Sjögren’s syndrome, also known as “Mikulicz’s disease” and “Sicca syndrome,” is a diffuse connective tissue disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva [
There are currently no known curative treatments for Sjögren’s syndrome. Management is symptomatic and the most common treatments are prednisone, immunosuppressant, and symptomatic support, with the aim of relieving clinical symptoms and preventing organs being damaged by disease progression. Moisture replacement therapies such as artificial tears can relieve the symptoms (dry eyes) and corticosteroids or immunosuppressive drugs may be prescribed to control severe complications [
There is no record of Sjögren’s syndrome as such in the classical literature of traditional Chinese medicine (TCM), but knowledge of its clinical manifestations and symptomatic treatment can be traced back over 2000 years. Modern TCM researchers have conducted clinical trials on Sjögren’s syndrome. A systematic review of these trials from 1997 to 2010 analyzed and evaluated randomized controlled trials of the Chinese herbal medicine (CHM) of treatment of Sjögren’s syndrome [
RCTs of CHM treating PSS were included, with no limitations on language or publication format. Trials were eligible when the study participants were patients with PSS, and there were no limitations on the participant’s age, gender, and nationality. Interventions included any form of CHM (including prescribed formulae, patent medicines, herbal decoctions, herbal extracts and herbal injections) based on syndrome differentiation, and treatment, used as a sole treatment or in conjunction with conventional therapies. Control treatments included standard conventional treatment, placebo, and waiting list controls. Outcomes included total effectiveness rate (response rate), lacrimal function, salivary gland function, quality of life, and adverse events.
Trials were excluded if any of the following were identified: (1) The study population included patients with secondary Sjögren’s syndrome, since this could not be differentiated from PSS; (2) if they involved the treatment of complications of PSS such as severe hepatic, renal damage or hematological damage; (3) if information about the participants or intervention was not clearly reported; (4) if controlled treatment included any use of CHMs as, in this case, it would be impossible to evaluate the specific effects of the intervention.
Both Chinese databases and English databases were searched, including China Knowledge Resource Integrated Database (CNKI), the Database for Chinese Technical Periodicals (VIP), Chinese Biomedical Database (CBM), Wanfang Data, PubMed, and the Cochrane Library (2012, Issue 2).
In the Chinese databases, we employed Sjögren’s syndrome and random* as the main search terms without limitation on the modalities CHM employed. We searched PubMed by using the MeSH term Sjögren’s syndrome with the following restrictions: humans as study participants, RCTs, or meta-analysis. When searching the Cochrane Library, we used Sjögren’s syndrome as the key search word. We searched all articles on treatment for PSS published before February 10, 2012. The search strategy for the databases was provided in Table
We employed the trial selection methods described in the Cochrane Handbook for Systematic Reviews of Interventions, version (1) import the search results from different databases into the reference management software NoteExpress2 (2.6 version); (2) exclude irrelevant articles by reading titles and abstracts; (3) obtain the full papers for all possibly relevant trials; (4) exclude articles with duplicate publication; (5) contact the authors when the data was not available; (6) recheck identified articles according to the above steps; (7) include the final trials for the review [
Data from the included trials were extracted by two authors independently. Any discrepancies were resolved by referral to the original article and, if necessary, a third author was consulted. The following data were extracted from included trials: methodological components, participant characteristics, interventions and controlled treatments, and outcome measures.
The Cochrane Collaboration’s tool for assessing the risk of bias was used to evaluate the methodological quality of included trials [
Dichotomous data (response rate) was presented as risk ratio (RR) and continuous data outcomes (including lacrimal function, salivary gland function, and quality of life) as mean difference (MD), both with 95% confidence intervals (CI). RevMan 5.0.17 was employed to conduct data synthesis. Homogeneity of risk ratio or mean difference in trials with unequal sample sizes within one type of comparisons was analyzed using I2 and Z values, and statistical models were chosen based on significance of heterogeneity.
A total of 559 articles were found from the initial searches. After reading titles and abstracts, 60 full-text papers were retrieved and further 8 studies were excluded for the following reasons: 2 trials were excluded for involving patients with haematological complications [
Flow-chart of study selection. PRISMA (preferred reporting items for systematic reviews and meta-analyses) flow-chart of study selection.
All the included trials were conducted in China, with a total number of 3,829 PSS patients, 12.9% of them were male (
CHM therapy followed traditional treatment principles to nourish yin, moisten dryness and generate body fluids, replenish qi and blood, tonify the “lungs” and “spleen,” strengthen the “spleen” to remove dampness, activate blood to remove stasis, and clear fire poison. CHM treatment principles also included dispersing and reinforcing methods to treat diseases caused by excess and deficiency patterns. This reflects the features of a very mixed syndrome presentations in PSS patients. The herbal medicines included multicomponent decoctions, patent medicines (pills and tablets), concentrated herbal granules, and herbal injections. Twenty trials tested patent medicines and fixed formula granules, while 32 trials tested individualized herbal decoctions, permitting modified formulae according to individual participant’s TCM syndrome. Conventional treatments included (1) symptomatic management, such as artificial tears, oculenta, artificial saliva, bromhexine, ambroxol hydrochloride, and parasympathomimetic alkaloid; (2) corticosteroids, such as prednisone; (3) immunosuppressive drugs, such as methotrexate, hydroxychloroquine, and cyclophosphamide; (4) other treatment, such as thymosin, vitamins, antibiotics, transfer factor, and nonsteroidal anti-inflammatory drugs.
All the included trials were classified into four comparisons according to the interventions: (1) CHM versus placebo (
48 different CHMs were tested in 52 trials. Two patent medicines and one herbal injection, Jinju Qingrun capsule [
Outcome measurements included response rate (total effectiveness rate), salivary gland function, lacrimal function, laboratory findings, TCM syndrome evaluation scores, and adverse events.
The response rate was a composite outcome index used throughout these trials, integrating factors from symptoms, signs, and laboratory findings [
Salivary gland function was tested by collecting saliva and determining the amount produced in a five-minute period, or by sugar-melt test. Lacrimal function was evaluated by Schirmer test to measure the production of tears. Laboratory findings of included trials included erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), antinuclear antibody (ANA), anti-Sjögren’s syndrome A antibody (anti-SSA), anti-Sjögren’s syndrome B antibody (anti-SSB), and IgA, IgG, and IgM. No trial employed quality of life to evaluate clinical outcome. Adverse events were reported in 36 trials.
Information on participants, interventions, comparators, and outcomes reported in each trial was presented in Table
Characteristics of included randomized controlled trials.
Study ID | Diagnostic criteria | Sample size | Mean age (years) | Gender (male/female) | Intervention | Control | Duration (months) | Followup | Outcome measures |
---|---|---|---|---|---|---|---|---|---|
Zhang 2011 [ |
2002 international |
59 | 38.0 | 3/54 | Jinju Qingrun capsule | Hydroxychloroquine sulfate | 3 | No | Response rate, amount of tear secretion, salivary flow rate, improvement of symptoms and signs, ESR, IgG, IgA, IgM, |
| |||||||||
Zheng 2010 [ |
2002 international |
60 | 38.0 | Female | Runzao formula and control intervention | Prednisone, methotrexate, and symptomatic support | 3 | No | Response rate, amount of tear secretion, salivary flow rate, GB, CRP, RF, and adverse effect |
| |||||||||
Yin 2010 [ |
2002 international |
40 | 49.0 | Female | Yangyin Qingre Jiedu decoction | Prednisone | 1 | No | Response rate, symptom score, Amount of tear secretion, WBC, RF, ESR, and adverse effect |
| |||||||||
Liu 2010 [ |
2002 international |
132 | 41.0 | 57/75 | Yuquan pill, Shengmai injection, and control intervention | Muscarinic receptor agonist, prednisone, |
1 | No | Response rate and adverse effect |
| |||||||||
Li 2010 [ |
Self-made criteria | 240 | 41.0 | 86/154 | Qingre Quyu decoction and control intervention | Symptomatic support | 6 | No | Response rate |
| |||||||||
Huang 2010 [ |
2002 international |
61 | 59.1 | 7/54 | Shenmai injection and control intervention | Anethol trithione tablets | 0.5 | No | Response rate, amount of tear secretion, salivary flow rate, and adverse effect |
| |||||||||
Hu 2010 [ |
2002 international |
64 | 46.2 | Female | Ziyin Yangxue Qingre formula and control intervention | Hydroxychloroquine sulfate tablets | 3 | No | Response rate, symptom score, amount of tear secretion, salivary flow rate, sugar-melt test, CRP, ESR, IgG, IgA, IgM, and adverse effect |
| |||||||||
Xuan 2010 [ |
2002 international |
60 | 53.0 | 21/39 | Shenglu Runzao decoction | Hydroxychloroquine sulfate tablets | 12 | No | Response rate, symptom score, RF, ESR, SS-A, and SS-B |
| |||||||||
He 2010 [ |
1992 Europe |
48 | 35.0 | Female | Total Glucosides of Paeony and Hydroxychloroquine sulfate tablets | Hydroxychloroquine sulfate tablets | 3 | No | Response rate, ESR, IgA, IgM, |
| |||||||||
Xie 2010 [ |
Dong 1996 [ |
60 | 55.2/52.6 | 11/49 | Yin-nourishing decoction | Prednisone, cyclophosphamide | 1 | No | Response rate, symptom score |
| |||||||||
Li 2010 [ |
2002 international |
40 | 54.1/48.6 | 1/39 | Yushu-Dihuang decoction | Hydroxychloroquine sulfate tablets | 2 | No | Response rate, symptom score, self-made quality of life, and adverse effect |
| |||||||||
Yu 2010 [ |
2002 international |
61 | 52.1/55.4 | 5/56 | Zi Zao Yin | Placebo | 3 | No | Response rate, symptom score, salivary flow rate, liver-kidney function, ESR, CRP, ANA, SSA, SSB, and IgG |
| |||||||||
Zhang 2009 [ |
2002 international |
100 | 40.6 | 6/89 | Jinju Qingrun capsule, placebo of prednisone and symptomatic support | Prednisone, placebo of Jinju Qingrun capsule and symptomatic support | 3 | No | Response rate, symptom score, amount of tear secretion, salivary flow rate, ESR, IgG, IgA, IgM, |
| |||||||||
Yang 2009 [ |
NA | 168 | 53.7 | 33/135 | Yangyin Shengjin Qingre Tongluo formula and prednisone | Prednisone and cyclophosphamide | 3 to 6 | No | Response rate |
| |||||||||
Wang 2009 [ |
2002 international |
50 | 45 to 78 | 5/45 | Xuefu Zhuyu oral liquid and control intervention | Transfer factor oral liquid | 3 | No | Response rate |
| |||||||||
Wang 2009 [ |
1992 Europe |
60 | 58.0 | 6/54 | Yangyin Jianpi Huoxue decoction, methotrexatum and hydroxychloroquine | Methotrexatum, hydroxychloroquine and brombexine | 3 | No | Scores of symptoms and signs, ESR, and CRP |
| |||||||||
Wan 2009 [ |
Dong 1996 [ |
60 | 28 to 73 | 7/53 | Quzao decoction and control intervention | Brombexine and symptomatic support | 2 | No | Response rate |
| |||||||||
Su 2009 [ |
1992 Europe |
60 | 53.1 | 2/58 | Yangyin Huoxue Shengjin formula and control intervention | Hydroprednisone and methotrexate | 6 | No | Response rate, symptom score, amount of tear secretion, sugar-melt test, ESR, IgG, IgA, IgM, and T lymphocyte subpopulation |
| |||||||||
Mao 2009 [ |
2002 international |
100 | 45 to 75 | 10/90 | Xuefu Zhuyu oral liquid and control intervention | Transfer factor capsule and symptomatic support | 3 | No | Response rate and adverse effect |
| |||||||||
Lu 2009 [ |
2002 international |
58 | 42.6 | 4/54 | Shengjin granules | Hydroxychloroquine | 3 | No | Response rate, symptom score, salivary flow rate, amount of tear secretion, ESR, CRP, TNF- |
| |||||||||
Lian 2009 [ |
2002 international |
40 | 52.1 | Female | Shengjin Runzao granules | Placebo | 1.5 | No | Response rate, improvement of symptoms and signs, ESR, IgG, RF, and adverse effect |
| |||||||||
Huang 2009 [ |
2002 international |
58 | 29 to 68 | 5/53 | Yiqi Yangyin Huoxue formula and control intervention | Anethol trithlone tablets | 1 | No | Response rate and adverse effect |
| |||||||||
Gao 2009 [ |
2002 international |
126 | 30 to 78 | 11/115 | Xuefu Zhuyu oral liquid and control intervention | Transfer factor capsule and symptomatic support | 3 | No | Response rate |
| |||||||||
Liu 2009 [ |
1992 Europe |
60 | 41.33/39.95 | 4/56 | Maiwei Dihuang decoction | Artificial tear, bromohexine hydrochloride | 3 | No | Response rate, symptom score, ESR, ALT, AST, IgG, IgA, IgM, RF, anti-SSA, anti-SSB, SIL-2R, and amount of tear secretion |
| |||||||||
Zhong 2008 [ |
2002 international |
256 | 37.0 | 26/230 | Chaihu Tongluo capsule, placebo of prednisone and methotrexate | Prednisone acetate, methotrexate, and placebo of Chaihu Tongluo capsule | 3 | No | Response rate, salivary flow rate, amount of tear secretion, ESR, CRP, A/G, Tb, IgG, IgA, IgM, and adverse effect |
| |||||||||
Feng 2008 [ |
2002 international |
78 | 47.4 | Female | Total glycosides of paeony and control intervention | Methotrexate | 9 | Yes | Response rate, amount of tear secretion, sugar-melt test, ESR, |
| |||||||||
Lv 2008 [ |
2002 international |
124 | 43.6 | 16/108 | Jinyuan decoction | Brombexine and symptomatic support | 3 | No | Response rate, T lymphocytes (NK cells, CD3, CD4, CD8), IgG, IgA, IgM, and adverse effect |
| |||||||||
Han 2008 [ |
2002 international |
58 | 32.6 | 5/53 | Xuanfei Bujin particle | Brombexine | 3 | No | Response rate, amount of tear secretion, corneal staining test, BUT test, |
| |||||||||
Wu 2007 [ |
Guidelines of China [ |
42 | 55.0 | 8/34 | Maiwei Dihuang decoction and control intervention | Brombexine, thymopeptide and symptomatic support | 2 | No | Response rate and improvement of symptoms |
| |||||||||
Yan 2007 [ |
NA | 56 | Median: 55.2/53.6 | 6/50 | Jiawei Shengmai drink and control intervention | symptomatic support | 4 | No | Response rate |
| |||||||||
Sun 2007 [ |
2002 international |
124 | 44.9 | 16/108 | Qingli Shutong formula and control intervention | Brombexine and symptomatic support | 3 | No | Response rate and salivary flow rate |
| |||||||||
Shen 2007 [ |
NA | 20 | 60 to 70 | Female | Hydrocortisone injection and compound glycyrrhizin injection | Hydrocortisone injection and diammonium glycyrrhizinate injection | 2 to 3 | Yes | Response rate and adverse effect |
| |||||||||
Mao 2007 [ |
1992 Europe |
40 | 53.1 | 4/36 | Yiqi Jianpi decoction | Prednisone | 3 | No | Response rate, symptom score, amount of tear secretion, salivary flow rate, sugar-melt test, ESR, CRP, RF |
| |||||||||
Li 2007 [ |
2002 international |
68 | 47.3 | 7/61 | Compound glycyrrhizin injection and control intervention | Hydroxychloroquine, brombexine, and symptomatic support | 1 | No | Response rate, amount of tear secretion, tear break-up time, salary flow rate, |
| |||||||||
Zhou 2006 [ |
2002 international |
60 | Median: 50/46.25 | 5/55 | Qingzao Jiedu Yangyin Runzao formula | Prednisone and symptomatic support | 3 | No | Response rate, amount of tear secretion, salivary flow rate, sugar-melt test, IgG, and adverse effect |
| |||||||||
Zhou 2006 [ |
2002 international |
45 | 55.0 | 11/34 | Dandi Qiongyu granules and control intervention | Brombexine, anethol trithione, thymopeptide, and symptomatic support | 2 | No | Response rate and symptom score |
| |||||||||
Shen 2006 [ |
Feng 1999 [ |
60 | 52.8 | 4/56 | Runzao oral liquid and control intervention | Bromhexine and symptomatic support | 3 | Yes | Response rate, amount of tear secretion, salivary flow rate, sugar-melt test, rose bengal staining test, foci lymphocyte infiltrates, ESR, RF, |
| |||||||||
Niu 2006 [ |
1992 Europe |
40 | 33.4 | 1/39 | Jianpi Huashi Qingre formula and control intervention | Prednisone and symptomatic support | 1 | No | Response rate, ESR, CRP, IgG, IgA, IgM, and improvement of symptoms and adverse effect |
| |||||||||
Chen 2006 [ |
1992 Europe |
60 | 52.8 | 5/55 | Suangan Shengjin formula | Prednisone | 6 | No | Response rate, RF, and ESR |
| |||||||||
Yang 2005 [ |
Feng 1999 [ |
84 | 41.5 | 3/81 | Yangyin Shengjin formula and acupuncture | Methotrexate | 3 | No | Response rate, amount of tear secretion, salivary flow rate, ESR, CRP, and IgG |
| |||||||||
Si 2005 [ |
TCM diagnosis of SATCM [ |
58 | 22 to 70 | 26/32 | Runzao Tuiyi Mingmu decoction and auricular-plaster therapy | Prednisone and symptomatic support | 1 to 3 | No | Response rate |
| |||||||||
Liu 2005 [ |
2002 international |
60 | Median: 48.5/48 | 5/55 | Qingzao formula | Prednisone | 3 | No | Response rate, improvement of symptoms, amount of tear secretion, salivary flow rate, ESR, CRP, and adverse effect |
| |||||||||
Zhao 2003 [ |
Dong 1996 [ |
60 | Median: 48/44 | 2/58 | Qiju Dihuang decoction | Hydroxychloroquine and symptomatic support | NA | No | Response rate and adverse effect |
| |||||||||
Qian 2003 [ |
NA | 72 | NA | 5/67 | Jinxueyuan granules | Brombexine | 3 | No | Response rate, improvement of symptoms, sugar-melt test, amount of tear secretion, and ESR |
| |||||||||
Li 2003 [ |
Dong 1996 [ |
60 | 35 to 59 | 6/54 | Shengmai injection and control intervention | Symptomatic support | 0.5 | No | Amount of tear secretion, salivary flow rate, and adverse effect |
| |||||||||
Wu 2002 [ |
Dong 1996 [ |
40 | Median: 56 | 4/36 | Ziyin Huoxue formula and control intervention | Thymosin and symptomatic support | 2 | No | Response rate, salivary flow rate and amount of tear secretion |
| |||||||||
Shen 2002 [ |
Feng et al. 1999 [ |
60 | 52.9 | 5/55 | Liuwei Dihuang decoction, Zengye decoction, and symptomatic support | Bromhexine and symptomatic support | 6 | Yes | Response rate, salivary flow rate, amount of tear secretion, sugar-melt test, tear break-up time, rose bengal staining test, lymphocytes Infiltration of a labial gland, RF, ESR, anti-SSA antibody, anti-SSB antibody, antinuclear antibody, and adverse effect |
| |||||||||
Hu 2001 [ |
Manthorpe 1981 [ |
150 | 43.9 | 23/127 | Zengye mixture formula | Brombexine and thymopeptide | 6 | No | Response rate, symptom improvement, amount of tear secretion, sugar-melt test, FL, ESR, ANA, RF, IgG, IgA, and IgM |
| |||||||||
Wang 2000 [ |
1992 Europe |
40 | 50.4 | 5/35 | Runzao mixture formula | hydrochloride salt and symptomatic support | NA | No | Response rate |
| |||||||||
Feng 2000 [ |
Dong1996 [ |
44 | 34 to 65 | 1/43 | Shengjin Runzao granules | Symptomatic support | 1 | No | Salivary flow rate |
| |||||||||
Zhou 1997 [ |
NA | 50 | 52.0 | 12/38 | Qiju Dihuang pill or Huanglian Shangqing pill or Maiwei Dihuang pill or Shihu Yeguang pill, fresh decoction of phragmites, Glycyrrhiza, and acupuncture | parasympathomimetic alkaloid and symptomatic support | NA | No | Response rate |
| |||||||||
Wang 2010 [ |
2002 international | 57 | Unclear | Unclear | Yiqi Yangyin quyu formula and placebo of hydroxychloroquine | Hydroxychloroquine and placebo of yiqi yangyin quyu formula | 6 | No | Sexual hormone, symptom improvement |
Note. 2002 international
Trials evaluating Chinese herbal medicines.
Study ID | Sample size | Response rate RR (95% CIs) | Schirmer test MD (95% CIs) (mm/5 min) | Salivary flow rate test MD (95% CIs) (mL/min) | Adverse effects | |
---|---|---|---|---|---|---|
CHM versus placebo | ||||||
| ||||||
Lian 2009 [ |
19/19 | 4.25 [1.76, 10.29] | NR | |||
Yu 2010 [ |
30/31 | 1.03 [0.86, 1.24] | −0.57 [−1.75, 0.60] | NR | ||
| ||||||
CHM versus conventional treatment | ||||||
| ||||||
Chen 2006 [ |
40/20 | 1.65 [1.04, 2.62] | NR | |||
Feng 2000 [ |
34/10 | 6.76 [1.04, 44.06] | 151.00 [46.32, 255.68] | NR | ||
Han 2008 [ |
38/20 | 1.87 [1.13, 3.10] | 2.98 [1.48, 4.48] | NR | ||
Hu 2001[ |
100/50 | 1.31 [1.09, 1.59] | −10.40 [−14.21, −6.59] | NR | ||
Huang 2009 [ |
32/28 | 1.23 [1.00, 1.51] | NR | |||
Li 2010 [ |
130/110 | 1.24 [1.12, 1.37] | no AE | |||
Liu 2009 [ |
30/30 | 1.67 [1.00, 2.76] | NR | |||
Liu 2005 [ |
30/30 | 1.05 [0.78, 1.40] | 0.26 [−1.12, 1.64] | −7011.40 [−7013.31, −7009.49] | C: 12 with central obesity, 2 with increased fasting blood glucose level, 1 with insomnia, 1 with hypertension, 1 with secondary fungus infection | |
Lu 2009 [ |
30/28 | 1.37 [0.98, 1.92] | 2.12 [0.75, 3.49] | 2.80 [1.94, 3.66] | T: 1 with diarrhea; C: 1 with blurred vision, 1 with pruritus | |
Lv 2008 [ |
74/50 | 1.35 [1.13, 1.61] | C: 2 with diarrhea | |||
Mao 2007 [ |
20/20 | 1.38 [0.97, 1.97] | 2.12 [0.75, 3.49] | −0.34 [−1.01, 0.33] | NR | |
Qian 2003 [ |
55/17 | 8.04 [2.18, 29.59] | 2.12 [0.75, 3.49] | −6.05 [−8.42, −3.68] | NR | |
Wang 2000 [ |
30/10 | 2.42 [1.13, 5.18] | NR | |||
Xie 2010 [ |
30/30 | 1.27 [1.01, 1.61] | NR | |||
Xuan 2010 [ |
30/30 | 1.80 [1.23, 2.62] | NR | |||
Yin 2010 [ |
20/20 | 0.94 [0.71, 1.25] | 0.05 [−1.15, 1.25] | no AE | ||
Zhao 2003 [ |
30/30 | 1.50 [1.03, 2.19] | gastrointestinal reactions: 10% versus 40% ( |
|||
Zhou 2006 [ |
30/30 | 1.09 [0.84, 1.40] | 2.33 [1.79, 2.87] | 0.40 [−0.25, 1.05] | NR | |
Wang 2010 [ |
30/27 | 1.66 [1.08, 2.56] | NR | |||
| ||||||
CHM plus conventional treatment versus conventional treatment | ||||||
| ||||||
Feng 2008 [ |
42/36 | 1.29 [0.91, 1.82] | 1.25 [0.57, 1.93] | −7.12 [−10.61, −3.63] | T: diarrhea (11.9%), 1 withdrawal with severe diarrhea; C: 2 withdrawal with increased ALT level and hypoplasia respectively, rashes (5.6%) | |
Gao 2009 [ |
63/63 | 1.63 [1.24, 2.13] | NR | |||
He 2010 [ |
26/22 | 1.79 [1.03, 3.11] | 3.24 [1.94, 4.54] | −5.36 [−8.74, −1.98] | Blurred vision, abdominal discomfort, stomachache, bowel movement frequency: 11.5% versus 9.1% | |
Hu 2010 [ |
33/31 | 1.36 [1.02, 1.82] | T: 1 with abdominal pain and diarrhea; control group: 1 with nausea | |||
Huang 2010 [ |
32/29 | 1.31 [1.00, 1.72] | 1.46 [0.33, 2.59] | C: 3 with abdominal discomfort, diarrhea; 1 with increased ALT level | ||
Li 2003 [ |
40/20 | 1.30 [0.54, 3.14] | 135.70 [50.56, 220.84] | no AE | ||
Li 2007 [ |
36/32 | 1.24 [0.97, 1.58] | 2.26 [1.11, 3.41] | 0.21 [0.18, 0.24] | T: 1 with edema; C: 1 with rashes, 2 with nausea | |
Li 2010 [ |
130/110 | 1.24 [1.12, 1.37] | NR | |||
Liu 2010 [ |
67/65 | 1.09 [0.97, 1.24] | C: 2 with nausea, vomiting | |||
Mao 2009 [ |
50/50 | 1.43 [1.11, 1.84] | NR | |||
Niu 2006 [ |
20/20 | 1.31 [0.90, 1.89] | thrombocytopenia: 15% versus 35% ( |
|||
Shen 2002 [ |
30/30 | 1.69 [1.18, 2.41] | 4.01 [3.06, 4.96] | 0.25 [0.21, 0.29] | T: 1 with swelling parotid gland and increased ESR; C: 1 with distal renal tubular acidosis | |
Shen 2006 [ |
30/30 | 3.69 [2.76, 4.62] | 0.23 [0.18, 0.28] | no AE | ||
Shen 2007 [ |
10/10 | 1.91 [1.04, 3.50] | edema: 10% versus 40% ( |
|||
Su 2009 [ |
30/30 | 1.86 [1.24, 2.79] | 0.85 [0.13, 1.57] | −5.73 [−9.45, −2.01] | NR | |
Sun 2007 [ |
74/50 | 1.35 [1.12, 1.63] | 35.50 [−19.76, 90.76] | NR | ||
Wan 2009 [ |
30/30 | 1.75 [1.24, 2.48] | NR | |||
Wang 2009 [ |
30/30 | −0.14 [−0.97, 0.69] | NR | |||
Wang 2009 [ |
25/25 | 1.47 [1.03, 2.08] | NR | |||
Wu 2007 [ |
22/20 | 1.44 [0.97, 2.14] | NR | |||
Wu 2002 [ |
30/10 | 2.00 [0.92, 4.36] | 2.40 [1.79, 3.01] | 199.00 [107.42, 290.58] | NR | |
Yan 2007(50) | 30/26 | 1.41 [1.01, 1.97] | NR | |||
Yang 2009 [ |
85/83 | 1.36 [1.14, 1.62] | NR | |||
Zhang 2009 [ |
49/46 | 1.19 [1.02, 1.39] | 3.26 [2.28, 4.24] | 435.46 [371.98, 498.94] | C: 2 with hepatic dysfunction, 1 with increased fasting blood glucose level, 1 with central obesity | |
Zhang 2011 [ |
29/28 | 1.51 [1.06, 2.15] | 1.70 [0.82, 2.58] | 0.80 [0.07, 1.53] | C: 1 with mild hepatic dysfunction | |
Zheng 2010 [ |
30/30 | 1.09 [0.84, 1.40] | 3.71 [1.88, 5.54] | 1.47 [1.18, 1.76] | T: 1 with nausea, 3 with stomachache; C: 2 with stomachache, 2 with diarrhea, 2 with increased ALT level, 1 with leucopenia; ( |
|
Zhong 2008 [ |
128/128 | 1.17 [1.07, 1.29] | C: 1 with increased blood glucose level, 2 with hyperlipoidemia, 1 with hepatic and renal dysfunction | |||
Zhou 2006 [ |
22/23 | 1.39 [1.01, 1.93] | T: 2 with abdominal swelling; C: 4 with obesity, 4 with stomachache, 2 with hypertension, 4 with insomnia | |||
| ||||||
CHM plus acupuncture/acupressure versus conventional treatment | ||||||
| ||||||
Yang 2005 [ |
42/42 | 2.98 [2.01, 3.95] | 2.39 [1.17, 3.61] | NR | ||
Zhou 1997 [ |
34/16 | 1.96 [1.01, 3.81] | NR | |||
Si 2005 [ |
38/25 | 1.15 [0.93, 1.43] | NR |
Note. C: control group; T: treatment group; NR: not reported; AE: adverse effects.
Search strategy.
Database | Search strategy |
---|---|
PubMed | “Sjögren’s syndrome” (mesh) and (“humans” (MeSH terms) and (meta-analysis (ptyp) OR randomized controlled trial (ptyp)) |
Cochrane Library | “Primary sjögren’s syndrome in record title in cochrane central register of controlled trials” |
China Knowledge Resource Integrated Database (CNKI) | “Sjögren’s syndrome in record title AND random |
VIP Database for Chinese Technical Periodicals (VIP) | “Sjögren’s syndrome in record title AND random |
Wanfang Data | “Sjögren’s syndrome in record title AND random |
Chinese Biomedical Database (CBM) | “Sjögren’s syndrome in record title AND random |
Methods to generate allocation sequence were reported in 14 trials [
The response rate was defined as numbers of participants in both treatment and control group who had global or partial symptomatic improvement, defined by either physician assessment or by laboratory tests. 94.2% (49/52) of the trials reported response rate but none of the trials reported the estimated effect using RR and 95% CIs. According to the primary data reported in their papers, we calculated the RR and 95% CIs of response rates, and the results showed that 65.3% (32/49) of the trials found a significant difference between CHM treatment and control groups. The overall estimates of effect within the four comparisons were:
In the above 49 trials, only one trial was assessed as having a low risk of bias [
A total of 20 trials employed the Schirmer test to determine whether the participants’ eyes could produce normal tears to keep the eyes moist. Five out of seven found significant improvement favoring the CHM over the conventional medicine [
There were 21 trials that either used a salivary flow rate test or sugar-melt test to determine the function of salivary glands, of which 52.4% (11/21) trials found that there was a significant difference between treatment and control groups, which favored the CHM 2 trials compared CHM to conventional medicine [
No trials used validated quality of life (QoL) measures, such as WHOQOL or SF-36, to evaluate clinical effectiveness. Among the included trials, one applied self-developed criteria to evaluate QoL, but found no statistical difference between the treatment and control group [
Adverse effects were reported in 19 trials [
A funnel plot was not conducted due to clinical heterogeneity of the included trials.
The data within this paper involving 52 trials cannot be synthesized into a meta-analysis because of their heterogeneity. The included trials report moderate effectiveness (overall response rate and function improvement on lacrimal and salivary gland) for PSS treatment for CHM when compared with conventional medicine or placebo. We evaluated the safety reports from the CHM: the adverse effects occurred in the CHM group appear less than those in the conventional medicine group.
There is no known cure in conventional medicine for PSS and this paper provides preliminary evidence that CHM may be a promising and safe intervention for this chronic long-term condition. However, there are important limitations in this paper that weaken the recommendation of CHM for their clinical use.
Almost all the randomized trials of CHM identified in this review evaluating treatment for PSS have a high risk of bias. Only 28.8% (15/52) of the included trials reported the randomization process and few trials reported allocation concealment or blinding, and no trial reported intention-to-treat analysis.
However, it is important to note that the methodological quality of RCTs in this field has shown signs of improvement over the last 3 years. Reports on the generation of allocation sequence account for 13.0% (3/23) of included trials published between 1997 and 2007, compared to 25.0% (4/16) in RCTs published between 2008 and 2009, and 61.5% (8/13) in RCTs published between 2010 and 2011. Application of blinding in study design accounted for 0% (0/23) of included trials published between 1997 and 2007, compared to 17.2% (5/29) that were published between 2008 and 2011. Reports of dropout rates and those lost to followup accounted for 8.7% (2/23) of included trials published between 2008 and 2011, compared to 17.2% (5/29) of trials published between 2008 and 2011. Nevertheless, the current quality of RCTs’ in CHM is still unsatisfactory, because only one in 52 trials reported all the items in the Cochrane
The majority (94.2%, 49/52) of included trials used response rate (total effectiveness rate) as the primary outcome measure. This is a composite outcome index, integrating factors from symptoms, signs, and laboratory findings. This subjective and vague outcome index is prone to bias and misinterpretation, particularly if there is insecure or no blinding. In the included trials, the procedure for determining effectiveness rate has not been standardized and different approaches to defining the response rate have led to an inconsistency and heterogeneity in the assessment of the efficacy of these interventions. Under these circumstances, although the results of most trials suggest CHM can improve “response rate” more significantly than standard conventional medicine or placebo, we must still remain highly circumspect about the specific effect of CHM on PSS.
In accordance with TCM theory interventions were designed to be adapted according to the specific presentations of PSS, so they varied from trial to trial. In addition CHM was frequently used in conjunction with other treatments including conventional herbal medicine, placebo, and acupuncture. This complexity of intervention makes it difficult to use double blinding (patients and physicians). It also complicates an assessment of the effects of different components of the interventions. In these instances we can only report the effectiveness of a whole therapeutic system such as TCM rather than a single isolated treatment.
PSS is a systemic autoimmune disease and requires long-term care and treatment. Therefore, evaluation of the effect of an intervention should be based on long-term treatment and followup. However in the included 52 trials, only six trials continued follow up beyond the six-month treatment [
fatigue is a common symptom in patients with Sjögren’s syndrome, and greatly influences patients’ quality of life [
Studies are beginning to, and must continue to, report randomization sequence generation and allocation concealment in detail and employ blinding in outcome measurement and evaluation as well as an intention to treat analysis and a clear description of dropout. If we want to study the specific efficacy of CHM interventions, double-blind and placebo controlled trials are necessary. However, due to the limited evidence available for conventional drugs most frequently used in PSS [
The Medical Research Council (MRC) guidelines for complex interventions highlighted that complex interventions might work best if tailored to local circumstances rather than being completely standardized [
We recommend that the diagnostic criteria from the 2002 International Classification of Sjögren’s syndrome be used for future TCM PSS research. We also recommend an extended course of treatment and followup time, using both quantitative and qualitative outcomes to make a proper assessment of the effectiveness of this intervention. In-validated outcomes such as “response rate” are unreliable, difficult to standardize and interpret, and should not be used.
52 RCTs were analyzed in this systematic review, testing various CHMs in the treatment of PSS. The findings from these trials suggest that CHM delivered either as a sole treatment or in conjunction with conventional medicine may be more effective than conventional medicine in managing PSS symptoms-with specific reference to lacrimal and salivary gland function. However, a high risk of bias in these studies and the heterogeneity of the CHM intervention and outcome assessment suggest that these positive findings must be interpreted with considerable caution; we cannot recommend any specific Chinese herbal medicines for clinical use. This preliminary evidence supports the continuing use and evaluation of individualized CHM as a potentially promising and safe intervention for this syndrome. We recommend that adequately powered and rigorously conducted further research should employ a variety of trial methodologies including double-blind placebo-controlled RCTs, pragmatic, and comparative equivalence trials, to investigate CHM treatment for PSS. If the evidence justifies it CHM can then be more widely recommended as a treatment for this common and troublesome condition.
The authors declared no conflict of Interests.
The study was supported by a grant from international cooperation project (no. 2009DFA31460) from the Ministry of Science and Technology of China, and in part supported by the basic operational funding for scientific research from Beijing University of Chinese Medicine (2011-CXTD-09). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.