The Effects of Antibiotics for Helicobacter pylori Eradication or Dapsone on Chronic Spontaneous Urticaria: A Systematic Review and Meta-Analysis

Background: Chronic spontaneous urticaria (CSU) is a disease with wheals and/or angioedema. Some drugs, especially antibiotics for Helicobacter pylori (H. pylori) eradication and the sulfone antibiotic dapsone, may be candidates for treating CSU. The present study assessed the efficacy of these antibiotic therapies for CSU. Methods: Databases (MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, the World Health Organization International Clinical Trials Platform Search Portal and ClinicalTrials.gov) were searched until October 2020. Study selection, data abstraction and quality assessments were independently performed using the Grading of Recommendations Assessment, Development and Evaluation approach. The outcomes were the remission of CSU-related symptoms, activities and adverse events due to antibiotics for H. pylori eradication or dapsone. Results: Nine randomized controlled trials (RCTs; 361 patients) were included. The antibiotics for H. pylori eradication increased the remission rate (risk ratio (RR) = 3.99, 95% confidence interval (CI) = 1.31 to 12.14; I2 = 0%), but dapsone did not (RR = 1.15, 95% CI = 0.74 to 1.78). Antibiotics for H. pylori eradication (standard mean difference (SMD) = 1.49, 95% CI = 0.80 to 2.18; I2 = 69%) and dapsone (SMD = 7.00, 95% CI = 6.92 to 7.08; I2 = 0%) improved symptoms. The evidence of certainty was moderate. Dapsone was associated with mild adverse events, whereas H. pylori eradication was not. Conclusion: Antibiotics, especially those for H. pylori eradication, improved the remission rate and symptoms of CSU with few adverse events. Further studies are needed.


Introduction
Chronic spontaneous urticaria (CSU) is a condition characterized by the development of wheals, angioedema or both and pruritus during a period of six or more weeks [1]. Chronic urticaria affects about 0.5-1% of the general population worldwide, and CSU accounts for over two-thirds of chronic urticaria cases, with affliction persisting for 20 years after the onset in up to 20% of patients [1][2][3]. CSU is not only an adult disease but also affects the pediatric population [4]. CSU thus has a significant impact on an impaired quality of life [5].
Previous systematic reviews showed that antibiotics for the eradication of chronic infections, such as Helicobacter pylori (H. pylori) infection, suppressed symptoms of CSU [6][7][8]. The antibiotics themselves might be more influential on this effect than the eradication of H. pylori [8]. The antibiotics used mainly for H. pylori eradication, such as amoxicillin, clarithromycin and metronidazole, may thus be closely involved in the pathology of CSU [7][8][9].
Dapsone is a sulfone antibiotic that can be used for antihistamine-refractory CSU; however, thus far, this drug is not fully recommended [1,2]. With this background, the quality of its supporting evidence in the guidelines was based on just one randomized control trial (RCT) and two case reports [10][11][12]. Therefore, the present study assessed the efficacy of antibiotics for chronic infections in CSU patients, especially antibiotics for H. pylori eradication and the sulfone antibiotic dapsone.

Literature Search and Study Selection
Only RCTs were included in our assessment of the effects of oral antibiotics on CSU, irrespective of language, observation period, year of publication, publication and unpublished data. The inclusion criteria were patients with CSU, defined as recurrent attacks of hives daily or almost daily persisting for six or more weeks [1]. The patients over 16 years old were included as the dose of antibiotics used at age 16 is generally the same as that for adults [14]. Oral antibiotics included the H. pylori eradication regimen and the sulfone antibiotic dapsone with immunomodulatory agents. The comparators were the corresponding placebo or no placebo. The outcomes were remission rates, improvement of CSU symptoms and adverse events. Remission of urticaria symptoms was defined as no attacks of wheals or pruritus at the end of the follow-up period [1]. The improvement of urticaria symptoms was defined by the difference in the urticaria activity score (UAS), which is the sum of the hives score and itch severity score, between the baselines and the end of follow-up [1]. When the total score was unknown, the urticaria (hives) score was adopted.
The electronic databases were searched using the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via Ovid and EMBASE via PROQUEST (Appendix B). The clinical trial registrations were searched using the website of the World Health Organization International Clinical Trials Platform Search Portal (ICTRP) and ClinicalTrials.gov (Appendix B). The reference lists of guidelines were searched for articles related to urticaria [1-3]. The reference lists were also hand-searched from the included trials. The authors were contacted to obtain further data as necessary.

Data Extraction and Quality Assessments
Two review authors (J.W. and J.S.) independently completed the construction of databases, article screening, study quality assessment and data extraction. Discrepancies were resolved by discussion with the third review author (K.K.). Data were extracted using a standardized data extraction form. Information collected included the characteristics (author, year, country, patient number, age, antibiotics, control, follow-up periods and eradication rate) and data (outcomes) from the included studies. The risk of bias was assessed using version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB2) tool [15].

Data Synthesis and Analyses
Relative risks with 95% confidence intervals (CIs) were calculated for the remission rate. The standard mean differences (SMD) and 95% CIs were calculated for the improvement of CSU symptoms. All adverse events were summarized according to the definition of each study.
The statistical heterogeneity was first assessed by a visual inspection of the forest plot and using the I 2 statistic (I 2 values of 0% to 40%: may not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%; considerable heterogeneity) [15]. When heterogeneity was identified (I 2 statistic > 50%), possible sources of heterogeneity were explored using subgroup analyses. The publication bias was evaluated by searching the clinical trial registries, but the funnel plot asymmetry was not assessed because the number of studies in each meta-analysis was <10 according to the Cochrane handbook [15]. In studies of H. pylori eradication, the subgroup analyses were H. pylori eradication rate: ≥80% versus <80% [6]. The following sensitivity analyses were performed: (1) only the participants who completed the study with full data and (2) exclusion of studies with a high overall risk of bias.
Meta-analyses with a random-effects model were performed using the Review Manager software program (RevMan 5.4.1). The findings for the outcomes were summarized in a table based on the Cochrane handbook [15]. The quality of evidence was evaluated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [16]. Figure 1 shows the selection process. After the initial screening of titles and abstracts with 1274 records until 4 October 2020, 14 records were identified. After the full-text screening, three studies were excluded because of participants having urticaria but not chronic urticaria [17], non-RCTs [18] and inappropriate controls [19]. A total of 10 RCTs (including one trial without publication (IRCT2016082114333N56 [20])) were detected for the qualitative synthesis. Ultimately, 9 trials with 361 participants were included in the quantitative synthesis because 1 trial did not report the remission rate or clinical improvement of urticarial-related symptoms in the control groups [21].  Table 1 summarizes the characteristics of the studies included in the quantitative synthesis [10,[22][23][24][25][26][27][28][29]. Antibiotics were used in the H. pylori eradication regimen in six trials, while dapsones was used in three trials. The follow-up periods were within three months in five trials and beyond three months in four trials. Tables 2, A1 and A2 show the risk of bias. Overall, only one study had a high risk of bias due to deviations from intended interventions, missing outcome data and an unclear measurement of the outcomes.

Overall Risk of Bias
Valsecchi [22] Some concerns High High High Some concerns High Schnyder [23] Some concerns Low Low Low Some concerns Some concerns Gaig [24] Some concerns Low Low Low Some concerns Some concerns Elhendawy [27] Low Low Low Low Some concerns Some concerns Engin [10] Low Some concerns Low Some concerns Some concerns Some concerns Table 3 shows the summary of findings, which include an overall grading of the evidence related to each of the outcomes using the GRADE approach [16].  Dapsone had mild adverse events, such as nausea, fatigue, and headache.

Outcomes
CI, confidence interval; RR, risk ratio; SMD, standard mean difference. * The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence: High certainty: We are very confident that the true effect lies close to that of the estimated effect. Moderate certainty: We are moderately confident in the estimated effect. The true effect is likely to be close to the estimated effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the estimated effect is limited. The true effect may be substantially different from the estimated effect. Very low certainty: We have very little confidence in the estimated effect. The true effect is likely to be substantially different from the estimated effect. a Downgraded because of imprecision due to the small sample size. b Downgraded because of a high risk of bias because the assessment was likely influenced by knowledge of intervention.

Adverse Events
One study on H. pylori and three studies on dapsone were identified. One study on H. pylori and one study on dapsone reported no adverse events [10,13,28,29]. One study on dapsone reported that 3/38 (7.9%) patients in dapsone groups had drug-related symptoms (nausea in 2 patients and fatigue and headache in 1 patient), and 1/27 (3.7%) patients in control groups had gastrointestinal upset [10]. In another study on dapsone, 4/10 (40%) patients in dapsone groups had adverse events (nausea in 2 patients, vaginal candidiasis in 1 patient and mild neuropathy in 1 patient), and 3/12 (25%) patients in control groups had viral respiratory infections [29]. The evidence of certainty was low.

Discussion
H. pylori infection is thought to have a potential trigger for CUS, and it is thus searched during the diagnostic work-up of CSU, even though the epidemiological/clinical evidence is not very strong, or at least inconsistent [30,31]. In the present systematic review and meta-analyses, antibiotic therapy for H. pylori eradication increased the remission rate and induced improvement in CSU with few adverse events. Dapsone might not increase the remission rates and could improve CSU with mild adverse events. Given the results of RCTs only, both antibiotics were recognized to be useful for CSU.
There is an earlier review showing that antibiotics for H. pylori eradication suppressed CSU symptoms and improved remission with or without H. pylori eradication [8]. In our subgroup analysis, high eradication rates of H. pylori increased remission of CSU, while low eradication rates did not. Keeping such observations in mind, we consider several hypotheses concerning the mechanisms of the effect of antibiotics on CSU: (1) alleviation of inflammation, (2) favorable modulation of gut microbiota or (3) eradication of H. pylori itself (in CUS patients with H. pylori infection) [32]. First, CUS-related systemic inflammation is caused by activated mast cells and induced cytokines [33,34]. Some antibiotics, such as clarithromycin, attenuate proinflammatory cytokine production during the innate immune response by inhibiting Th2 cytokine secretion [35]. Second, the diversity of the microbiota is a regulator in the gut-skin axis [36][37][38][39]. Antibiotics can modulate favorably the microbiota, resulting in the reduction of systemic inflammation [40]. In addition, as H. pylori itself induced the release of histamine by mast cells, H. pylori eradication by antibiotics would have a favorable effect on the pathophysiology of CSU [41,42].
In the guidelines that included only one RCT in Europe, dapsone had little evidence on CSU [1,2]. The present review included three RCTs, suggesting that dapsone might not increase the remission rates but did improve the symptoms. The significant improvement in the symptoms by dapsone is important because patients with CSU have an impaired quality of life due to their symptoms [43]. The mechanism underlying the effects of dapsone on CSU remains unclear, but dapsone cannot affect H. pylori. The various antiinflammatory effects of dapsone seem to be involved; namely, dapsone prevents the production of 5-lipoxygenase products in neutrophils, downregulates leukotrienes and inhibits prostaglandin and leukotriene activities [44][45][46][47][48].
Our present finding that adverse events may be more likely to occur with dapsone than with H. pylori eradication should be interpreted with caution. In our review, only one of the six studies concerning H. pylori eradication reported adverse events, while all three studies concerning dapsone reported these data. In previous systematic reviews, antibiotic therapy for H. pylori eradication increased the rate of mild adverse events, such as gastrointestinal symptoms, compared to no eradication therapy [49,50]. Furthermore, dapsone has been safely used in the long term as a treatment for leprosy. However, patients using dapsone require regular examinations, as this agent causes some rare but major adverse events, such as met-hemoglobinemia, hemolysis, agranulocytosis and peripheral neuropathy with primarily motor function loss [43].
The present review has strengths compared to the previous systematic reviews [6][7][8]. First, a rigorous methodology was adopted according to the PRISMA statement [13], including a comprehensive search and duplicate assessments for evidence. Second, the GRADE approach was used to assess the certainty of the evidence [16]. Although the certainty was very low in a previous systematic review [6], the present review showed moderate evidence and provided a practical estimate of the effects of antibiotics for CUS. The present review had several limitations. First, this review included only antibiotics for H. pylori eradication and dapsone. Although previous studies have largely focused on antibiotics of H. pylori itself and inflammation, further studies focusing on three mechanisms, including gut microbiota, are needed. As candidates of other antibiotics, tetracycline used in bismuth quadruple therapy has a high eradication rate of H. pylori and improves urticaria [17,51]. Second, all studies included in this review had a small sample size. Further large-scale studies are needed to increase the certainty and generalizability of the evidence.

Conclusions
In conclusion, the present systematic review and meta-analysis showed that antibiotic therapies, especially those for H. pylori eradication, improved the remission rates and symptoms of CSU with few adverse events. These findings provide relevant information that physicians can use antibiotics for CSU. Further studies are warranted to assess the efficacy and safety of antibiotics on CSU.