Oral doxycycline (40 mg/day; 30 mg immediate release and 10 mg delayed release) is a well-established, FDA-approved treatment option for rosacea (57). Its benefits have been validated by a phase III randomized controlled trial (49). Submicrobial doses of doxycycline can effectively alleviate inflammation by suppressing the production of proinflammatory cytokines, reactive oxygen species, nitric oxide synthetase, and MMPs, while also avoiding antibiotic resistance or dysbiosis (58, 59). Furthermore, doxycycline can inhibit the cathelicidin activation pathway and immune cell recruitment (59). These anti-inflammatory effects of doxycycline have led to its recommendation by treatment guidelines (46, 60). While tetracyclines are commonly used in rosacea and acne for their anti-inflammatory effects, their antimicrobial properties likely alter the composition of the skin microbiome. A systematic review found that these treatments mostly decrease Cutibacterium acnes and increase the alpha diversity of the cutaneous microbiota (61).

Other tetracyclines also demonstrate significant anti-inflammatory effects, including the inhibition of chemotaxis, granuloma formation, and proteases (62). Therefore, various tetracycline drugs, formulations, and dosages are commonly used off-label in rosacea treatment (62). These alternatives include tetracycline (250–1000 mg/day), doxycycline (100–200 mg/day), and minocycline (100–200 mg/day). These agents are effective against PPR (59, 63, 64).

Other forms of oral tetracyclines have recently shown efficacy in treating rosacea. DFD-29, a minocycline extended-release oral capsule (40 mg), exhibited a significantly higher level of efficacy than did placebo and doxycycline (40 mg) in the treatment of PPR with the plasma level of drug was maintained below its antimicrobial threshold (65).

A new generation tetracycline, sarecycline, has proven effective and safe in the treatment of PPR. Compared with control, sarecycline significantly improved patients’ IGA scores, reduced inflammatory lesion counts, and alleviated rosacea’s secondary symptoms such as burning sensation, without causing any adverse effects (66). While not extensively examined in humans, sarecycline has demonstrated anti-inflammatory activity comparable to doxycycline and minocycline in a rat paw edema model (67).

Notably, the mechanism of action of tetracyclines in rosacea primarily involves modulating immune dysregulation, not neurovascular dysregulation. Therefore, when using tetracyclines in patients with ETR, significant improvement is generally not expected (46). Tetracycline may inhibit the proinflammatory process induced by the ATP analogue in vascular endothelial cells in vitro (41, 68). While there may be a slight effect on persistent erythema, the level of evidence supporting this is not strong (46).

Azelaic acid gel (15%) is a well-established, FDA-approved topical agent. According to standard guidelines and multiple randomized controlled, double-blinded multicenter trials, azelaic acid is beneficial against mild to moderate inflammatory papules or pustules (46, 57, 60, 69, 70). However, it exhibits a low level of efficacy against erythema, primarily in patients with the papulopustular phenotype (51, 52). Azelaic acid works by suppressing KLK5 and cathelicidin expression and activating peroxisome proliferator-activated receptor γ, thus reducing the degrees of inflammatory responses and the levels of proinflammatory factors such as IL-1, IL-6, and TNF-α (71, 72). Additionally, this medication can suppress the UV-induced activation of nuclear factor (NF)-κB p65 subunit (73).

Minocycline foam 1.5% (FMX103), which was approved by the US FDA in 2020, was found to be effective and safe against moderate to severe papulopustular rosacea (PPR) in two 12-week, randomized, double-blinded, vehicle-control phase III trials (50). Another topical formulation is minocycline gel, whose 1% and 3% concentrations were tested in a 12-week, randomized, double‐blinded, vehicle‐controlled phase IIb trial; the results revealed that both concentrations, particularly the 3% concentration, significantly reduced inflammatory lesion counts and improved the Investigator’s Global Assessment (IGA) scores (74). As mentioned above, oral minocycline act as anti-inflammatory agents. While topical minocycline shows promise in delivering anti-inflammatory effects with reduced risk of systemic adverse effects, further evaluation is needed.

Isotretinoin is an off-label treatment option for rosacea. It is indicated for moderate to severe PPR (46, 57, 60). Isotretinoin is typically administered at a low daily dose (0.25–0.3 mg/kg) over a 4-month period; this is followed by a gradual dose reduction (54). Mechanistically, isotretinoin works by downregulating TLR2 expression in keratinocytes (53, 54). By inhibiting the activity of the sebaceous gland and reducing the production of sebum, isotretinoin can delay the progression of inflamed phyma when used during the prefibrotic phase of PPR (54, 75). Although the anti-inflammatory effect of isotretinoin might theoretically benefit erythema by inhibiting neuro- inflammation, its efficacy in treating erythema in rosacea patients shows inconsistent results (76). Some studies indicate that low-dose (0.25 mg/kg/day) isotretinoin is not effective in treating erythema and telangiectasia (77), while others suggest that an intermediate dose (20 mg/day) effectively improves erythema within four weeks (78).

Macrolide drugs, such as erythromycin, clarithromycin, and azithromycin, are secondary agents used in the systemic treatment of rosacea. For azithromycin, the dosage is 500 mg three times weekly for 4 weeks, followed by 250 mg three times weekly for additional weeks. For clarithromycin, the dosage is 250 mg twice daily for 4 weeks, followed by 250 mg once daily for the next 4 weeks. They are particularly useful for patients with contraindications to tetracycline, such as those who are refractory or pregnant (57, 79). The therapeutic effects of macrolides extend beyond their antimicrobial properties to include immunomodulatory effects. For example, azithromycin can modulate transcription factors such as NF-κB, reduce the release of inflammatory cytokines, impede the migration of neutrophils, inhibit the activation of neutrophils and eosinophils, and suppress the release of reactive oxygen species (57, 80). However, despite the low level of evidence for the efficacy of azithromycin in treating rosacea, its gastrointestinal adverse effects are increasingly becoming a concern (81, 82).

Hydroxychloroquine effectively suppresses the activation of mast cells by inhibiting Ca²⁺-activated K+ channels, leading to a reduction in local Ca²⁺ influx (83). This suppression results in the inhibition of inflammatory factor release, chemotaxis, and degranulation, ultimately reducing chemokine production and neutrophil and monocyte recruitment (83).

Patients who received hydroxychloroquine for 8 weeks exhibited improvements in their rosacea phenotypes along with improved IGA and Clinician Erythema Assessment (CEA) scores, indicating a tendency toward symptomatic relief (83). In a separate multicenter, randomized, double-blind, double-placebo pilot study, participants received either oral hydroxychloroquine (200 mg twice daily) or doxycycline (100 mg once daily) along with their respective placebos for 8 weeks; in this study, hydroxychloroquine was found to be noninferior to doxycycline in terms of rosacea-specific quality-of-life scores (84).

IL-17, a proinflammatory cytokine produced by Th17 cells, has been implicated in rosacea-related inflammation (31, 85). Th17 activation contributes to the upregulation of LL-37 expression, which, in turn, promotes the production of cathelicidin (85). The synergistic actions of LL-37 and IL-17 result in the release of C-X-C motif chemokine ligand 8 and IL-6, facilitating neutrophil chemotaxis and Th17 differentiation, respectively (85). This Th1/Th17 polarized inflammation, often underrecognized, is common across all subtypes of rosacea (31). In an exploratory study having an open-label, rater-blinded design, secukinumab, an IL-17A inhibitor, significantly reduced papule counts and improved global severity and median RosaQOL scores after 16 weeks of systemic therapy (86). However, more comprehensive and definitive evidence from high-quality randomized controlled trials is needed to fully understand the efficacy of secukinumab in the management of rosacea.

The JAK-STAT signaling pathway plays a pivotal role in the proinflammatory processes within immune cells. In the pursuit of effective rosacea treatments, oral JAK inhibitors like tofacitinib and abrocitinib have been explored (87, 88). A compelling case series involving 21 patients with erythematotelangiectatic and papulopustular rosacea demonstrated promising results, with 71.4% experiencing significant regression of facial erythema (IGA ≤ 1) and a mean change of -2.24 in the IGA score (87). Additionally, a separate case series highlighted the efficacy of abrocitinib in improving steroid-induced rosacea (88). These findings underscore the substantial potential of JAK inhibitors for broader utilization in the management of rosacea.

Pimecrolimus cream proves to be an effective treatment option for those with mild to moderate inflammatory rosacea (55). Pimecrolimus exhibits anti-inflammatory activity against PPR by inhibiting the activation of T cells, suppressing the production of inflammatory cytokines, and preventing the release of cytokines from T and mast cells through the inhibition of calcineurin phosphatase (89). The calcineurin inhibitor tacrolimus can treat erythema on rosacea patients (90). However, a higher level of evidence is available for 1% pimecrolimus than for tacrolimus (55, 56, 60). Prescribing these drugs should be done cautiously due to the potential risk of causing rosacea-like eruptions (91). The potential adverse events may be attributable to their immunosuppressive effects, which results in the overgrowth of microorganisms such as D. folliculorum (91). Therefore, pimecrolimus and tacrolimus may be regarded as dual-edged swords in the treatment of rosacea (91).

Mammalian target of rapamycin complex 1 (mTORC1) can regulate cathelicidin through a positive feedback loop (92). In this loop, LL-37 activates mTORC1 signaling by binding to TLR2, thereby upregulating the expression of cathelicidin in keratinocytes (92). Excess LL-37 may induce NF-κB activation through mTORC1 signaling, leading to the production of disease-specific cytokines and chemokines (92). Overexpression of TLR7 in keratinocytes stimulates the mTORC1 pathway through NF-κB signaling (93). In a pilot study involving 18 women with rosacea, the patients were randomized to receive either a placebo (n = 8) or 0.4% topical rapamycin (sirolimus) ointment (n = 10) for 4 weeks (92). After the intervention, the level of clinical improvement was significantly higher in the rapamycin group than in the placebo group. Topical treatment with rapamycin significantly reduced the patients’ CEA and IGA scores (92).

Artemisinin, a widely recognized antimalarial drug, effectively suppressed the infiltration of CD4+ T cells in a mouse model of LL-37-induced rosacea (94, 95). This drug also suppressed the LL-37-induced invasion of neutrophils and macrophages, thereby mitigating innate immune responses against rosacea (95). In HaCaT cells, artemisinin suppressed the release of proinflammatory factors, potentially through the NF-κB pathway (95). An open-label trial involving 130 patients with rosacea who received artemether emulsion, one of the most extensively studied lipid-based derivatives of artemisinin, revealed markedly reduced papule and pustule scores as early as 4 weeks into treatment; notably, the erythema scores of patients treated with artemether emulsion were similar to those of patients treated with standard metronidazole for 4 weeks (96).

The 26S proteasome, a protein complex responsible for NF-κB degradation, regulates the activation of NF-κB. Therefore, inhibiting the 26S proteasome can result in the inhibition of NF-κB; this offers a novel target for rosacea treatment. A two-arm, vehicle-controlled trial evaluated the efficacy of a novel proteasome inhibitor, topical ACU-D1—pentaerythritol tetrakis (3-(3, 5-di-tert-butyl-4-hydroxyphenyl) propionate). The trial included 27 patients in the active arm and 12 patients in the vehicle arm, all presenting with moderate to severe PPR. ACU-D1 was found to be safe and well-tolerated by the patients; it effectively reduced inflammatory lesions and erythema in the patients. Although this trial lacked the statistical power to determine between-arm significance, the evaluation of both efficacy and safety yielded favorable results (97).

Dapsone exerts its anti-inflammatory effects by inhibiting the production of ROS, mitigating the effects of eosinophil peroxidase on mast cells, and suppressing inflammatory responses mediated by neutrophils (98). A case report indicated sustained remission of granulomatous rosacea after the systemic administration of dapsone (dose: 100 mg/day) (99). A double-blind, randomized clinical trial involving 56 adults with PPR demonstrated that 5% dapsone gel exhibited efficacy similar to that of 0.75% metronidazole gel in improving IGA scores and reducing the lesion counts (100). The first to study dapsone use on ETR, reported that 5% dapsone gel used alone for 12 weeks showed significant improvement in the Investigators Global Assessment score, burning sensation, pruritus, edema, and erythema (101).

ϵ-Aminocaproic acid can effectively inhibit trypsin-like proteases, including KLK5, which regulates the cleavage of the cathelicidin precursor protein into LL-37 (102). In a randomized, double-blind, placebo-controlled study involving 11 patients with PPR, no significant differences in the IGA or CEA scores were noted between the treatment and placebo groups at any time point. Notably, in the treatment group, these scores were significantly improved in week 12 compared with baseline (102).

Tranexamic acid (TXA), an antifibrinolytic drug used to treat bleeding conditions, functions by inhibiting the conversion of plasminogen to plasmin, thus suppressing plasmin-induced angiogenesis (103). This suppression is achieved through the reduction of CD31⁺ microvessel counts and the downregulation of vascular endothelial growth factor expression (104). In the context of skin inflammation, TXA inhibits the production of TLR2, proinflammatory cytokines (IL-6 and TNF-α), and chemokines in keratinocytes primed by LL-37 (104). In an unblinded study, TXA solution–infused wet dressing and microneedling with TXA solution ameliorated the symptoms of erythematotelangiectatic rosacea (103). In a retrospective study investigating the effects of intradermal microinjections of TXA on erythematotelangiectatic rosacea, the observed improvements in symptoms persisted for 3 months (105). In a randomized, vehicle-controlled, split-face study, topical TXA enhanced the barrier function of the epidermal layer and alleviated the clinical signs of rosacea (106). These effects are attributed to the inhibition of protease activated receptor 2 activation, which reduces the calcium influx (106). For oral TXA, one study divided patients into two groups. Seventy patients were treated with doxycycline therapy plus oral TXA or doxycycline therapy alone for 8 weeks. The results showed that the TXA group had better outcomes compared to doxycycline (107).

Among drugs targeting neurovascular dysfunction in rosacea, two have received FDA approval (46). The first one is brimonidine topical gel (0.33%), which is a vasoconstrictive alpha-2 adrenergic receptor agonist acting on the microvascular smooth muscles of the facial skin (46). Brimonidine specifically addresses facial erythema instead of papules and pustules (60). Clinical trials ranging in duration from 1 month to 12 months have consistently demonstrated that topical brimonidine is both safe and effective as a maintenance therapy for rosacea (111, 112). A short-term multicenter, randomized study demonstrated its efficacy in improving moderate rosacea (at least a 1-grade improvement) (113). However, brimonidine is not effective in managing telangiectasia (57, 60). Brimonidine had significant risk of developing adverse effects include local erythema, pruritus, burning sensation, and exacerbated flushing symptoms (57, 60, 114).

Oxymetazoline is the second FDA-approved vasoconstrictor for the topical management of persistent erythema in patients with rosacea (46). As a sympathomimetic agent, oxymetazoline acts as a selective alpha1A adrenoreceptor agonist, exhibiting vasoconstrictive and anti-inflammatory properties (57). Multiple phase III clinical trials have reported that 1% oxymetazoline hydrochloride cream, administered for either 29 days or 52 weeks, was well-tolerated, safe, and effective in treating persistent facial erythema in patients with rosacea (115–117). Only a small proportion of patients experienced adverse effects such as apparent worsening of facial erythema, rebound effects, and occasional paradoxical erythema (115–117). A meta-analysis of adverse effects found that using oxymetazoline, compared to the vehicle, had a significantly higher risk of application-site dermatitis (RR = 8.91, 95% CI: 1.76–45.23), while other adverse effects did not show significant statistical differences (118). These findings highlight the differences between oxymetazoline and topical brimonidine in terms of safety and efficacy (114).

The potential mechanism of action of non-selective beta-blockers lies in the inhibition of beta-2 receptors on cutaneous blood vessels, reducing vasodilation (108). Additionally, systemic administration exhibits a reduction in sympathetic tone, thereby alleviating patient anxiety (119). A systematic review indicates that carvedilol and propranolol are effective for rosacea patients with persistent facial erythema and flushing (108). For carvedilol, the dosage ranges from 6.25 to 37.5 mg daily, which can be divided into doses such as 6.25 mg twice daily. For propranolol, the dosage is typically 30-40 mg daily. In a randomized controlled trial, carvedilol demonstrated superior efficacy compared to brimonidine in addressing telangiectasia and facial erythema (120). Moreover, carvedilol significantly improved patients’ depression or anxiety status (120). While beta-blockers offer alternative therapeutic options for rosacea, it is essential to be cautious about common side effects such as hypotension, bradycardia, bronchospasm, and dizziness (121).

Treatment with paroxetine, a potent selective serotonin (5-HT) reuptake inhibitor, led to improvements in CEA scores, flushing, and burning sensation in a multicentered, randomized, double-blinded, and placebo-controlled trial involving patients with rosacea (109). Paroxetine modulates 5-HT uptake, and dysfunctional 5-HT regulation may result in abnormal blood vessel dilation and constriction (2, 122, 123). Mast cells and platelets were also proved to release 5-HT in several inflammatory skin diseases (124, 125). An association has been reported between rosacea and a single-nucleotide polymorphism of the 5-HT2A receptor (126).

PACAP is a potent vasodilator that directly affects smooth muscle cells in arterioles (127). A study reported elevated levels of PACAP expression in rosacea-affected tissues, suggesting its potential relevance in TRPV-mediated edema (29). Another study utilizing both clinical and experimental models confirmed that PACAP38 induces sustained flushing and facial edema (110). In a double-blind, randomized, placebo-controlled, crossover trial, sumatriptan alleviated these symptoms (110). Sumatriptan acts as a 5-HT1B/1D receptor agonist, inhibiting mast cell degranulation and reducing PACAP levels (128, 129). A case report suggested that oral sumatriptan (50 mg) successfully treated a patient with severe and painful rosacea, markedly reducing burning sensation, swelling, redness, and pain (130).

Erenumab, galcanezumab, fremanezumab, and eptinezumab are four FDA-approved monoclonal antibodies that target CGRP. These antibodies are primarily used for preventing migraine (131, 132). Another novel oral CGRP inhibitor in the pipeline for chronic migraine is atogepant (133). CGRP is involved in the pathophysiology of migraine through nociceptive processes in the trigeminovascular system (134). Notably, CGRP serves as a vasoactive neurotransmitter in rosacea, causing vasodilation and inducing inflammatory response (3, 135). In 2020, an exploratory trial was initiated to investigate the efficacy and tolerability of erenumab in the preventive treatment of persistent redness and flushing associated with rosacea; this trial was anticipated to conclude in 2021 (136). Furthermore, an exploratory comparative case series involving 13 patients explored the benefits of CGRP monoclonal antibodies for patients with both rosacea and migraine (28). The results revealed marked posttreatment improvements in the patients’ severity scores (28). However, two patients experienced dermatitis at the injection site (28). Although most patients in this study experienced improvements in rosacea, large-scale randomized clinical trials are still needed to confirm the efficacy and safety of CGRP monoclonal antibodies.

Botulinum toxin (BTX) improves neurovascular dysfunction in rosacea by blocking the release of neurotransmitters, such as acetylcholine, calcitonin gene-related peptide, vasoactive intestinal peptide, substance P, and glutamate, or by reducing non-noxious stimulation (135, 137, 138). This action inhibits the skin’s vasodilator system (stimulated by peripheral autonomic nerves), thereby suppressing rosacea-associated neuroinflammation and vasodilation (4, 139). BTX inhibits the activation of TRPV1 by disrupting the lipid raft activity associated with TRPV1 through structural and functional interactions with it (140). Moreover, BTX directly blocks the degranulation of mast cells by cleaving SNARE protein in these cells (141). In a randomized, controlled, split-face study involving 22 patients, one side of the cheek was treated with a combination of BTX and broadband light. Compared with the pretreatment condition and control groups, the experimental group exhibited reduced global flushing symptom scores, erythema index scores, transepidermal water loss, and sebum secretion (142). The effects of using BTX typically appear within 1-2 weeks and can last for 3-6 months. The most common side effect was localized pain, while the rarer and more concerning side effect was paralysis of motor muscles, with a pooled incidence of 4.3% (95% CI: 1.8 - 7.8%). Most cases of paralysis resolved on their own (143).

Because of its dual efficacy as an antibiotic and antiparasitic agent, FDA-approved topical metronidazole is widely used for the treatment of rosacea across the globe and indirectly reduces inflammation by putative reduction of Demodex colonization. Demodex mites are implicated in the pathogenesis of rosacea, and the antiparasitic effect of metronidazole plays a key role in this context (57). Metronidazole’s efficacy in rosacea treatment is also attributed to its anti-inflammatory, immunosuppressive, and antioxidative characteristics, involving the reduction of reactive oxygen species production from neutrophils and inhibition of IL-17 (152–154). The efficacy of topical metronidazole is supported by clinical trials, including randomized, placebo-controlled double-blind studies, as highlighted in a Cochrane review (82, 144). Clinical guidelines recommend topical metronidazole for the treatment of PPR (46, 57, 60). The efficacy of oral metronidazole was evaluated in a double-blind trial, where a combination therapy comprising metronidazole (200 mg twice a day) and 1% hydrocortisone cream was administered for 6 weeks; this therapy reduced the severity of rosacea in 10 out of 14 patients (147).

The US FDA have approved 1% ivermectin cream for the treatment of PPR (155). Clinical guidelines recommend topical ivermectin as a first-line treatment for rosacea, citing high-level evidence for its efficacy in addressing papules and pustules—the key features of rosacea (46, 60). A 2016 network meta-analysis identified ivermectin 1% cream to be the most effective treatment option for inflammatory papules and pustules (145). Regarding the Demodex decrease rate, both topical and systemic ivermectin are superior to other anti-Demodex therapies, achieving nearly a 100% decrease rate (156). Its therapeutic mechanism involves effectively reducing Demodex infestation through neurotoxic activity (157). Owing to its anti-inflammatory properties, ivermectin reduces the levels of IL-1b and TNF-α while increasing the level of IL-10. Additionally, ivermectin reduces the expression of proinflammatory genes such as IL-8, LL-37, human β-defensin 3, and TNF-α (158). At the protein level, significant reductions were observed in the levels of LL-37 and IL-8 (158).

The US FDA-approved topical treatment also included sulfur preparations in various formulation such as creams, gels and cleansers. The most common formulation is sodium sulfacetamide, 10% (46). Sulfur preparations have shown positive effects on both erythematotelangiectatic rosacea (ETR) and papulopustular rosacea (PPR), similar to metronidazole (159). This effect may be due to the significant reduction in Demodex count with the sulfur-sodium combination (160). However, sulfur has a more noticeable irritating effect compared to metronidazole, permethrin, lindane, and crotamiton (161).

Benzoyl peroxide, a potent oxidizing agent, is commonly used in acne treatment (155) and indirectly reduces inflammation through putative antibacterial effects. In 2022, the US FDA approved encapsulated cream benzoyl peroxide (E-BPO) 5% for patients with rosacea (155). The advantage of this silica-based encapsulated formulation is that it facilitates a gradual release of benzoyl peroxide into the skin. This approach enhances efficacy and prevents skin irritation associated with traditional bolus formulations of benzoyl peroxide, thereby improving tolerability (155, 162). Although E-BPO’s mechanism of action in the treatment of rosacea remains hypothetical, it primarily centers around the antibacterial effect of this drug (136, 163). In two 12-week, identical, parallel, randomized, double-blind phase III trials, a high proportion of E-BPO-treated patients achieved a clear/almost clear status in the IGA and a reduced lesion count (146). However, a few adverse events were noted; these included pain, erythema, pruritus, and edema (146). Furthermore, a 52-week, single-arm phase III trial investigating the long-term use of E-BPO indicated that prolonged E-BPO use is a safe and well-tolerated therapeutic approach (164).

The role of Demodex mites in the development of rosacea is well-established and its anti-inflammatory effect is indirect though putative reduction of mites that may stimulate the immune system. Researchers have explored permethrin, an antiparasitic belonging to the pyrethrin group, as a treatment choice for rosacea (154). The results indicated a notable decrease in the density of Demodex mites, indicating permethrin as a primary treatment choice for Demodex infestation (165). In a 12-week, double-blind study involving 20 patients with PPR, the application of 5% permethrin cream resulted in a marked reduction in the density of Demodex mites and an improvement in the symptoms of rosacea compared with the effects of a cream base (140). However, the use of permethrin for the treatment of rosacea is currently considered off-label.

Omiganan is an anti-microbial peptide tested against rosacea. In randomized, double-blind, vehicle-controlled, parallel-group, multicenter phase III trial involving patients with severe PPR, topical application of 1.6% omiganan gel significantly outperformed the vehicle in reducing mean inflammatory lesion counts and improving IGA scores in week 12 compared with baseline (149). The underlying mechanism of action involves the rapid bactericidal and fungicidal effects of omiganan against a wide range of pathogens (166).

Rifaximin, a non-absorbed, gut-active antibiotic with broad-spectrum efficacy, is used to treat small intestinal bacterial overgrowth (SIBO) (155). Studies have indicated a higher prevalence of SIBO among patients with rosacea than in the normal population (167, 168). Administering rifaximin to these patients not only mitigate SIBO but also ameliorate rosacea symptoms. The underlying mechanism suggests that SIBO disrupts immunity, triggering rosacea by increasing the levels of TNF-α or other cytokines, reducing the level of IL-17, and stimulating Th1-mediated immune response (150). In a prospective trial involving 113 patients, a 10-day treatment rifaximin (1200 mg/day) significantly reduced the number of cutaneous lesions compared with the findings in the control group (150). Nonetheless, further research is needed to confirm the efficacy of rifaximin. In 2022, a phase IIa, multicenter, double-blind, placebo-controlled, randomized clinical trial (NCT 05150587) investigated the efficacy and safety of extended-release rifaximin against moderate to severe rosacea (169). The research results are yet to be published.