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Objectives: To evaluate the effective and the safety of pulse methylprednisolone (MP) in severe systemic lupus erythematosus (SLE) flares. Subjects and methods: An interventive and comparative study was carried out on 80 patients with SLE flares.
JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 INTRAVENOUS PULSE METHYLPREDNISOLONE IN SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS Huynh Van Khoa*; Le Anh Thu*; Le Thu Ha** SUMMARY Objectives: To evaluate the effective and the safety of pulse methylprednisolone (MP) in severe systemic lupus erythematosus (SLE) flares Subjects and methods: An interventive and comparative study was carried out on 80 patients with SLE flares Results: We followed 80 patients with severe lupus flare who were treated with pulse MP in 12 weeks The patients were assessed before the treatment (T0), week after the treatment (T1), weeks after the treatment (T2) and 12 weeks after the treatment (T3) The anti-dsDNA titer significantly decreased after the treatment (163.91 ± 92.67 at T0, 82.90 ± 75.61 at T1, 54.22 ± 50.66 at T2 and 35.88 ± 27.68 at T3 The SLEDAI score also significantly improved with the mean decrease (23.33 at T0, 14.03 at T1, 8.63 at T2 and 6.85 at T3) The rate of patients with SLEDAI above 20 decreased after the treatment (65% at T0, 11.3% at T1, 1.3% at T2, and 0% at T3) As for 47 patients with nephrotic syndrome, at T1, no patients had complete response rate, partial response were seen in 31.9% and no response 68.1%, at T2, 6.4%; 51.1% and 42.6%, respectively, at T3, 19.1%; 70.2% and 10.6%, respectively The infection was seen in 12.5% of those patients, mostly in the first week after the pulse MP Conclusion: Pulse MP seemed to be effective in the SLE patients on severe flares The most common adverse effect of this therapy is the infection, especially in the first week after the pulse * Keywords: Severe systemic lupus erythematosus; Nephrotic syndrome; Pulse therapy INTRODUCTION Lupus is a systemic autoimmune disease that occurs when your body's immune system attacks tissues and organs Inflammation caused by lupus can affect many different body systems, including joints, skin, kidneys, blood cells, brain, heart and lungs Lupus can be difficult to diagnose because its signs and symptoms often mimic those of other ailments The most distinctive sign of lupus, a facial rash that resembles the wings of a butterfly unfolding across both cheeks occurs in many but not all cases of lupus Severe organ damage is one of the most common causes of mortality in systemic lupus erythematosus, directly or indirectly [10] Intravenous high dose of methylprednisolone (pulse therapy) given as monotherapy or in combination with other immunosuppressive agents has been used in life threatening flares of SLE, and has been shown to be effective by many trials [1, 2, 8, 9] This study aimed to: Evaluate the effectiveness and the safety of pulse MP therapy in patients with severe flares of SLE * Choray Hospital ** Central Military Hospital 108 Corresponding author: Huynh Van Khoa (khoa_hv@yahoo.com) Date received: 30/09/2017 Date accepted: 22/11/2017 177 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 SUBJECTS AND METHODS Subjects This study was carried out at Rheumatology Department, Choray Hospital from May 2011 to December 2015 We enrolled 80 patients having SLE according to American College of Rheumatology criteria in 1997 with severe flare (SLEDAI ≥ 12 and at least severe organ damage) [6] They were given pulse methylprednisolone (pulse MP) gram per day in consecutive days, and were periodically assessed the clinical, laboratory test and SLEDAI indexes before treatment (T0), week (T1), weeks (T2) and 12 weeks (T3) after the pulse MP to evaluate the treatment effectiveness - Severe organ damages were defined as lupus nephritis with nephrotic syndrome, severe hemolytic anemia, alveolar hemorrhage and myocarditis - The effective outcomes were the improvement of anti-dsDNA titer and SLEDAI - As for the treatment of nephrotic syndrome, based on KDIGO 2012 (Kidney Disease Improving Global Outcomes) criteria [7], the response was defined as: + Complete response: Proteinuria is lower than 0.5 g per day, albuminemia at least g/dL; GFR > 60 mL/min or GFR increase more than 50% after the treatment, no urinary blood and cast + Partial response: Proteinuria decreases more than 50% after treatment, albuminemia < g/dL and GFR improvement > 50% after treatment + No response: Proteinuria > g per day, proteinuria decrease < 50% after treatment and GFR decrease < 20% after treatment Methods Interventive trial with compare pre- and post-treatment RESULTS AND DISCUSSION Treatment response: anti-dsDNA outcome Table 1: Change of anti-dsDNA AntidsDNA titer ≥ 50 UI/mL Mean After treatment p value Before treatment T1 T2 T3 (n = 80), n % (n = 80), n % (n = 80), n % (n = 79), n % 63 (78.8) 43 (53.8) 31 (38.8) 23 (29.1) p0-1 163.91 ± 92.67 82.90 ± 75.61 54.22 ± 50.06 35.88 ± 27.68 p0-2 p0-3 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 Positive anti-dsDNA test rate and mean anti-dsDNA titer decreased week, week and 12 weeks after treatment The frequency of patients with positive anti-dsDNA (≥ 50 IU/mL) reduces post-treatment in comparison with pre-treatment, and trends to decrease with time The same observation was seen with anti-dsDNA level Anti-dsDNA level was shown to correlate with disease activity in SLE, and was a tool in monitoring 178 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 the treatment effect in other previous studies [3] Some authors proved that anti-dsDNA could not only used in disease activity assessment but also in monitoring the treatment response and has a tight correlation with SLEDAI Anti-dsDNA titer decreased week, weeks and 12 weeks after pulse MP Anti-dsDNA titer decrease reflected the response of the patients to the treatment Response rate: SLEDAI outcome Table 2: SLEDAI change pre- and post-treatment Post-treatment p value Pre-treatment week weeks 12 weeks (n = 80) n% (n = 80) n% (n = 80) n% (n = 79) n% 12 - 19 28 (35.0) 71 (88.8) 79 (98.8) 79 (100) ≥ 20 52 (65.0) (11.3) (1.3) Mean 23.33 ± 8.04 14.03 ± 6.43 8.63 ± 4.58 6.85 ± 3.83 12 - 49 - 42 - 29 - 18 SLEDAI (Min-max) p0-1 p0-2 p0-3 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 High and very high disease activity rates decreased week, weeks and 12 weeks after treatment The mean of SLEDAI decrease with time: 23.33 ± 8.04 pretreatment, 14.03 ± 6.43 one week, 6.63 ± 4.58 four weeks and 6.85 ± 3.83 twelve weeks after treatment In table showed that the mean SLEDAI before treatment was 23.33 (SLEDAI ≥ 20 occupied 65% of the total population), and the SLEDAI significantly decrease week, weeks and 12 weeks after pulse MP In detail, the mean SLEDAI after weeks was 8.63 (1.3% of patients having SLEDAI ≥ 20), and weeks 6.85 (no patient with SELDAI ≥ 20) In a trial on lupus nephritic patients, Pham Huy Thong proved that pulse MP had favorable effects on SLEDAI outcome after month and months of follow-up [2] According to Basda's study, the effect of pulse MP at different doses showed a significant reduction in SLEDAI after months of follow-up [4] Our study showed that the pulse MP had a rapid effectiveness, only after week, and the effectiveness was the highest at weeks after treatment Nephrotic syndrome group Of 80 patients treated with pulse MP, there were 47 ones fulfilled nephrotic syndrome criteria Table 3: Response classification of patients having nephrotic syndrome (n = 47) Response After week, n (%) weeks, n (%) 12 weeks, n (%) (6.4) (19.1) Partial 15 (31.9) 24 (51.1) 33 (70.2) No response 32 (68.1) 20 (42.6) (10.6) Complete p < 0.001 179 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 After week, there was no patient with complete response, 31.9% of them achieved partial response and 68.1% no response These rates at weeks were respectively 6.4%; 51.1% and 42.6%; after 12 weeks 19.1%; 70.2% and 10.6%, respectively Pham Huy Thong’s study showed that after month of treatment, 14.28% of the patients achieved complete response, 50% partial response and 35.72% non-response; after months, 32.14% had complete response, 35.71% partial response and 32.1% non-response [2] The complete response rate after months of treatment in our study was lower than in Pham Huy Thong’s study, but the partial response was higher and non-response in our study was lower than in his This discrepancy could be explained by the differences of population Pham Huy Thong’s study characteristics between studies We included only those with nephrotic syndrome, while Pham Huy Thong’s study enrolled all patients with prolonged renal insufficiency more than months, and proteinuria more than g per day in more than months [2] After 12 weeks of follow-up, we concluded that the response rate of SLE patients with nephrotic syndrome was 89.3% (of which complete response 19.1% and partial response 70.2%) According to Kimberly’s study, pulse MP was considered to be effective in improving renal function in 12/34 (35.29%) of patients after months [9] So, pulse MP has a good response rate in the renal injury patients with nephrotic syndrome 180 Adverse events of pulse MP (n = 80) Table 4: Adverse events of pulse MP (n = 80) Adverse events Severe infection week n (%) weeks 12 weeks 10 (12.5%) Pneumonia tuberculosis (lung) urinary tract infection Epigastric pain 1 (2.5%) Hyperglycemia (1.3%) Disorders of electrolytes Hypertension Cushing syndrome (2.5%) (7.5%) (1.3%) 12 (15%) The most important adverse events after pulse MP: infection 12.5%, epigastric pain 2.5%, hypertension 2.5% Cushing syndrome was seen in 15% of patients after treatment Among the adverse events observed in 12 weeks of follow-up, infection was the most remarkable Our study showed 10 severely infected patients (12.5%), especially in the first week after treatment Pneumonia was quite common, among those with pneumonia, there was one with severe pneumonia who was fatally ill and was discharged as the family’s will The other manifestation less frequent were epigastric pain (2.5%), hypertension (2.5%) Cushing syndrome was common with 15% of patients after 12 weeks, though this could be due to the prolonged corticosteroid rather than to the pulse MP In Pham Huy Thong’s study, infection was the most common adverse events at the rate of 16.6% [2] This was also seen in other studies on pulse MP Boumpas studying pulse MP in 25 SLE patients showed that cases infected with Herpes JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 zoster, cases of osteonecrosis, cases of cataract [5] Zonana’s study on adverse effects of corticosteroid in lupus showed that the accumulative dose of corticosteroid had a relationship with the increased osteoporotive fracture, stroke, cataract, avascular osteonecrosis, and mellitus diabetes risk Pulse MP caused only a slight increase in osteoporotic fracture risk, but not statistically significant CONCLUSION Our study showed that pulse MP therapy was effective in SLE flare by significantly lowering the anti ds-DNA titer and SLEDAI score In the nephrotic syndrome group, we noticed that after week, there was no patient achieving complete response, 31.9% partial response and 68.1% no response; after weeks, the complete response rate was 6.4%, partial response 51.1% and non-response 42.6%; after 12 weeks, 19.1% had complete response, 70.2% partial response and 10.6% nonresponse Infection occurred in 12.5% of patients on pulse MP, especially in the first week after the treatment REFERENCES Đoàn Văn Đệ Kết bước đầu phương pháp điều trị lupus ban đỏ hệ thống methyl prednisolon liều cao (pulse therapy) Y học thực hành 1996, (318), tr.2-3 Phạm Huy Thơng, Phan Quang Đồn Nghiên cứu hiệu điều trị lupus ban đỏ hệ thống có đợt cấp tổn thương thận methylprednisolon đường tĩnh mạch liều cao Y học thực hành 2012, (813), tr.83-85 Alba P, Bento L, Cuadrado M.J, Karim Y, Tungekar M.F et al Anti-dsDNA, anti-Sm antibodies, and the lupus anticoagulant: significant factors associated with lupus nephritis Annals of the Rheumatic Diseases 2003, 62 (6), pp.556-560 Badsha Humeira, Edwards Christopher J Intravenous pulses of methylprednisolone for systemic lupus erythematosus Seminars in Arthritis and Rheumatism Elsevier 2003 Boumpas Dimitrios T, Austin H.A, Balow J.E, Vaughan E.M, Yarboro C.H et al Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis The Lancet 1992, 340 (8822), pp.741-745 Criteria American College of Rheumatology Ad Hoc Committee on systemic lupus erythematosis response The American College of Rheumatology response criteria for systemic lupus erythematosus clinical trials: measures of overall disease activity Arthritis and Rheumatism 2004, 50 (11), p.3418 Eckardt Kai-Uwe, Kasiske Bertram L KDIGO clinical practice guideline for glomerulonephritis foreword Nature Publishing th Group 75 Varick ST, FLR, New York, NY 10013-1917 USA 2012 Isenberg D.A, Morrow W.J, Snaith M.L Methyl prednisolone pulse therapy in the treatment of systemic lupus erythematosus Annals of the Rheumatic Diseases 1982, 41 (4), pp.347-351 Kimberly Robert P, Lockshin Michael D, Sherman Raymond L, McDougal J Steven, Inman Robert D et al High-dose intravenous methylprednisolone pulse therapy in systemic lupus erythematosus The American Journal of Medicine 1981, 70 (4), pp.817-824 10 Narayanan K, Marwaha V, Shanmuganandan K, Shankar S Correlation between systemic lupus erythematosus disease activity index, C3, C4 and anti-dsDNA antibodies Medical Journal Armed Forces India 2010, 66 (2), pp.102-107 181 ... Raymond L, McDougal J Steven, Inman Robert D et al High-dose intravenous methylprednisolone pulse therapy in systemic lupus erythematosus The American Journal of Medicine 1981, 70 (4), pp.817-824... According to Kimberly’s study, pulse MP was considered to be effective in improving renal function in 12/34 (35.29%) of patients after months [9] So, pulse MP has a good response rate in the... after pulse MP: infection 12.5%, epigastric pain 2.5%, hypertension 2.5% Cushing syndrome was seen in 15% of patients after treatment Among the adverse events observed in 12 weeks of follow-up, infection