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.

Methods and materials

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.

Results

Our initial search of the literature yielded 2,630 non-duplicate studies for screening. After full-text screening, we narrowed our study pool to 50. Of these 50 studies, 38 studies evaluated the efficacy of systemic antibiotics, while 12 studies evaluated the efficacy of tonsillectomy, and two studies evaluated both (McMillin and Whyte). The studies consisted of 10 randomized controlled trials (RCTs) [10,11,12,13,14,15,16,17,18,19], 3 open-label studies [20,21,22], 1 crossover trial [23], 2 single-arm studies [24, 25], 1 prospective observational study [26], 1 case–control study [27], 1 retrospective questionnaire analysis [28], 2 cohort studies [29, 30], 13 case series [31,32,33,34,35,36,37,38,39,40,41,42,43], and 16 case reports [44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59].

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).

Table 1 The efficacy of systemic antibiotics in the treatment of psoriasis
Full size table

Penicillins/aminopenicillins

Twenty-one studies assessed penicillins/aminopenicillins' effectiveness. Two RCTs [10, 11] investigated penicillin's role in psoriasis treatment. Dogan et al. [10] found no significant PASI score differences in guttate psoriasis patients treated with benzathine phenoxymethylpenicillin (n = 14), erythromycin (n = 14), or no treatment (n = 15). All 43 patients had confirmed streptococcal infection. Conversely, Dogra et al. [11] demonstrated notable PASI improvement in moderate-to-severe chronic plaque psoriasis (n = 50) with penicillin treatment (400 mg twice daily for 12 weeks) compared to placebo (n = 50), without testing for streptococcal infection. An open-label study [20] by Caca-Biljanovska et al. showed no significant difference in mean PASI change for guttate psoriasis patients treated with penicillin (n = 10) alongside steroids and phototherapy, compared to without penicillin (n = 10). Two single-arm trials [24, 25] found penicillin effective: Masood et al. [24] in acute guttate psoriasis (n = 100; 80% cleared) and exacerbations (n = 80; 50% cleared), and Saxena et al. [25] in chronic plaque psoriasis (n = 30), with positive ASO titers in 50% and streptococcus cultures in 7%. Bedi et al. [29] found improvement in guttate psoriasis (n = 4) with penicillin (130 mg thrice daily) and confirmed throat streptococcal infection, but lesions often recurred post-treatment. Five [31, 33, 35, 36, 39] of six case series showed positive penicillin outcomes, while one [34] reported ineffectiveness for guttate psoriasis. Eight case reports [45,46,47,48,49,50,51, 53] noted psoriasis resolution with penicillin, amoxicillin, or amoxicillin-clavulanate, but one [54] didn't respond to amoxicillin. McMillin et al.’s [33] case series lacked streptococcal testing. Remaining case series and reports confirmed streptococcal infection by culture or serology.

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 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 streptococcal-infected psoriasis patients. Masood et al. [32] included 60 patients without streptococcal testing. Tsankov et al. [38] included 10 patients, 6 with confirmed streptococcal infection. The remaining cases had confirmed streptococcal infection by culture/serology.

Other systemic antibiotics

Two randomized controlled trials (RCTs) assessed macrolides' efficacy in improving psoriasis. In an RCT by Dogan et al. [10], erythromycin showed no significant improvement in PASI. Another RCT by Saxena et al. [14] examined azithromycin (n = 30) and vitamin C tablets (n = 20) in chronic plaque psoriasis patients. After 48 weeks, the azithromycin group displayed a notable mean PASI change (21.65 ± 0.83) versus the vitamin C group (0.40 ± 0.83) (p < 0.001). ASO titers were > 200 IU/ml in 54% of patients. Polat et al. [21] conducted an open-label trial comparing erythromycin and topical steroids to steroids alone. The treatment group (n = 36) showed a statistically significant mean PASI change (8.57 ± 2.90) compared to the control group (n = 24) (p = 0.03). Streptococcal culture was positive for 2 patients in the treatment arm. In a crossover trial by Ward et al. [23] on palmoplantar pustulosis patients (n = 60), clomocycline and placebo were examined, with 37% non-response, 25% preference for clomocycline, and 3% for placebo. Streptococcal infection was not reported. Farrell et al. [27] conducted a case–control study on guttate psoriasis patients (n = 230) treated with antibiotics (n = 78) versus controls (n = 152) with ASO titers > 200 IU/ml in all. Various antibiotics were used, including penicillin (40%), macrolide (28%), cephalosporin (25.5%), and others (6.5%). Antibiotics did not significantly affect time to clearance compared to controls (χ2 = 0.92, p = 0.82). Four case series [31, 34, 36, 37] on erythromycin/terramycin for streptococcal-induced guttate psoriasis reported positive outcomes. Additionally, five case reports [44, 46, 52, 55, 56] demonstrated positive results for cephalexin, clindamycin, and erythromycin. All cases confirmed streptococcal infection by culture or serology.

Efficacy of tonsillectomy

In 14 studies involving 409 patients (Table 2), the efficacy of tonsillectomy for psoriasis treatment was assessed. Thorleifsdottir et al. [18] conducted an RCT comparing tonsillectomy (n = 15) with control (n = 14) in chronic plaque psoriasis patients with a history of psoriasis exacerbation after throat infections. Without streptococcal testing, 13 of 15 participants showed 30–90% reduction in PASI score, with 50% lesion reduction in 9 of 15. The control group demonstrated no improvement; 86% used topical treatment vs. 27% in the treatment group. Similarly, Thorleifsdottir et al. [19] noted reduced Psoriasis Disability Index (PDI) in treatment over time (p = 0.026) and vs. controls (p = 0.037). Ueda et al. [26] prospectively studied post-tonsillectomy pustulosis palmaris et plantaris (PPP, n = 33) using skin severity scores (SSS); post-tonsillectomy mean SSS was 3.5 ± 2.2. Nyfors et al. [28] retrospectively analyzed 74 psoriasis vulgaris patients; after tonsillectomy, 32% cleared, 39% improved, 22% unchanged, 7% worsened. Takahara et al. [30] assessed 138 PPP patients post-tonsillectomy for SSS (n = 138) and Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI)(n = 80); 44% and 78% showed complete improvement at 12 and 24 months, respectively, with 70% and 95% seeing 80% + improvement. Fifty percent of patients had positive ASO antibodies. Six case series [33, 39,40,41,42,43] demonstrated tonsillectomy's efficacy, mainly in streptococcal-associated guttate and chronic plaque psoriasis. Two case reports [57, 58] detailed guttate psoriasis patients; psoriasis resolved post-tonsillectomy. One case report [59] investigated plaque psoriasis; PASI reduced from 26.8 to 1 after tonsillectomy. The remaining case series and reports included patients with confirmed streptococcal infection via culture or serology.

Table 2 The efficacy of tonsillectomy in the treatment of psoriasis
Full size table

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 may explain why the two smaller studies [10, 20] with controls were not powered to detect a difference in outcomes. Additional larger studies with control groups are needed to confirm penicillin antibiotics' benefit in psoriasis treatment. Studies should stratify outcomes based on confirmed streptococcal infection presence, providing insight into antibacterial or anti-inflammatory effects.

Rifampin, evaluated in ten studies (including five RCTs), demonstrated effectiveness in treating psoriasis, particularly in guttate psoriasis. The RCTs conducted by Grozdev et al. [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 anti-inflammatory 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.