Antistreptococcal treatment of psoriasis: a systematic review

Streptococcal infections may contribute to psoriasis development, and antistreptococcal treatments are considered potential therapies, but their effectiveness remains uncertain due to limited systematic evidence. Our objective was to analyze antistreptococcal therapies' effectiveness in improving psoriasis. We conducted a systematic review following PRISMA guidelines, evaluating antistreptococcal treatment efficacy in psoriasis patients from PubMed, Scopus, and Embase databases until August 14, 2022. Eligible studies included psoriasis patients undergoing antistreptococcal therapy, regardless of demographics or psoriasis type. 50 studies (1778 patients) were analyzed, with penicillins/aminopenicillins as the most studied antibiotics (21 studies), showing mixed outcomes, some reporting significant improvement in guttate psoriasis, while others showed no significant difference. Rifampin demonstrated positive results in most of ten studies, and macrolides showed varying effectiveness in two studies. Tonsillectomy in 14 studies (409 patients) mainly focusing on guttate and chronic plaque psoriasis showed positive outcomes, indicating improved symptoms and quality of life. Limitations include heterogeneous studies, sampling bias, and quality of evidence. This systematic review reveals limited and varied evidence for systemic antibiotic therapy efficacy in psoriasis treatment, while tonsillectomy emerges as a potentially beneficial antistreptococcal option, urging further well-designed, controlled studies with larger sample sizes and standardized protocols for better comparisons.


Introduction
Psoriasis is a common skin condition affecting approximately 2% of the population [1].The association between Streptococcus pyogenes infection and both guttate and plaque psoriasis has been well documented [2].It is theorized that treating an associated streptococcal infection in a patient with psoriasis will lead to improvement of the psoriasis.However, the effectiveness of treating psoriasis patients who have concurrent streptococcal infection with systemic antibiotics or tonsillectomy is still a matter of debate [3].Other reviews have been conducted to analyze anti-streptococcal therapy for psoriasis but have only included randomized controlled trials [4].While randomized controlled trials are considered the gold standard for evaluating treatment efficacy, they have certain limitations, including strict inclusion and exclusion criteria that may limit the generalizability of the findings.Therefore, in this review, we aim to conduct a comprehensive analysis of studies of all designs which evaluate the effectiveness of antistreptococcal therapy in improving psoriasis.

Literature search
This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in PROSPERO (338,776) [5].PubMed, Scopus, and Embase databases were searched from their inception until August 14, 2022.The search strategy was validated by a qualified and experienced healthcare librarian.Two authors independently screened abstracts to determine eligibility for inclusion in the systematic review based on the criteria below.Any disagreements were resolved by a third author.

Inclusion and exclusion criteria
All study designs were considered for inclusion.However, studies had to be original and include patients with any type of psoriatic lesions treated with any form of systemic antibiotics or tonsillectomy.Studies in languages other than English and studies without full text accessible were excluded.

Data extraction
When applicable, the following data were collected from each published study: title, author, year of publication, country, study design, aim of study, randomization, number of participants, sex, mean age, participant withdrawals or exclusions, duration of participation, psoriasis type, psoriasis severity, intervention, dosage, duration of treatment, co-interventions, outcomes, evaluation, and comparison to control.Two authors independently extracted data.

Risk of bias assessment
A risk of bias assessment was performed for each of the included articles.The Cochrane RoB 2.0 tool was used for RCTs, the ROBINS-I tool was used for non-randomized studies, the Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses was used for case-control studies, the JBI Critical Checklist for Case Series was used for case series, and the JBI Critical Checklist for Case Reports was used for case reports [6][7][8][9].Risk of bias assessment was conducted by one author and verified by a second author.

Efficacy of systemic antibiotic therapy
In total, 38 studies with a total of 1,369 patients investigated the efficacy of systemic antibiotic therapy in the treatment of psoriasis (Table 1).

Rifampin
Ten studies assessed rifampin's efficacy for improving psoriasis.Grozdev et al. [12] found rifampin significantly more effective than placebo in treating guttate psoriasis (p < 0.005), regardless of streptococcal infection.Notably, 12% of chronic plaque psoriasis patients achieved PASI 75 after 60 days.In another study by Grozdev et al. [13], 78% of guttate psoriasis patients with streptococcal  to 100% disappearance of lesions, good response = 80% to 95% improvement; less than good response < 80% improvement.F TBSA = total body surface area.This was estimated by the rule of nines, diminution of scaling, erythema, and thickness of erythroderma and plaque-type psoriasis, and disappearance of pustules in pustular psoriasis ASO = antistreptolysin-O infection achieved PASI 75 with rifampin vs. 72% without, compared to 41% with chronic plaque psoriasis and 20% with placebo.Tsankov et al. [15] demonstrated rifampin's superiority over placebo in reducing mean PASI for guttate psoriasis (p < 0.005), irrespective of streptococcal infection.Tsankov et al. [16] had similar findings using Physician Global Assessment (PGA).Vincent et al. [17] showed no clinical change with rifampin or placebo combined with penicillin V/erythromycin for guttate psoriasis (n = 20), despite streptococcal colonization evidence.In an open-label trial, Tsankov et al. [22] showed PASI improvement with rifampin, regardless of streptococcal infection (p < 0.001).Case series [32,36,38], and a case report [45] displayed positive responses to rifampin in streptococcalinfected psoriasis patients.

Efficacy of tonsillectomy
In 14 studies involving 409 patients (Table 2), the efficacy of tonsillectomy for psoriasis treatment was assessed.Thorleifsdottir et al. [18]

Discussion
The findings of this review suggest a potential role of systemic antibiotic therapy in the treatment of psoriasis, particularly guttate psoriasis, with or without confirmed streptococcal infection.Among 38 studies assessing systemic antibiotics' efficacy in psoriasis treatment, penicillins/aminopenicillins were most studied (21 studies).In the largest RCT, Dogra et al. [11] demonstrated significant improvement in PASI scores with penicillin treatment compared to placebo.Two studies [24,25] without control arms reported marked improvement in guttate psoriasis with penicillins.The effect size of the improvement in outcomes after treatment with penicillins was modest in the largest RCT, which  [12,13] both reported positive outcomes, with rifampin showing superiority over placebo in improving PASI scores.However, both studies showed no statistical difference in improvement when patients with confirmed streptococcal infection were compared to those without.Likewise, the RCTs by Tsankov et al. [15,16] showed significant improvement in PASI and PGA respectively for psoriasis patients treated with rifampin compared to placebo.In both studies, there was no significant difference in the response to rifampin comparing patients with guttate psoriasis with and without concomitant infection.This suggests that rifampin's positive outcomes are independent of a psoriasis patient's concurrent streptococcal infection.One possible rationale behind this independent influence could be attributed to rifampin's anti-inflammatory attributes rather than its antimicrobial properties [60].In dermatology, antibiotics, especially tetracyclines, are extensively employed for their antiinflammatory rather than antibacterial traits [61].Although primarily used to treat conditions like acne and hidradenitis suppurativa, these anti-inflammatory effects could potentially yield benefits in psoriasis as well.
Macrolides, evaluated in two RCTs and one case-control study, showed mixed results.Azithromycin demonstrated significant PASI improvement [14], while erythromycin's effect was inconclusive due to small sample sizes [10] and potential confounding by concurrent phototherapy [27].
Tonsillectomy's potential as a treatment for psoriasis was assessed across 14 studies, indicating favorable effects on patients with chronic plaque psoriasis and guttate psoriasis.Notably, Thorleifsdottir et al. [18] conducted an RCT revealing improved PASI scores in chronic plaque psoriasis patients post tonsillectomy.Additionally, another study by Thorleifsdottir et al. [19] exhibited a noteworthy reduction in Psoriasis Disability Index (PDI), indicating improved quality of life.While streptococcal infection confirmation was lacking, patients in these studies showed psoriasis exacerbation post throat infections.Observational studies demonstrated psoriasis symptom amelioration after tonsillectomy in cases of psoriasis vulgaris and recurrent tonsillitis.Similarly, Ueda et al. [26] found reduced mean SSS in PPP patients, and Takahara et al. [30] noted significant SSS and PPPASI score improvements at 12-and 24-months post tonsillectomy.Positive outcomes were also reported in case series and reports.
The evidence compiled in this review is mixed.Several studies demonstrated improved outcomes with various systemic antibiotics, especially in patients with guttate psoriasis.However, these studies exhibited significant variability in the antibiotics and dosages used.Future studies should compare the efficacy of varying doses of different antibiotics to identify an optimal treatment regimen for patients with guttate psoriasis.Furthermore, these studies should compare outcomes in patients with and without concurrent streptococcal infection.Although limited to studies with rifampin, current studies show no difference in benefit from antibiotics between patients with and without concurrent confirmed streptococcal infection.It may be the case that patients with guttate psoriasis benefit from antibiotic treatment regardless of their streptococcal infection status, making the common practice of testing for streptococcal infection in these patients unnecessary.When considering the repeated use of antibiotics for patients with recurrent streptococcal infections, it is important to carefully evaluate and weigh the risk of developing antibiotic resistance [62].The studies discussed in this review that assess the efficacy of tonsillectomy in patients with psoriasis suggest that it is beneficial in improving outcomes.Further studies are warranted to determine at what threshold a patient with psoriasis and recurrent streptococcal infections should be considered for tonsillectomy.Given the morbidity associated with tonsillectomy, it is important to weigh the risks of a tonsillectomy against the potential benefit to be gained in improving a patient's psoriasis.
Several limitations warrant consideration when interpreting the findings from this systematic review.Firstly, the included studies displayed heterogeneity in study design, patient attributes, treatment protocols, and outcome gauges.While enhancing generalizability, this heterogeneity limits the strength of assertions regarding the effectiveness of individual antistreptococcal treatments within distinct patient populations.Secondly, evident sampling bias arises from tonsillectomy studies solely encompassing patients with recurrent streptococcal infections, whereas certain antibiotic studies scrutinized patients lacking confirmed streptococcal infections.Thirdly, the quality of evidence exhibited variation among the encompassed studies, primarily consisting of observational studies and case reports.This limitation highlights the need for larger, controlled studies of antistreptococcal treatment in psoriasis.

Conclusion
This systematic review compiles the evidence for efficacy of antistreptococcal treatments, specifically systemic antibiotics and tonsillectomy, in the management of psoriasis.The findings suggest that systemic antibiotic therapy improves outcomes in psoriasis, especially guttate psoriasis and is not dependent on the presence of streptococcal infection.The antibiotic regimens used varied significantly, including penicillins, rifampin, and macrolides.Further research is required to identify an optimal systemic antibiotic treatment regimen for patients with psoriasis.Tonsillectomy showed efficacy in improving psoriasis and quality of life in patients in multiple studies.Further studies should delineate the patient population whose benefit from tonsillectomy outweighs the procedures associated risks.
, 1 = no change; 2 = moderate improvement (partial reduction in scaling and/or erythema and/or infiltration), 3 = considerable improvement (significant reduction in all three variables), and 4 = clearing (almost no skin changes left, except residual erythema as in macular psoriasis).b At least a 75% improvement in the Psoriasis Area and Severity Index.c Remission = no erythemous and squamous plaques; residual discoloration may be present, Marked improvement = single erythemous plaques are present; no desquamation; no infiltration; hypo-or hyperpigmented post-lesional macules are present, Improvement = more than 50% of the plaques are in remission; erythemous plaques with infiltration and desquamation; hypo-or hyperpigmented postlesional macules are present, No change = status idem, Worse = appearance of new erythemous and squamous plaques; dissemination and generalization of the lesions.d 31 (40%) patients were prescribed a penicillin antibiotic, 22 (28%) macrolide, 20 (25.5%) cephalosporin and 5 (6.5%) other antibiotic (2 tetracycline, 2 fluoroquinolone and 1 lincosamide).e Excellent response = 95%

Table 1
The efficacy of systemic antibiotics in the treatment of psoriasis [38]od etal.[32]included60patientswithout streptococcal testing.Tsankov et al.[38]included 10 patients, 6 with confirmed streptococcal infection.The remaining cases had confirmed streptococcal infection by culture/serology.

Table 2
The efficacy of tonsillectomy in the treatment of psoriasisThe skin severity score prior to tonsillectomy in each patient was defined as 10 points, regardless of the skin condition.The skin severity score at 3 months after tonsillectomy was rescored on hospital chart by a dermatologist and/