Impact of fatigue on rheumatic diseases

Fatigue is a common, disabling, and difficult-to-manage problem in rheumatic diseases. The concept of fatigue is difficult to define. No clear and widely accepted definition of fatigue is available. The symptoms of fatigue are defined as an overwhelming, debilitating, and sustained sense of exhaustion that decreases the ability to function and carry out daily activities. Prevalence estimates of fatigue within musculoskeletal diseases vary considerably (35%–82%). In this review, we present data about the role of fatigue for the patients’ quality of life, tools for diagnosing fatigue, factors contributing to fatigue like disease activity and psychological factors, and some experimental studies to verify the biological background of fatigue. Management of fatigue including pharmacological and non-pharmacological treatment is also part of this publication. Overall data are scarce for fatigue in rheumatic diseases, and further studies are warranted to identify the role of biological mechanism such as inflammation, hormonal changes, and autonomic nervous system in the pathogenesis of fatigue.     

Prevalence of fatigue functional and social impairment among patients with rheumatic diseases compared to patients without: A cross-sectional comparison

Rheumatic diseases (RD) are chronic diseases that significantly affect the lives of patients. Assessing health outcomes through a patient-reported outcome measurement information system (PROMIS) is essential for RD management. Moreover, these tend to be less favorable among individuals than among the rest of the population. This study aimed to compare PROMIS between RD patients and other patients. This cross sectional study was conducted in the year 2021. Information about patients with RD was obtained from the RD registry at King Saud University Medical City. Patients without RD were recruited from family medicine clinics. Patients were contacted electronically through WhatsApp^© to complete the PROMIS surveys. We compared the individual PROMIS scores between the 2 groups using linear regression, adjusting for sex, nationality, marital status, education level, employment, family history of RD, income, and chronic comorbidities. There were 1024 individuals (512 with RD and 512 without RD). The most common RD was systemic lupus erythematosus (51.6%), followed by rheumatoid arthritis (44.3%). Individuals with RD reported significantly higher PROMIS T-scores for pain [β = 6.2; 95% confidence interval (CI) = 4.76, 7.71] and fatigue (β = 2.9; 95% CI = 1.37, 4.38) compared to those without RD. Moreover, RD individuals reported lower physical functioning (β = −5.4; 95% CI = −6.50, −4.24) and social interaction (β = −4.5; 95% CI = −5.73, −3.20). Patients with RD in Saudi Arabia, particularly those with systemic lupus erythematosus and rheumatoid arthritis, have significantly greater impairment in physical functioning and social interaction and report higher levels of fatigue and pain. Addressing and ameliorating these negative outcomes is necessary to improve quality of life.     

Assessment of nutritional deficiency manifestations in patients with rheumatic diseases

BackgroundInflammatory diseases can interfere with adequate nutrition and even lead to a malnourished state. Nutritional deficiency manifestations may be similar to rheumatologic manifestations.Aim of the workTo assess whether malnutrition is an associated feature of rheumatic diseases (RDs).Patients and methodsA multicenter study included Egyptian patients with different RDs; nutrition measurements and common features of deficiency were assessed; general appearance, skin, hair/nail changes, spooning of nails, night blindness, mouth problems, edema, tetany, dysphagia, diarrhea, thyromegaly, loss of appetite and weight loss.ResultsThe study included 284 patients with various RDs: rheumatoid arthritis (RA) (n = 128), systemic lupus erythematosus (n = 120), Behçet’s disease (n = 17), spondyloarthritis (n = 6), systemic sclerosis (n = 5), dermatomyositis (n = 2), relapsing polychondritis (n = 2), and one patient each with familial Mediterranean fever, Gout, Still's disease and undifferentiated connective tissue disease. Muscle wasting was present in 44(15.5%) patients, spooning of nails in 26(9.2%), night blindness in 38(13.4%), glossitis in 48(16.9%), tetany in 32(11.3%) and loss of appetite in 51(18%). Although there was significant differences among RDs in some nutritional deficiency signs, the type and their durations did not significantly affect symptoms or signs of nutritional deficiency, while age was associated with peripheral edema (p = 0.014) and tetany (p = 0.009); azathioprine was associated with hair/nail changes (p = 0.04); methotrexate with peripheral edema and hair/nail changes (p = 0.002, p = 0.01 respectively); and hydroxychloroquine was negatively associated with skin rash, wasting and hair/nail changes (p = 0.011, p = 0.001 and p < 0.0001 respectively).ConclusionNutritional deficiency is common among RD patients especially elderly and should be monitored frequently regardless type and onset.     

Serum interleukin-6 in primary fibromyalgia syndrome patients: Impact on disease burden,severity, quality of life and sleep

Aim of the workTo assess serum interleukin-6 (IL-6) level in primary fibromyalgia syndrome (FMS) patients and to study its relation to disease burden parametersPatients and methodsForty primary FMS patients and 40 age and sex matched controls were studied. Patients answered multiple questionnaires. Fatigue was assessed by multidimensional fatigue inventory (MFI-20), pain severity by visual analogue scale (VAS-pain) and sleep quality by sleep quality numerical rating scale (NRS). The 36-Item Short Form (SF-36) was used to assess quality of life and fibromyalgia Impact Questionnaire (FIQ) was used to evaluate patient status, progress and outcomes.ResultsThe patients mean age was 36.5 ± 7.1 years and disease duration 5.3 ± 2.95 years and they were 38 females and 2 males. The mean serum IL-6 level was significantly higher in patients (134.9 ± 67.3 pg/ml) than control (41.1 ± 8.5 pg/ml)(p = 0.001). The mean VAS-pain was 6.2 ± 1.3 (4–8), FIQ was 58 ± 6.1 (50–70), SF-36 47 ± 10.2 (30–60), MFI20 was 76.5 ± 10.6 (60–95) and sleep quality NRS was 6.9 ± 1.2 (5–9). The values of the studied parameters and scores were significantly different from the control 1.4 ± 0.5; 14.4 ± 6.5; 93.9 ± 3.5 10 ± 5.2 and 0.9 ± 0.8 respectively; p = 0.001 for all). There was a significant correlation between serum IL-6 levels and VAS-pain (r = 0.72, p = 0.001), FIQ (r = 0.58, p = 0.001), SF-36 (r = 0.78, p = 0.001), MFI-20 (r = 0.74, p = 0.001) and sleep NRS (r = 0.78,p = 0.001). On regression, IL-6 level had a greater impact on sleep NRS (p = 0.001), SF-36 (p = 0.005) and MFI20 (p = 0.01).ConclusionsSerum IL-6 level is high in primary FMS patients. Also, serum IL-6 is significantly related to the parameters of fatigue, functional status, sleep quality and pain.     

Disease burden of rheumatic diseases in India: COPCORD perspective

The maiden WHO ILAR COPCORD (community oriented program for control of rheumatic diseases) Bhigwan (1996–2014) demonstrated that musculoskeletal (MSK) pain was the commonest self-reported ailment in the community, soft tissue rheumatism, ill-defined MSK symptoms and osteoarthritis (OA) were the predominant disorders and about 10% cases suffered from inflammatory arthritis. The burden of rheumatoid arthritis (RA) was high with point prevalence of 0.7%. Bone and joint decade (BJD) India conducted several standardized and uniform surveys (2004–2010) all over India and collected data from over 55,000 persons at 12 sites. The pooled age sex adjusted (India census population 2001) prevalence reported by the recent surveys was – RA (0.34), OA knees (3.34), undifferentiated inflammatory arthritis (0.22), Spondyloarthritis (0.23), ankylosing spondylitis (0.03), psoriatic arthritis (0.01) soft tissue rheumatism (1.39), gout (0.05) lupus (0.01); prevalence percent in parenthesis. Several forms of collagen vascular disorders and vasculitis are described in hospital based case series. Musculoskeletal infections including tuberculosis remain an important clinical burden. The 2006 India Chikungunya epidemic has put an additional burden of chronic MSK pain and arthritis. The recently launched national health programs pertaining to non-communicable diseases, rural and women health does not even mention rheumatic diseases thus there is urgent need to study the burden of rheumatic diseases and its impact on society.     

Assessment of fatigue in a large series of 1492 Brazilian patients with Spondyloarthritis

Abstract

Background. The aim of the present study was to analyze the score of fatigue in a large cohort of Brazilian patients with SpA, comparing different disease patterns and its association with demographic and disease-specific variables.

Methods. A common protocol of investigation was prospectively applied to 1492 Brazilian patients classified as SpA according to the European Spondyloarthropathies Study Group (ESSG) criteria, attended at 29 reference centers. Clinical and demographic variables were recorded. Fatigue was evaluated using the first item of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) questionnaire.

Results. The mean BASDAI fatigue score was 4.20 ± 2.99. There was no significant difference in the fatigue score between the different SpA. Fatigue was higher in female patients (p < 0.001), with mixed (axial + peripheral) involvement (p < 0.001) and in those who did not practice exercises (p < 0.001). Higher scores of fatigue were significantly associated with inflammatory low back pain (p = 0.013), alternating buttock pain (p = 0.001), cervical pain (p = 0.001), and hip involvement (p = 0.005). Fatigue presented a moderate positive statistical correlation with Bath Ankylosing Spondylitis Functional Index (BASFI) (0.469; p < 0.001) and Ankylosing Spondylitis Quality of Life (0.462; p < 0.001).

Conclusion. In this large series of Brazilian SpA patients, higher fatigue scores were associated with female gender, sedentary, worse functionality, and quality of life.     

Neutrophil gelatinase levels in plasma and synovial fluid of patients with rheumatic diseases

To examine the clinical significance of neutrophil gelatinase in rheumatic diseases, plasma and synovial fluid (SF) gelatinase levels were determined in 62 patients with rheumatoid arthritis (RA), 12 patients with ankylosing spondylitis (AS), 18 patients with osteoarthritis (OA) and 17 healthy controls. The gelatinase level was measured by enzyme-linked immunoassay (ELISA). The assay had a sensitivity of 1 ng/ml and a working range of 5–25 ng/ml. Gelatinase levels were significantly higher in the plasma of patients with RA and of patients with RA complicated by amyloidsis or vasculitis as compared to those of healthy controls. Moreover, the mean value of gelatinase in the plasma of patients with RA complicated by vasculitis was found to be significantly higher than that of RA patients without vasculitis. A significant increase in gelatinase concentration was also observed in the plasma of AS patients but not in the plasma of patients with OA. The concentration of gelatinase in the RA SF samples was much higher (18-fold) than the level of the enzyme in the plasma of RA patients. There was also a higher concentration of gelatinase (fourfold) in OA SF compared with OA plasma. The results suggested that circulating gelatinase may reflect some degree of neutrophil activation in patients with inflammatory arthritis, especially in those with RA complicated by vasculitis. However, the results did not allow a differentiation between chronic and acute inflammation.     

Joint symptoms and diseases associated with moisture damage in a health center

Rheumatic diseases do not usually cluster in time and space. It has been proposed that environmental exposures may initiate autoimmune responses. We describe a cluster of rheumatic diseases among a group of health center employees who began to complain of symptoms typically related to moldy houses, including mucocutaneous symptoms, nausea and fatigue, within a year of moving into a new building. Dampness was found in the insulation space of the concrete floor below ground level. Microbes indicating mold damage and actinobacteria were found in the flooring material and in the outer wall insulation. The case histories of the personnel involved were examined. All 34 subjects working at the health center had at least some rheumatic complaints. Two fell ill with a typical rheumatoid factor (RF)-positive rheumatoid arthritis (RA), and 10 had arthritis that did not conform to any definite arthritic syndrome (three met the classification criteria for RA). Prior to moving into the problem building one subject had suffered reactive arthritis, which had then recurred. Another employee had undiagnosed ankylosing spondylitis and later developed psoriatic arthritis, and another developed undifferentiated vasculitis. A total of 16 subjects developed joint pains, 11 of these after beginning work at the health center. Three subjects developed Raynauds symptom. Fourteen cases had elevated levels of circulating immune complexes in 1998, 17 in 1999, but there were only three cases in 2001, when the health center had been closed for 18 months. The high incidence of joint problems among these employees suggests a common triggering factor for most of the cases. As some of the symptoms had tended to subside while the health center was closed, the underlying causes are probably related to the building itself and possibly to the abnormal microbial growth in its structures.Abbreviations RF rheumatoid factor - RA rheumatoid arthritis - CFU colony-forming units - CRP C-reactive protein - DMARD Disease-modifying antirheumatic drug     

类风湿关节炎患者疲乏症状与疾病活动及生活质量关系的研究

目的 评价类风湿关节炎(RA)患者疲乏症状的发生率,并探讨疲乏与疾病活动、功能状态及生活质量的关系.方法 入选RA患者230例,应用疲乏目视模拟测试表(VAS)评分评估患者疲乏的发生率,探讨疲乏评分≥50 mm和<50 mm的RA患者临床指标、疾病活动、功能状态、生活质量及实验室炎性指标的变化,并对疲乏的相关因素进行分析.结果 85.7%的RA患者疲乏VAS评分≥20 mm,51.7%的患者疲乏VAS评分≥50 mm.疲乏评分≥50 mm的患者与<50 mm的患者相比,晨僵时间、疼痛VAS评分、患者对自身健康状况的总体评估(PGA)、医生总体评价、压痛关节数(TJC)、压痛关节指数(TJI)、肿胀关节数(SJC)、肿胀关节指数(SJI)、疾病活动指数28(DAS28)、健康评估问卷(HAQ)得分及红细胞沉降率(ESR)明显增高,而健康测量量表SF-36中有关生理和心理健康8个维度得分明显降低,差异均有统计学意义.双变量相关分析显示:疲乏与晨僵时间、疼痛VAS评分、PGA、医生总体评价、TJC、TJI、SJC、SJI、DAS28、HAQ及SF-36中有关生理和心理健康的8个维度均有低至中等程度的相关性,与ESR、C反应蛋白(CRP)之间具有较弱的相关性.结论 疲乏是RA患者的一个重要症状,并与患者疼痛、疾病活动、功能状态及生活质量相关.     

Correlation of different bone markers with bone density in patients with rheumatic diseases on glucocorticoid therapy

Osteoporosis is a common concomitant disease in patients with rheumatic diseases on glucocorticoid (GC) therapy. Bone status is usually evaluated by determination of bone density in combination with clinical examinations and laboratory tests. However, the strength of individual biochemical bone makers in GC-induced osteoporosis has yet to be fully clarified. For this reason, different bone markers were investigated in correlation with bone density in patients with rheumatic diseases. Approximately 238 patients (212 women, 26 men) with a rheumatic disease and under GC therapy were examined consecutively for the first time with regard to bone density (BMD) and bone markers {osteocalcin, bone-specific alkaline phosphatase (precipitation method/tandem-MP ostase), crosslinks [pyridinoline (PYD), deoxypyridinoline (DPX), N-terminal telopeptide (NTX)]}. The daily glucocorticoid dose was 10 mg prednisone equivalent (median), and the cumulative dose was 12 g prednisone equivalent (median). None of the patients had previously taken medication for osteoporosis. Osteoporosis was demonstrated in 35.3% of the patients, osteopenia in 47.5%, and a normal BMD in 17.2%. The results of tandem-MP ostase correlated with the BMD of the lumbar spine and of the femoral neck. The values for N-terminal telopeptide and pyridinoline correlated only with the bone density of the femoral neck. All results were statistically significant, although the correlation coefficients were low. After classification of the patients according to their BMD values (osteoporosis, osteopenia and normal BMD), there were significantly more patients with bone markers above the norm in the osteoporosis group and in the osteopenia group than in the group with normal bone density. All bone markers recorded behaved similarly in relation to the bone density values. The same analysis was also undertaken for the different disease groups. In these subgroups there was also a correlation between ostase/crosslinks with BMD, but the correlation coefficients were low. A general recommendation for the routine use of a specific bone marker in patients with rheumatic diseases on glucocorticoid therapy cannot be made from a cost-benefit point of view mainly because of limited predictive power (low correlation coefficients, incomplete correlation with different sites of BMD measurement).     

Epigenetics and methylation in the rheumatic diseases

Objectives

Rheumatic diseases encompass a wide range of conditions of poorly characterized etiopathology, many having both genetic and environmental susceptibility factors. Epigenetic studies are providing new insights into disease pathogenesis. Recent rheumatology literature related to DNA methylation studies—both epigenome-wide and candidate gene—are discussed, as well as methodological issues.

Method

A PubMed search for articles published until April 2013 was conducted using the following keywords: (“methylation” OR “epigenetics”) AND (“rheumatoid arthritis” OR “lupus” OR “autoimmune disease” OR “osteoporosis” OR “osteoarthritis” OR “musculoskeletal disorder”) and EWAS. The reference lists of identified articles were searched for further articles.

Results

Several genome-wide methylation studies have been reported recently, mostly in autoimmune rheumatic diseases. Overall, these studies have identified methylation signatures in disease, clustering of subgroups as well as new and known epigenetic associations. Methodological issues, small sample sizes and reduced coverage of methylation assays render many results preliminary.

Conclusions

There have been a number of epigenetic advances in rheumatic diseases recently. The new technologies and emerging field of epigenome-wide association will provide novel perspectives in disease etiology, diagnosis, classification, and therapy.     

Association of complementary or alternative medicine use with quality of life, functional status or cumulated damage in chronic rheumatic diseases

Quality of life, functional status, or cumulated damage were compared between users and non-users of complementary and alternative medicine (CAM) in 445 rheumatic patients (rheumatoid arthritis [RA]: 64; systemic lupus erythematosus [SLE]: 192; fibromyalgia [FM]: 34; and knee osteoarthritis [KOA]: 155). CAM use was reported by 249 subjects (55.9%; 95%CI; 51.4–60.6). After a general linear model was applied, CAM use was associated with lower scores in the physical function (p = 0.02) and bodily pain (p = 0.03) domains of the SF-36 survey. In FM, RA and KOA, functional status was not different between users and non-users. CAM use was associated with higher cumulated damage (p = 0.04) in SLE. In patients with chronic rheumatic diseases, CAM use was not associated with better quality of life. Additionally, in SLE patients, CAM use was associated with higher cumulated damage. More research on CAM use in chronic rheumatic diseases is needed to better delineate its risk/benefit profile.     

Pharmacoepidemiologic research in Australia: challenges and opportunities for monitoring patients with rheumatic diseases

The topic of drug safety has received great attention in recent years. Pharmacoepidemiology is the study of the use and effects of medicines in large populations using epidemiological methods. Pharmacoepidemiologic research can fill the knowledge gaps due to the limitations of existing pharmacovigilance systems that rely on randomised controlled trials and voluntary reporting. This review discusses the present state of pharmacoepidemiologic research in Australia. In Australia, linking administrative data on use of medications and medical services is possible to a certain extent. Data from patient registries with respect to rheumatology are also available. These data are valuable for better understanding of the beneficial and adverse effects of medicines. Opportunities and challenges of using these data sources to address issues from clinical pharmacology are also highlighted. Australia is well-placed internationally to make major contributions to the knowledge base of outcomes of medicines in the real-world setting. Developments in pharmacoepidemiology are critical to clinicians treating patients with rheumatic and other conditions.     

Safety and reported adverse effects of coronavirus disease-2019 (COVID-19) vaccines in patients with rheumatic diseases

BackgroundCoronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Symptoms and severity of COVID19 are variable.Aim of the workTo evaluate the effectiveness and to identify side effects of the COVID-19 vaccines among Egyptian patients with autoimmune rheumatic diseases (RDs).Patients and methodsThe study included 126 patients with various RDs and 200 control. Detailed medical history was recorded with special concern regarding COVID-19 vaccination, types, doses, side effects, post-vaccination infection and treatment.ResultsIn patients, BBIBP-CorV (Sinopharm) was the most frequent vaccine 42.3 % (n = 52); CoronaVac (Sinovac) 22 % (n = 27); ChAdOx1 (AstraZeneca) 17.9 % (n = 22); BNT162 (Pfizer BioNTech) 14.6 % (n = 18); Sputnik V 1.6 % (n = 2) and Ad26.COV2-S (Johnson & Johnson) 1.6 % (n = 2). Regarding the control, 34.4 % (n = 62) received AstraZeneca; 26.1 % (n = 47) Sinopharm; 16.7 % (n = 30) Pfizer; 11.7 % (n = 21) Sinovac; 6.7 % (n = 12) Sputnik; 3.3 % (n = 6) Johnson & Johnson and 1.2 % (n = 2) mRNA1273 (Moderna). COVID-19 infection decreased after vaccination from 32 (25.4 %) to 7 (5.6 %), and from 162 (81.0 %) to 85 (42.7 %) in RD patients and the control respectively. ICU admission decreased from (6.3 %) among RD patients and from (1.3 %) in control to 0 % after vaccination in both groups. In RD patients, body ache was the commonest reported vaccine adverse effect (44.4 %). Pain at the injection site was the commonest among control (77 %). ChAdOx1 (AstraZeneca) had the highest incidence of side effects, mRNA1273 (Moderna) showed the lowest.ConclusionCOVID-19 vaccine was effective in decreasing infection and disease severity in RDs patients and control, with similar, mild adverse effects.     

Analysis of clinical features and prognostic factors in Chinese patients with rheumatic diseases in an intensive care unit

Aim of the work

To describe the clinical features and prognostic factors in patients with rheumatic diseases (RDs) admitted to the intensive care unit (ICU).

风湿性疾病患者合并结核分枝杆菌潜伏感染诊治的专家共识

风湿性疾病作为一类常见的自身免疫性疾病,治疗上经常使用糖皮质激素、免疫抑制剂、生物制剂和小分子靶向药物等,这些药物的应用往往会导致患者自身免疫功能异常,致使其具有较高的LTBI发生风险,且发展为活动性结核病的风险也显著增加。因此,在临床工作中,需要对符合筛查条件的风湿性疾病患者进行LTBI筛查。这就要求风湿免疫科医师和结核科医师加强协作,提高意识,针对需要进行LTBI筛查的风湿性疾病患者进行科学评估,制定规范的筛查流程和预防性治疗方案,以防范风湿性疾病患者合并LTBI后发展为活动性结核病。基于此,国家感染性疾病临床医学研究中心/深圳市第三人民医院、北京大学深圳医院、中国医学科学院北京协和医院、中国防痨协会、《中国防痨杂志》编辑委员会和深圳市炎症与免疫性疾病重点实验室共同组织国内结核病和风湿性疾病领域专家撰写了《风湿性疾病患者合并结核分枝杆菌潜伏感染诊治的专家共识》(简称“共识”)。本共识基于我国风湿性疾病患者合并LTBI的流行病学、循证医学证据和临床研究等方面数据,经过多次研讨并达成一致意见,供同道参考借鉴。     

风湿性疾病患者结核分枝杆菌潜伏感染激活机制的研究进展

风湿性疾病是一组自身免疫与炎症性疾病,其主要特征是免疫系统的紊乱。同时,随着各种免疫抑制剂、生物制剂在风湿性疾病中的应用,机体的免疫状态大大改变,从而使结核分枝杆菌潜伏感染激活的风险增加。为更好地了解风湿性疾病患者结核分枝杆菌潜伏感染激活的机制,以期进一步降低结核病的发生率和患者病亡率,笔者从结核感染的免疫反应机制、风湿性疾病患者结核分枝杆菌潜伏感染激活的机制、增加结核分枝杆菌潜伏感染激活风险的治疗药物等方面进行综述,以供参考。     

Low detection of hepatitis B and occult hepatitis B infection in patients with rheumatic diseases

Background

A new form of hepatitis B virus (HBV) infection, occult hepatitis B infection (OBI), has been identified and reported among patients with rheumatic diseases.

肿瘤坏死因子拮抗剂治疗风湿性疾病安全性的短期临床观察

目的 描述肿瘤坏死因子(TNF)-α拮抗剂治疗风湿性疾病发生的不良反应,评价临床应用的安全性和耐受性.方法 对2007年1月至2008年10月使用TNF-α拮抗剂的患者从临床症状、体征及实验室检查方面记录使用过程中发生的不良反应及程度和最终结局.结果 78例患者中35%(27/78)为类风湿关节炎(RA),41%(32/78)为强直性脊柱炎(AS),17%(13/78)为银屑病关节炎(PsA),6%(5/78)为未分化脊柱关节病(uSpA).59例患者使用依那西普,7例(12%)发生注射局部反应、上呼吸道感染及结核病等不良反应.19例患者使用英夫利西单抗,3例(16%)发生不良反应,1例(AS)为上呼吸道感染,1例(AS)前两次均在输注完24 h内出现伞身红色丘疹及心悸,1例(RA)输注4次后出现不明原因发热.部分不良反应可自行消失,其余经适当处理后痊愈.结论 证实依那西普和英夫利西单抗治疗风湿性疾病具有较好的安全性和耐受性,发生的不良反应是温和的,经适当处理可痊愈.