[Long-term follow-up of patients with refractory systemic lupus erythematosus during rituximab treatment].

AIM: To evaluate the impact of anti-B-cell therapy on the clinical and immunological parameters of systemic lupus erythematosus (SLE) activity, on the time course of changes in these parameters during long-term follow-up, and on the tolerability of repeated rituximab (RTM) therapy cycles. SUBJECTS AND METHODS: RTM was given to 97 patients with high activity of SLE refractory to treatment with glucocorticosteroids (GCS) and cytostatics. The follow-up lasted 18 (12-36) months. The most common clinical manifestations of SLE were lupus nephritis (LN) (62%) and skin (33%) and nervous system (22.7%) involvements. Clinical SLE activity was assessed applying the SLE disease activity index 2000 (SLEDAI2K); therapeutic effectiveness was evaluated using indicators, such as partial response (PR), complete response (CR) and exacerbation. The exacerbation was classified as moderate and severe using the Selena-Sledai Flare index (SFI). RESULTS: Depletion was identified in 78% of the patients with SLE immediately after RTM therapy. During 3.5 years of follow-up, the effect of RTM was seen in 82% of the patients after repeated RMT therapy cycles (CR 56% and PR 28%). Exacerbations were observed in a total of 24 (24.7%) patients; the exacerbation lasted 12 (12-24) months after RTM therapy: of them 17.5% with LN and 7.2% with extrahepatic manifestations of SLE (exacerbations occurred 12 (12-24) and 18 (6-48) months after RMT therapy). In 24 exacerbated patients, B cells recovered at 6 (3-12) months. A year after RMT therapy, a group of 35 patients who were observed to have complete B cell depletion achieved CR statistically significantly more frequently than a group of 20 patients who had B-cell recovery (65.7 and 30% respectively, p = 0.03). CR was observed significantly more often in patients after repeated RTM therapy cycles than those who had received only one RTM therapy cycle (p = 0.02). The long-term follow-up showed a reduction in SLEDAI2K, normalization of laboratory values, and a decrease in the daily dose of GCS. Most patients tolerated well both the first and repeated RTM therapy cycles. CONCLUSION: According to the results of the long-term follow-up, RTM therapy is a highly effective treatment option for SLE patients in whom the previous standard therapy with GCS and cytostatics was previously ineffective. The 3.5-year follow-up showed a good tolerability of RTM and revealed no increase in the risk of infectious complications or adverse reactions.

[Advances and prospects in the treatment of systemic lupus erythematosus].

AIM: To reveal the priorities of Russian rheumatology to develop treatment options for systemic lupus erythematosus (SLE). MATERIALS AND METHODS: The data available in the Russian and foreign literature, the archives and publications by the researchers of the Institute of Rheumatology on systemic lupus erythematosus in 1958 to 2008 were analyzed. RESULTS: Analyzing the literature references has ascertained that the researchers of the Institute of Rheumatology, Russian Academy of Medical Sciences, have initiated studies to develop therapy methods for SLE since 1958. Diagnostic criteria for and SLE course type definitions and classification have been first developed in Russian and foreign medicine; the principles of optimal glucocorticoid, cytostatic therapy, and follow-up of patients with SLE have been proposed on the basis of a long-term observation. In Russian medicine, the Institute's researchers have first developed an algorithm of therapy for lupus nephritis, by using plasmapheresis, pulse therapy with methylprednisolone and cyclophosphan, and suppressing and maintaining doses of glucocorticoids. The practical application of the SLE treatment methods developed at the Institute have reduced mortality and increased 10-year survival in patients with SLE up to 90%. The Institute of Rheumatology has first provided data on the efficiency of anti-B-cell therapy for SLE in Russian rheumatology. CONCLUSION: Prognosis in patients with SLE has substantially changed in the past 50 years. The Russian rheumatologists have studied the clinical manifestations of the disease in detail; its diagnosis has improved; the specific features of SLE have been revealed; the treatment methods adequate to the clinical manifestations of the disease have been developed. Multicomponent therapy for SLE, monitoring, and follow-ups have solved the problem of curing SLE.

[Synchronous programmed intensive therapy of patients with severe rheumatoid arthritis]. / Sinkhronnaia programmnaia intensivnaia terapiia bol'nylh revmatoidnym artritom tiazhelogo techeniia.

AIM: To evaluate efficiency and safety of intensive treatment program (synchroneous plasmapheresis, large-dose methotrexate and methypred) for patients with severe rheumatoid arthritis (RA). MATERIAL AND METHODS: 45 patients with highly active and progressive RA, systemic symptoms, corticosteroid dependence who had intolerance to standard therapy or had not responded to it were divided into 2 comparable groups. 25 patients of group 1 for a month got 6 plasmapheresis procedures with synchroneous intravenous injection of 40 mg of methotrexate and 250 mg of methypred. 20 patients of group 2 received pulse therapy with methypred (3 g) and methotrexate (200 mg). The intensive therapy was followed in all the patients with methotrexate in a dose 10-20 mg/week. RESULTS: One, six and twelve months after treatment patients of group 1 demonstrated a decrease in RA clinical activity and inflammation. In a year remission by ACR criteria was achieved in one-third of the patients. CONCLUSION: The sychroneous program of intensive therapy is highly effective in RA patients with vasculitis, ineffective standard therapy and corticosteroid dependence.

[Treatment with megadoses of dexaven (dexamethasone) versus methypred (6-methylprednisolone) of patients with rheumatoid arthritis]. / Sravnitel'noe izuchenie éffektivnosti sverkhvysokikh doz deksavena (deksametazona) i metipreda (6-metilprednizolona) u bol'nykh revmatoidnym artritom.

AIM: To compare clinical effectiveness and tolerance of methylprednisolone (methypred) and dexamethasone (dexaven) in patients with rheumatoid arthritis (RA), to estimate side effects and complications rate. MATERIALS AND METHODS: The trial included 31 patients with seropositive RA (27 females, 4 males) stage II and III. Dexaven pulse-therapy was given to 16 patients in a dose 2 mg/kg for 3 days, 15 patients received methypred in a classic dose 1000 mg for 3 days. Clinical response was assessed on day 1, 7 and 30 after the treatment. RESULTS: Both drugs significantly reduced severity of arthralgia, morning joint stiffness, number of inflamed joints, the disease activity diminished 2-3-fold. Side effects were minimal. CONCLUSION: Dexaven (dexamethasone) is a drug of choice in pulse-therapy of RA. It is not inferior to routine treatment with methylprednisolone (methypred).

[Synchronous intensive treatment for patients with systemic lupus erythematosus having poor life prognosis]. / Sinkhronnaia intensivnaia terapiia u bol'nykh sistemnoi krasnoi volchankoi s neblagopriiatnym zhiznennym prognozom.

Synchronous intensive treatment (SIT) involving two-stage programmed use of pulse therapy (PT), plasmapharesis (P) or hemosorption with methylprednisolone and cyclophosphamide was performed in 56 patients with systemic lupus erythematosus (SLE). All the patients were found to have a combination of factors showing a poor life prognosis: the onset of SLE in adolescence or youth (52%), nephritis (70%), arterial hypertension (54%), cerebropathy (50%), generalized vasculitis (34%), cryoglobulinemia (66%). After a year therapy, remission and the minimum progression were observed in 19.6 and 53.6%, respectively. The highest effect of SIT was found in the patients with SLE of duration of under a year and with the highest progression. A long-term follow-up that lasted 78 +/- 24 months revealed persistent improvement, the minimum activity and remission in 71% of patients. The synchronous programmed use of P and PT produces a rapid and effective impact on clinical and laboratory manifestations and improves life prognosis in patients with SLE.

[The combined intensive therapy of rheumatoid arthritis with systemic manifestations]. / Kombinirovannaia intensivnaia terapiia revmatoidnogo artrita s sistemnymi proiavleniiami.

The efficacy of pulse therapy in combination with hemosorption or plasmapheresis, pulse therapy without extracorporeal treatment and methotrexate has been compared for 40 patients with rheumatoid arthritis (RA) with extra-articular manifestations. All kinds of intensive treatment were effective. Extracorporeal methods and pulse therapy relieved extra-articular symptoms. Isolated pulse therapy alleviated articular syndrome. The best results were obtained in double filtration of plasma in combination with pulse therapy. Such approach ensured improvement both articular and extra-articular inflammation. Combined intensive therapy proved an effective modality in RA able to produce responses in severe disease.

[Splenic perfusion in the combined treatment of patients with systemic lupus erythematosus]. / Splenoperfuziia v kompleksnom lechenii bol'nykh sistemnoi krasnoi volchankoi.

Twenty patients suffering from severe systemic lupus erythematosus (SLE) underwent 52 sessions of splenoperfusion (SP) by means of extracorporeal perfusion of the patient's blood through isolated porcine spleen. It got prepared directly before the perfusion. The organ was obtained from a healthy animal in sterile conditions, washed from the blood after cannulation of the artery and vein. The patient's blood was pumped from the peripheral vein to the spleen artery. After passing through the splenic vascular bed the blood outflew from the spleen vein into the opposite peripheral vein of the patient. SP was followed by positive clinical changes: normalization of body temperature, regression of skin symptoms and articular syndrome, reduction of lymphadenopathy, hepato- and splenomegaly. The tests indicated inhibition of SLE activity. Sp-related immunocorrective effect was also present as shown by depression of B-cell hyperreactivity and T-cell immunity stimulation. 1-4-year follow-up of 19 patients showed them to be in remission. The data obtained favour SP inclusion into intensive therapy of severe SLE.

[A comparative evaluation of combined immunocorrective therapy in rheumatoid arthritis with systemic manifestations (joint Soviet-Polish research)]. / Sravnitel'naia otsenka kompleksnoi immunokorrigiruiushchei terapii revmatoidnogo artrita s sistemnymi proiavleniiami (sovmestnoe sovetsko-pol'skoe issledovanie).

Thirty-two patients with rheumatoid arthritis were included in the trial. Each of them was assigned to one of the 4 groups comparable by the main features. Each group entered 8 patients. Group 1 patients underwent hemosorption weekly for 3 weeks. After the second procedure cyclophosphamide was added at a single IV dose 1000 mg. After the third procedure the treatment was continued with methotrexate (7.5 mg, weekly). Group 2 began the treatment with methotrexate (7.5 mg, weekly). Group 3 received cyclophosphamide 200 mg IV twice a week 6 times and then 200 mg weekly orally till a total dose of 2 g. Group 4 received azathioprine in a daily dose 100 mg. The treatment with nonsteroidal antirheumatic drugs and corticosteroids was continued unchanged. After 6 months we did not see significant differences between the 4 groups.

[The prediction of thrombosis development in patients with systemic lupus erythematosus: the role of antibodies to cardiolipin]. / Prognozirovanie razvitiia tromboza u bol'nykh sistemnoi krasnoi volchankoi: rol' antitel k kardiolipinu.

In patients with systemic lupus erythematosus (SLE), the synthesis of antibodies to cardiolipin (A-CL) is associated with the development of venous and arterial thromboses localized in minor and middle-sized vessels, in the venous system and capillaries. The determination of various A-CL isotypes may be used to predict thromboses in SLE patients. Overall 210 patients (185 women and 25 men) with a verified diagnosis of SLE were examined. The patients were not screened in accordance with some or other clinical signs of the antiphospholipid syndrome. The control group comprised 100 healthy subjects (donors). The IgG, IgA and IgM isotypes of A-CL were determined by ELISA. Sera of SLE patients showed an increase of the concentration of A-CL of both certain isotypes and their potential combinations. Among A-CL-positive patients, the IgG isotype of A-CL was detected in 75% of cases, the IgM isotype of A-CL in 61%, and the IgA isotype of A-CL in 36% of cases. Thrombotic complications were recorded in 19% of patients. They were induced by hyperproduction of the three combinations of the A-CL isotypes: A-CL IgM, IgM+IgA, and IgG+IgA+IgM. Patients whose sera contained A-CL of all three types at a time were most prone to thrombotic complications. It has turned out that the percentage of SLE patients with thromboses was higher than that of SLE patients without thromboses, starting from the definite A-CL concentration (21 GPL).(ABSTRACT TRUNCATED AT 250 WORDS)

[Pulse therapy with methylprednisolone and cyclophosphamide in systemic juvenile rheumatoid arthritis: the results of an open, parallel, controlled, randomized, 12-month study]. / Pul's-terapiia metilprednizolonom i tsiklofosfamidom pri sistemnom iuvenil'nom revmatoidnom arterite: rezul'taty otkrytogo parallel'nogo kontroliruemogo randomizirovannogo 12-mesiachnogo issledovaniia.

The treatment for systemic JRA is among actual problems of pediatric rheumatology. To evaluate the effectiveness of pulse therapy (PT) with methylprednisolone 25-30 mg/kg/day for 3 consecutive days combined with cyclophosphamide 0.4-0.5 g/sq. m body surface area (BSA) on the 3rd day, repeated quarterly for 12 months, 30 patients with systemic JRA were randomized into 3 groups: 1--those with disease duration (DD) less than 2 years receiving PT (n = 13), 2--with DD 2 years and more (n = 8) receiving PT, and 3--with DD less than 2 years receiving no PT. Children in all 3 groups received concomitant medication (one of nonsteroidal anti-inflammatory drugs, methotrexate 10 mg/sq. m BSA/week and oral steroids). A rapid and significant improvement, according to systemic and articular manifestations as well as laboratory indices occurred in the 1st group, in most of the measured parameters exceeded effects in the other two groups and gave the opportunity to avoid the administration of oral steroids or to give the lesser initial dose. Side effects were minor and completely reversible.

[Clinico-immunological characteristics of patients with systemic lupus erythematosus and cryoglobulinemia]. / Kliniko-immunologicheskie osobennosti bol'nykh sistemnoi krasnoi volchsnkoi s krioglobulinemiei.

Sixty patients with systemic lupus erythematosus (SLE) were examined: 40 patients with cryoglobulinemia and 20 patients without it. Cryoglobulinemia was observed in patients with SLE, as a rule, in the acute course of the disease ending in renal affection. Cryoglobulinemia in SLE was accompanied by the phenomenon of generalized vasculitis in the form of skin and mucosa lesions with ulcero-necrotic changes and affections of the central and peripheral nervous system and the kidneys. The clinical picture of SLE accompanied by cryoglobulinemia was characterized by a polysyndrome phenomenon and infrequent presence of the ARA criteria. Cryoglobulinemia was accompanied by high titres of anti-DNA. Thus, cryoglobulinemia can be regarded as one of the important factors of immunocomplex damage in SLE.

[Cryoglobulinemia and fibronectin in systemic lupus erythematosus]. / Krioglobulinemiia i fibronektin pri sistemnoi krasnoi volchanke.

EIA was used to measure the concentration of fibronectin in plasma and cryoprecipitates of 37 patients suffering from systemic lupus erythematosus coupled with cryoglobulinemia. A definite relationship was discovered between the level of cryoglobulins and the activity of SLE, the concentration of fibronectin in plasma and liver damage. A tendency was revealed towards increase of the fibronectin content in plasma of patients with a high level of antibodies to native DNA and CIC as was a significant correlation between the concentration of cryoglobulin protein and the concentration of fibronectin in cryoprecipitates.

[Disturbance of immunogenesis in patients with systemic lupus erythematosus]. / Narushenie immunogeneza u bol'nykh sistemnoi krasnoi volchankoi.

Using a modified model, 16 patients with systemic lupus erythematosus were examined for the activity of nonspecific Con A-induced suppressors with the aid of different test systems. The suppressors of both patients and donors were employed. The proliferation of the test culture lymphocytes appeared to be activated. The immunogenetic abnormalities indicated seem likely to be related to extreme activity of the countersuppressor cells blocking the function of the suppressors, correlating with the clinical picture of the disease.

[Circulating immune complexes and clinico-immunologic subtypes of systemic lupus erythematosus. II]. / Tsirkuliriushchie immunnye kompleksy i kliniko-immunologicheskie podtipy sistemnoi krasnoi volchanki (soobshchenie II).

Characterization of clinicoimmunological subtypes of systemic lupus erythematosus was based on a detailed serological investigation of 90 SLE patients. Association between excessive formation of circulating immune complexes and the development of some clinical and serological manifestations of systemic lupus erythematosus including active lupus nephritis without the nephrotic syndrome, systemic vasculitis and Sjogren's syndrome was established.