effects and complications were compared. Prospidin showed a more pronounced antirheumatic effect, making for a smaller daily requirement of nonsteroid anti-inflammatory agents or hormones in hormone-dependent cases. Unlike cyclophosphamide, prospidin was not associated with severe side effects and complications precluding further use of the drug. Both drugs demonstrated a regulatory effect on RA-associated immunologic disorders.