Psoriasis

The U.S. Food and Drug Administration has approved the biosimilar adalimumab-aaty (Yuflyma) in a citrate-free, high-concentration formulation, the manufacturer, Celltrion USA, announced today. It is the ninth biosimilar of adalimumab (Humira) to be approved in the United States.
 

Yuflyma is approved for the treatment of adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. It is also approved for polyarticular juvenile idiopathic arthritis for patients aged 2 years or older, as well as for Crohn’s disease in adults and in pediatric patients aged 6 years or older.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The formulation was approved on the basis of a comprehensive data package of analytic, preclinical, and clinical studies, according to Celltrion USA, “demonstrating that Yuflyma is comparable to the reference product Humira in terms of efficacy, safety, pharmacokinetics, and immunogenicity up to 24 weeks and 1 year following treatment.”

The company conducted a double-blind, randomized phase 3 trial that compared switching from reference adalimumab to Yuflyma with continuing either reference adalimumab or Yuflyma for patients with active rheumatoid arthritis. In that trial, the efficacy, pharmacokinetics, safety, and immunogenicity of Yuflyma and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to Yuflyma.

“Currently, more than 80% of patients treated with Humira in the United States rely on a high-concentration and citrate-free formulation of this medication. The availability of a high-concentration and citrate-free formulation adalimumab biosimilar provides an important treatment option for patients with inflammatory diseases who benefit from this effective therapy,” said Jonathan Kay, MD, of the University of Massachusetts, Worcester, in the press release.

The citrate-free formulation is thought to lead to less pain on injection.

Yuflyma will be available in prefilled syringe and autoinjector administration options.

Celltrion USA plans to market the drug in the United States in July 2023. Following the initial launch of 40 mg/0.4 mL, the company plans to launch dose forms of 80 mg/0.8 mL and 20 mg/0.2 mL.

Celltrion USA is also seeking an interchangeability designation from the FDA following the completion of an interchangeability trial of 366 patients with chronic plaque psoriasis. The interchangeability designation would mean that patients successfully switched from Humira to Yuflyma multiple times in the trial. The interchangeability designation would allow pharmacists to autosubstitute Humira with Yuflyma. In these cases, individual state laws control how and whether physicians will be notified of this switch.

If interchangeability is approved for Yuflyma, which the company tentatively expects in the fourth quarter of 2024, it would be just the third interchangeable biosimilar approved by the FDA overall and the second adalimumab biosimilar to be designated as such, after adalimumab-adbm (Cyltezo) in October 2021.

Yuflyma was approved in Canada in December 2021 for 10 indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

In February 2022, the European Commission granted marketing authorization for Yuflyma across those 10 indications, as well as for nonradiographic axial spondyloarthritis, pediatric plaque psoriasis, and pediatric Crohn’s disease.

In April 2022, Celltrion USA signed a licensing agreement with AbbVie, the manufacturer of Humira. Under that agreement, Celltrion will pay royalties to AbbVie on sales of their individual biosimilars, and AbbVie agreed to drop all patent litigation.

The full prescribing information for Yuflyma is available here.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved the biosimilar adalimumab-aaty (Yuflyma) in a citrate-free, high-concentration formulation, the manufacturer, Celltrion USA, announced today. It is the ninth biosimilar of adalimumab (Humira) to be approved in the United States.
 

Yuflyma is approved for the treatment of adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. It is also approved for polyarticular juvenile idiopathic arthritis for patients aged 2 years or older, as well as for Crohn’s disease in adults and in pediatric patients aged 6 years or older.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The formulation was approved on the basis of a comprehensive data package of analytic, preclinical, and clinical studies, according to Celltrion USA, “demonstrating that Yuflyma is comparable to the reference product Humira in terms of efficacy, safety, pharmacokinetics, and immunogenicity up to 24 weeks and 1 year following treatment.”

The company conducted a double-blind, randomized phase 3 trial that compared switching from reference adalimumab to Yuflyma with continuing either reference adalimumab or Yuflyma for patients with active rheumatoid arthritis. In that trial, the efficacy, pharmacokinetics, safety, and immunogenicity of Yuflyma and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to Yuflyma.

“Currently, more than 80% of patients treated with Humira in the United States rely on a high-concentration and citrate-free formulation of this medication. The availability of a high-concentration and citrate-free formulation adalimumab biosimilar provides an important treatment option for patients with inflammatory diseases who benefit from this effective therapy,” said Jonathan Kay, MD, of the University of Massachusetts, Worcester, in the press release.

The citrate-free formulation is thought to lead to less pain on injection.

Yuflyma will be available in prefilled syringe and autoinjector administration options.

Celltrion USA plans to market the drug in the United States in July 2023. Following the initial launch of 40 mg/0.4 mL, the company plans to launch dose forms of 80 mg/0.8 mL and 20 mg/0.2 mL.

Celltrion USA is also seeking an interchangeability designation from the FDA following the completion of an interchangeability trial of 366 patients with chronic plaque psoriasis. The interchangeability designation would mean that patients successfully switched from Humira to Yuflyma multiple times in the trial. The interchangeability designation would allow pharmacists to autosubstitute Humira with Yuflyma. In these cases, individual state laws control how and whether physicians will be notified of this switch.

If interchangeability is approved for Yuflyma, which the company tentatively expects in the fourth quarter of 2024, it would be just the third interchangeable biosimilar approved by the FDA overall and the second adalimumab biosimilar to be designated as such, after adalimumab-adbm (Cyltezo) in October 2021.

Yuflyma was approved in Canada in December 2021 for 10 indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

In February 2022, the European Commission granted marketing authorization for Yuflyma across those 10 indications, as well as for nonradiographic axial spondyloarthritis, pediatric plaque psoriasis, and pediatric Crohn’s disease.

In April 2022, Celltrion USA signed a licensing agreement with AbbVie, the manufacturer of Humira. Under that agreement, Celltrion will pay royalties to AbbVie on sales of their individual biosimilars, and AbbVie agreed to drop all patent litigation.

The full prescribing information for Yuflyma is available here.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved the biosimilar adalimumab-aaty (Yuflyma) in a citrate-free, high-concentration formulation, the manufacturer, Celltrion USA, announced today. It is the ninth biosimilar of adalimumab (Humira) to be approved in the United States.
 

Yuflyma is approved for the treatment of adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. It is also approved for polyarticular juvenile idiopathic arthritis for patients aged 2 years or older, as well as for Crohn’s disease in adults and in pediatric patients aged 6 years or older.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The formulation was approved on the basis of a comprehensive data package of analytic, preclinical, and clinical studies, according to Celltrion USA, “demonstrating that Yuflyma is comparable to the reference product Humira in terms of efficacy, safety, pharmacokinetics, and immunogenicity up to 24 weeks and 1 year following treatment.”

The company conducted a double-blind, randomized phase 3 trial that compared switching from reference adalimumab to Yuflyma with continuing either reference adalimumab or Yuflyma for patients with active rheumatoid arthritis. In that trial, the efficacy, pharmacokinetics, safety, and immunogenicity of Yuflyma and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to Yuflyma.

“Currently, more than 80% of patients treated with Humira in the United States rely on a high-concentration and citrate-free formulation of this medication. The availability of a high-concentration and citrate-free formulation adalimumab biosimilar provides an important treatment option for patients with inflammatory diseases who benefit from this effective therapy,” said Jonathan Kay, MD, of the University of Massachusetts, Worcester, in the press release.

The citrate-free formulation is thought to lead to less pain on injection.

Yuflyma will be available in prefilled syringe and autoinjector administration options.

Celltrion USA plans to market the drug in the United States in July 2023. Following the initial launch of 40 mg/0.4 mL, the company plans to launch dose forms of 80 mg/0.8 mL and 20 mg/0.2 mL.

Celltrion USA is also seeking an interchangeability designation from the FDA following the completion of an interchangeability trial of 366 patients with chronic plaque psoriasis. The interchangeability designation would mean that patients successfully switched from Humira to Yuflyma multiple times in the trial. The interchangeability designation would allow pharmacists to autosubstitute Humira with Yuflyma. In these cases, individual state laws control how and whether physicians will be notified of this switch.

If interchangeability is approved for Yuflyma, which the company tentatively expects in the fourth quarter of 2024, it would be just the third interchangeable biosimilar approved by the FDA overall and the second adalimumab biosimilar to be designated as such, after adalimumab-adbm (Cyltezo) in October 2021.

Yuflyma was approved in Canada in December 2021 for 10 indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

In February 2022, the European Commission granted marketing authorization for Yuflyma across those 10 indications, as well as for nonradiographic axial spondyloarthritis, pediatric plaque psoriasis, and pediatric Crohn’s disease.

In April 2022, Celltrion USA signed a licensing agreement with AbbVie, the manufacturer of Humira. Under that agreement, Celltrion will pay royalties to AbbVie on sales of their individual biosimilars, and AbbVie agreed to drop all patent litigation.

The full prescribing information for Yuflyma is available here.

A version of this article first appeared on Medscape.com.

Psoriasis is an inflammatory autoimmune skin condition that affects approximately 125 million individuals worldwide, with approximately 8 million patients in the United States.¹ Psoriasis not only involves a cosmetic component but also comprises other comorbidities, such as psoriatic arthritis, cardiovascular disease, and psychiatric disorders, that can influence patient quality of life.^2-4 In addition, the costs associated with psoriasis are substantial, with an estimated economic burden of $35.2 billion in the United States in 2015.⁵ Given the prevalence of psoriasis and its many effects on patients, it is important that providers have high-quality evidence regarding efficacious treatment options.

Systematic reviews, which compile all available evidence on a subject to answer a specific question, represent the gold standard of research.⁶ However, studies have demonstrated that when referencing research literature, physicians tend to read only the abstract of a study rather than the entire article.^7,8 A study by Marcelo et al⁸ showed that residents at a tertiary care center answered clinical questions using only the abstract of a paper 69% of the time. Based on these findings, it is imperative that the results of systematic reviews be accurately reported in their abstracts because they can influence patient care.

Referencing only the abstracts of systematic reviews can be problematic if the abstract contains spin. Spin is a form of reporting that inappropriately highlights the benefits of a treatment with greater emphasis than what is shown by the results.⁹ Research has identified the presence of spin in the abstracts of randomized controlled trials.^10-12 For example, Cooper et al¹⁰ found that 70% (33/47) of abstracts in otolaryngology randomized controlled trials contained spin. Additionally, Arthur et al¹¹ and Austin et al¹² had similar findings within abstracts of orthopedic and obesity trials, where 44.8% (112/250) and 46.7% (21/45) contained spin, respectively. Ottwell et al¹³ found that the presence of spin in abstracts is not limited to randomized controlled trials; they demonstrated that the abstracts of nearly one-third (31% [11/36]) of systematic reviews focused on the treatment of acne vulgaris contained spin.

In our study, we aimed to evaluate the presence of spin in the abstracts of systematic reviews focused on the treatment of psoriasis.

Methods

Reproducibility and Reporting—Our study did not meet the regulatory definition for human subjects research per the US Code of Federal Regulations because the study did not involve human research subjects. The study also was not subject to review by the institutional review board. Our protocol, data set, analysis scripts, extraction forms, and other material related to the study have been placed on Open Science Framework to provide transparency and ensure reproducibility. To further allow for analytic reproducibility, our data set was given to an independent laboratory and reanalyzed with a masked approach. Our study was carried out alongside other studies assessing spin in systematic reviews regarding different specialties and disease states. Because these studies were similar in design, this methodology also has been reported elsewhere. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)¹⁴ and the guidelines for meta-epidemiological studies developed by Murad and Wang¹⁵ were used in drafting this article.

Search Strategy—The search strategies for the MEDLINE (Ovid) and Embase (Ovid) databases were created by a systematic review librarian (D.N.W.) to identify systematic reviews and meta-analyses regarding treatments for psoriasis (Figure 1). The searches were performed on June 2, 2020, and uploaded to Rayyan, a systematic review screening platform.¹⁶ After duplicates were removed, the records were screened for eligibility by 2 authors (C.H. and A.L.) using the titles and abstracts. Screening was conducted independently while each of these authors was masked to the other’s results; disagreements were resolved through discussion.

Eligibility Criteria—An article had to meet the following criteria for inclusion in our study: (1) be a systematic review with or without a meta-analysis; (2) relate to the treatment of psoriasis; and (3) be written in English and include human patients only. The PRISMA definition of systematic reviews and meta-analyses was applied.¹⁷

Training—Various training occurred throughout our study to ensure understanding of each step and mitigate subjectivity. Before beginning screening, 2 investigators (C.H. and A.L.) completed the Introduction to Systematic Review and Meta-Analysis course offered by Johns Hopkins University.¹⁸ They also underwent 2 days of online and in-person training on the definition and interpretation of the 9 most severe types of spin found in the abstracts of systematic reviews as defined by Yavchitz et al.⁹ Finally, they were trained to use A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) to appraise the methodological quality of each systematic review. Our protocol contained an outline of all training modules used.

Data Extraction—The investigators (C.H. and A.L.) analyzed included abstracts for the 9 most severe types of spin (Table 1). Data were extracted in a masked duplicate fashion using the Google form. AMSTAR-2 was used to assess systematic reviews for methodological quality. AMSTAR-2 is an appraisal tool consisting of a 16-item checklist for systematic reviews or meta-analyses. Scores range from critically low to high based on the methodological quality of the review. Interrater reliability of AMSTAR-2 scores has been moderate to high across studies. Construct validity coefficients have been high with the original AMSTAR instrument (r=0.91) and the Risk of Bias in Systematic Reviews instrument (r=0.84).¹⁹

During data extraction from each included systematic review, the following additional items were obtained: (1) the date the review was received; (2) intervention type (ie, pharmacologic, nonpharmacologic, surgery, light therapy, mixed); (3) the funding source(s) for each systematic review (ie, industry, private, public, none, not mentioned, hospital, a combination of funding not including industry, a combination of funding including industry, other); (4) whether the journal submission guidelines suggested adherence to PRISMA guidelines; (5) whether the review discussed adherence to PRISMA¹⁴ or PRISMA for Abstracts²⁰ (PRISMA-A); (6) the publishing journal’s 5-year impact factor; and (6) the country of the systematic review’s origin. When data extraction was complete, investigators (C.H. and A.L.) were unmasked and met to resolve any disagreements by discussion. Two authors (R.O. or M.V.) served as arbiters in the case that an agreement between C.H. and A.L. could not be reached.

Statistical Analysis—Frequencies and percentages were calculated to evaluate the most common types of spin found within systematic reviews and meta-analyses. One author (M.H.) prespecified the possibility of a binary logistic regression and calculated a power analysis to determine sample size, as stated in our protocol. Our final sample size of 173 was not powered to perform the multivariable logistic regression; therefore, we calculated unadjusted odds ratios to enable assessing relationships between the presence of spin in abstracts and the various study characteristics. We used Stata 16.1 for all analyses, and all analytic decisions can be found in our protocol.

Results

General Characteristics—Our systematic search of MEDLINE and Embase returned 3200 articles, of which 665 were duplicates that were removed. An additional 2253 articles were excluded during initial abstract and title screening, and full-text screening led to the exclusion of another 109 articles. In total, 173 systematic reviews were included for data extraction. Figure 2 illustrates the screening process with the rationale for all exclusions.

Of the 173 included systematic reviews and meta-analyses, 150 (86.7%) focused on pharmacologic interventions. The majority of studies did not mention adhering to PRISMA guidelines (125/173 [72.3%]), and the publishing journals recommended their authors adhere to PRISMA for only 66 (38.2%) of the included articles. For the articles that received funding (90/173 [52.0%]), industry sources were the most common funding source (40/90 [44.4%]), followed by private (27/90 [30%]) and public funding sources (23/90 [25.6%]). Of the remaining studies, 46 articles did not include a funding statement (46/83 [55.4%]), and 37 studies were not funded (37/83 [44.6%]). The average (SD) 5-year impact factor of our included journals was 4.68 (4.64). Systematic reviews were from 31 different countries. All studies were received by their respective journals between the years 2000 and 2020 (Table 2).

Abstracts Containing Spin—We found that 37 (21.4%) of the abstracts of systematic reviews focused on psoriasis treatments contained at least 1 type of spin. Some abstracts had more than 1 type; thus, a total of 51 different instances of spin were detected. Spin type 6—selective reporting of or overemphasis on harm outcomes or analysis favoring the safety of the experimental intervention—was the most common type ofspin, found in 19 of 173 abstracts (11.0%). The most severe type of spin—type 1 (conclusion contains recommendations for clinical practice not supported by the findings)—occurred in only 1 abstract (0.6%). Spin type 8 did not occur in any of the abstracts (Table 1). There was no statistically significant association between the presence of spin and any of the study characteristics (Table 2).

AMSTAR Ratings—After using AMSTAR-2 to appraise the included systematic reviews, we found that 6 (3.5%) of the 173 studies could be rated as high; 36 (20.8%) as moderate; 25 (14.5%) as low; and 106 (61.3%) as critically low. Of the 37 abstracts containing spin, 2 (5.4%) had an AMSTAR-2 rating of high, 10 (27%) had a rating of moderate, 6 (16.2%) had a rating of low, and 19 (51.4%) had a rating of critically low (Table 2). No statistically significant associations were seen between abstracts found to have spin and the AMSTAR-2 rating of the review.

Nearly all (160/173 [92.5%]) of the included reviews were compliant with the inclusion of Population, Intervention, Comparison, and Outcome (PICO) method. Only 17 of 173 (9.8%) reviews reported funding sources for the studies included. See Table 3 for all AMSTAR-2 items.

Comment

Primary Findings—We evaluated the abstracts of systematic reviews for the treatment of psoriasis and found that more than one-fifth of them contained spin. Our study contributes to the existing literature surrounding spin. Spin in randomized controlled trials is well documented across several fields of medicine, including otolaryngology,¹⁰ obesity medicine,¹² dermatology,²¹ anesthesiology,²² psychiatry,²³ orthopedics,²⁴ emergency medicine,²⁵ oncology,²⁶ and cardiology.²⁷ More recently, studies have emerged evaluating the presence of spin in systematic reviews. Specific to dermatology, one study found that 74% (84/113) of systematic reviews related to atopic dermatitis treatment contained spin.²⁸ Additionally, Ottwell et al¹³ identified spin in 31% (11/36) of the systematic reviews related to the treatment of acne vulgaris, which is similar to our results for systematic reviews focused on psoriasis treatments. When comparing the presence of spin in abstracts of systematic reviews from the field of dermatology with other specialties, dermatology-focused systematic reviews appear to contain more spin in the abstract than systematic reviews focused on tinnitus and glaucoma therapies.^29,30 However, systematic reviews from the field of dermatology appear to contain less spin than systematic reviews focused on therapies for lower back pain.³¹ For example, Nascimento et al³¹ found that 80% (53/66) of systematic reviews focused on low-back pain treatments contained spin.

Examples of Spin—The most common type of spin found in our study was type 6.⁹ An example of spin type 6 can be found in an article by Bai et al³² that investigated the short-term efficacy and safety of multiple interleukin inhibitors for the treatment of plaque psoriasis. The conclusion of the abstract states, “Risankizumab appeared to have relatively high efficacy and low risk.” However, in the results section, the authors showed that risankizumab had the highest risk of serious adverse events and was ranked highest for discontinuation because of adverse events when compared with other interleukin inhibitors. Here, the presence of spin in the abstract may mislead the reader to accept the “low risk” of risankizumab without understanding the study’s full results.³²

Another example of selective reporting of harm outcomes in a systematic review can be found in the article by Wu et al,³³ which focused on assessing IL-17 antagonists for the treatment of plaque psoriasis. The conclusion of the abstract indicated that IL-17 antagonists should be accepted as safe; however, in the results section, the authors discussed serious safety concerns with brodalumab, including the death of 4 patients from suicide.³³ This example of spin type 6 highlights how the overgeneralization of a drug’s safety profile neglects serious harm outcomes that are critical to patient safety. In fact, against the safety claims of Wu et al,³³ brodalumab later received a boxed warning from the US Food and Drug Administration after 6 patients died from suicide while receiving the drug, which led to early discontinuation of the trials.^34,35 Although studies suggest this relationship is not causal,^34-36 the purpose of our study was not to investigate this association but to highlight the importance of this finding. Thus, with this example of spin in mind, we offer recommendations that we believe will improve reporting in abstracts as well as quality of patient care.

Recommendations for Reporting in Abstracts—Regarding the boxed warning³⁷ for brodalumab because of suicidal ideation and behavior, the US Food and Drug Administration recommends that prior to prescribing brodalumab, clinicians consider the potential benefits and risks in patients with a history of depression and/or suicidal ideation or behavior. However, a clinician would not adequately assess the full risks and benefits when an abstract, such as that for the article by Wu et al,³³ contains spin through selectively reporting harm outcomes. Arguably, clinicians could just read the full text; however, research confirms that abstracts often are utilized by clinicians and commonly are used to guide clinical decisions.^7,38 It is reasonable that clinicians would use abstracts in this fashion because they provide a quick synopsis of the full article’s findings and are widely available to clinicians who may not have access to article databases. Initiatives are in place to improve the quality of reporting in an abstract, such as PRISMA-A,²⁰ but even this fails to address spin. In fact, it may suggest spin because checklist item 10 of PRISMA-A advises authors of systematic reviews to provide a “general interpretation of the results and important implications.” This item is concerning because it suggests that the authors interpret importance rather than the clinician who prescribes the drug and is ultimately responsible for patient safety. Therefore, we recommend a reform to abstract reporting and an update to PRISMA-A that leads authors to report all benefits and risks encountered instead of reporting what the authors define as important.

Strengths and Limitations—Our study has several strengths as well as limitations. One of these strengths is that our protocol was strictly adhered to; any deviations were noted and added as an amendment. Our protocol, data, and all study artifacts were made freely available online on the Open Science Framework to strengthen reproducibility (https://osf.io/zrxh8/). Investigators underwent training to ensure comprehension of spin and systematic review designs. All data were extracted in masked duplicate fashion per the Cochrane Handbook for Systematic Reviews of Interventions.³⁹

Regarding limitations, only 2 databases were searched—MEDLINE and Embase. Therefore, our screening process may not have included every available systematic review on the treatment of psoriasis. Journal impact factors may be inaccurate for the systematic reviews that were published earlier in our data date range; however, we attempted to negate this limitation by using a 5-year average. Our study characteristic regarding PRISMA adherence did not account for studies published before the PRISMA statement release; we also could not access prior submission guidelines to determine when a journal began recommending PRISMA adherence. Another limitation of our study was the intrinsic subjectivity behind spin. Some may disagree with our classifications. Finally, our cross-sectional design should not be generalized to study types that are not systematic reviews or published in other journals during different periods.

Conclusion

Evidence of spin was present in many of the abstracts of systematic reviews pertaining to the treatment of psoriasis. Future clinical research should investigate any reporting of spin and search for ways to better reduce spin within literature. Continued research is necessary to evaluate the presence of spin within dermatology and other specialties.

Psoriasis is an inflammatory autoimmune skin condition that affects approximately 125 million individuals worldwide, with approximately 8 million patients in the United States.¹ Psoriasis not only involves a cosmetic component but also comprises other comorbidities, such as psoriatic arthritis, cardiovascular disease, and psychiatric disorders, that can influence patient quality of life.^2-4 In addition, the costs associated with psoriasis are substantial, with an estimated economic burden of $35.2 billion in the United States in 2015.⁵ Given the prevalence of psoriasis and its many effects on patients, it is important that providers have high-quality evidence regarding efficacious treatment options.

Systematic reviews, which compile all available evidence on a subject to answer a specific question, represent the gold standard of research.⁶ However, studies have demonstrated that when referencing research literature, physicians tend to read only the abstract of a study rather than the entire article.^7,8 A study by Marcelo et al⁸ showed that residents at a tertiary care center answered clinical questions using only the abstract of a paper 69% of the time. Based on these findings, it is imperative that the results of systematic reviews be accurately reported in their abstracts because they can influence patient care.

Referencing only the abstracts of systematic reviews can be problematic if the abstract contains spin. Spin is a form of reporting that inappropriately highlights the benefits of a treatment with greater emphasis than what is shown by the results.⁹ Research has identified the presence of spin in the abstracts of randomized controlled trials.^10-12 For example, Cooper et al¹⁰ found that 70% (33/47) of abstracts in otolaryngology randomized controlled trials contained spin. Additionally, Arthur et al¹¹ and Austin et al¹² had similar findings within abstracts of orthopedic and obesity trials, where 44.8% (112/250) and 46.7% (21/45) contained spin, respectively. Ottwell et al¹³ found that the presence of spin in abstracts is not limited to randomized controlled trials; they demonstrated that the abstracts of nearly one-third (31% [11/36]) of systematic reviews focused on the treatment of acne vulgaris contained spin.

In our study, we aimed to evaluate the presence of spin in the abstracts of systematic reviews focused on the treatment of psoriasis.

Methods

Reproducibility and Reporting—Our study did not meet the regulatory definition for human subjects research per the US Code of Federal Regulations because the study did not involve human research subjects. The study also was not subject to review by the institutional review board. Our protocol, data set, analysis scripts, extraction forms, and other material related to the study have been placed on Open Science Framework to provide transparency and ensure reproducibility. To further allow for analytic reproducibility, our data set was given to an independent laboratory and reanalyzed with a masked approach. Our study was carried out alongside other studies assessing spin in systematic reviews regarding different specialties and disease states. Because these studies were similar in design, this methodology also has been reported elsewhere. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)¹⁴ and the guidelines for meta-epidemiological studies developed by Murad and Wang¹⁵ were used in drafting this article.

Search Strategy—The search strategies for the MEDLINE (Ovid) and Embase (Ovid) databases were created by a systematic review librarian (D.N.W.) to identify systematic reviews and meta-analyses regarding treatments for psoriasis (Figure 1). The searches were performed on June 2, 2020, and uploaded to Rayyan, a systematic review screening platform.¹⁶ After duplicates were removed, the records were screened for eligibility by 2 authors (C.H. and A.L.) using the titles and abstracts. Screening was conducted independently while each of these authors was masked to the other’s results; disagreements were resolved through discussion.

Eligibility Criteria—An article had to meet the following criteria for inclusion in our study: (1) be a systematic review with or without a meta-analysis; (2) relate to the treatment of psoriasis; and (3) be written in English and include human patients only. The PRISMA definition of systematic reviews and meta-analyses was applied.¹⁷

Training—Various training occurred throughout our study to ensure understanding of each step and mitigate subjectivity. Before beginning screening, 2 investigators (C.H. and A.L.) completed the Introduction to Systematic Review and Meta-Analysis course offered by Johns Hopkins University.¹⁸ They also underwent 2 days of online and in-person training on the definition and interpretation of the 9 most severe types of spin found in the abstracts of systematic reviews as defined by Yavchitz et al.⁹ Finally, they were trained to use A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) to appraise the methodological quality of each systematic review. Our protocol contained an outline of all training modules used.

Data Extraction—The investigators (C.H. and A.L.) analyzed included abstracts for the 9 most severe types of spin (Table 1). Data were extracted in a masked duplicate fashion using the Google form. AMSTAR-2 was used to assess systematic reviews for methodological quality. AMSTAR-2 is an appraisal tool consisting of a 16-item checklist for systematic reviews or meta-analyses. Scores range from critically low to high based on the methodological quality of the review. Interrater reliability of AMSTAR-2 scores has been moderate to high across studies. Construct validity coefficients have been high with the original AMSTAR instrument (r=0.91) and the Risk of Bias in Systematic Reviews instrument (r=0.84).¹⁹

During data extraction from each included systematic review, the following additional items were obtained: (1) the date the review was received; (2) intervention type (ie, pharmacologic, nonpharmacologic, surgery, light therapy, mixed); (3) the funding source(s) for each systematic review (ie, industry, private, public, none, not mentioned, hospital, a combination of funding not including industry, a combination of funding including industry, other); (4) whether the journal submission guidelines suggested adherence to PRISMA guidelines; (5) whether the review discussed adherence to PRISMA¹⁴ or PRISMA for Abstracts²⁰ (PRISMA-A); (6) the publishing journal’s 5-year impact factor; and (6) the country of the systematic review’s origin. When data extraction was complete, investigators (C.H. and A.L.) were unmasked and met to resolve any disagreements by discussion. Two authors (R.O. or M.V.) served as arbiters in the case that an agreement between C.H. and A.L. could not be reached.

Statistical Analysis—Frequencies and percentages were calculated to evaluate the most common types of spin found within systematic reviews and meta-analyses. One author (M.H.) prespecified the possibility of a binary logistic regression and calculated a power analysis to determine sample size, as stated in our protocol. Our final sample size of 173 was not powered to perform the multivariable logistic regression; therefore, we calculated unadjusted odds ratios to enable assessing relationships between the presence of spin in abstracts and the various study characteristics. We used Stata 16.1 for all analyses, and all analytic decisions can be found in our protocol.

Results

General Characteristics—Our systematic search of MEDLINE and Embase returned 3200 articles, of which 665 were duplicates that were removed. An additional 2253 articles were excluded during initial abstract and title screening, and full-text screening led to the exclusion of another 109 articles. In total, 173 systematic reviews were included for data extraction. Figure 2 illustrates the screening process with the rationale for all exclusions.

Of the 173 included systematic reviews and meta-analyses, 150 (86.7%) focused on pharmacologic interventions. The majority of studies did not mention adhering to PRISMA guidelines (125/173 [72.3%]), and the publishing journals recommended their authors adhere to PRISMA for only 66 (38.2%) of the included articles. For the articles that received funding (90/173 [52.0%]), industry sources were the most common funding source (40/90 [44.4%]), followed by private (27/90 [30%]) and public funding sources (23/90 [25.6%]). Of the remaining studies, 46 articles did not include a funding statement (46/83 [55.4%]), and 37 studies were not funded (37/83 [44.6%]). The average (SD) 5-year impact factor of our included journals was 4.68 (4.64). Systematic reviews were from 31 different countries. All studies were received by their respective journals between the years 2000 and 2020 (Table 2).

Abstracts Containing Spin—We found that 37 (21.4%) of the abstracts of systematic reviews focused on psoriasis treatments contained at least 1 type of spin. Some abstracts had more than 1 type; thus, a total of 51 different instances of spin were detected. Spin type 6—selective reporting of or overemphasis on harm outcomes or analysis favoring the safety of the experimental intervention—was the most common type ofspin, found in 19 of 173 abstracts (11.0%). The most severe type of spin—type 1 (conclusion contains recommendations for clinical practice not supported by the findings)—occurred in only 1 abstract (0.6%). Spin type 8 did not occur in any of the abstracts (Table 1). There was no statistically significant association between the presence of spin and any of the study characteristics (Table 2).

AMSTAR Ratings—After using AMSTAR-2 to appraise the included systematic reviews, we found that 6 (3.5%) of the 173 studies could be rated as high; 36 (20.8%) as moderate; 25 (14.5%) as low; and 106 (61.3%) as critically low. Of the 37 abstracts containing spin, 2 (5.4%) had an AMSTAR-2 rating of high, 10 (27%) had a rating of moderate, 6 (16.2%) had a rating of low, and 19 (51.4%) had a rating of critically low (Table 2). No statistically significant associations were seen between abstracts found to have spin and the AMSTAR-2 rating of the review.

Nearly all (160/173 [92.5%]) of the included reviews were compliant with the inclusion of Population, Intervention, Comparison, and Outcome (PICO) method. Only 17 of 173 (9.8%) reviews reported funding sources for the studies included. See Table 3 for all AMSTAR-2 items.

Comment

Primary Findings—We evaluated the abstracts of systematic reviews for the treatment of psoriasis and found that more than one-fifth of them contained spin. Our study contributes to the existing literature surrounding spin. Spin in randomized controlled trials is well documented across several fields of medicine, including otolaryngology,¹⁰ obesity medicine,¹² dermatology,²¹ anesthesiology,²² psychiatry,²³ orthopedics,²⁴ emergency medicine,²⁵ oncology,²⁶ and cardiology.²⁷ More recently, studies have emerged evaluating the presence of spin in systematic reviews. Specific to dermatology, one study found that 74% (84/113) of systematic reviews related to atopic dermatitis treatment contained spin.²⁸ Additionally, Ottwell et al¹³ identified spin in 31% (11/36) of the systematic reviews related to the treatment of acne vulgaris, which is similar to our results for systematic reviews focused on psoriasis treatments. When comparing the presence of spin in abstracts of systematic reviews from the field of dermatology with other specialties, dermatology-focused systematic reviews appear to contain more spin in the abstract than systematic reviews focused on tinnitus and glaucoma therapies.^29,30 However, systematic reviews from the field of dermatology appear to contain less spin than systematic reviews focused on therapies for lower back pain.³¹ For example, Nascimento et al³¹ found that 80% (53/66) of systematic reviews focused on low-back pain treatments contained spin.

Examples of Spin—The most common type of spin found in our study was type 6.⁹ An example of spin type 6 can be found in an article by Bai et al³² that investigated the short-term efficacy and safety of multiple interleukin inhibitors for the treatment of plaque psoriasis. The conclusion of the abstract states, “Risankizumab appeared to have relatively high efficacy and low risk.” However, in the results section, the authors showed that risankizumab had the highest risk of serious adverse events and was ranked highest for discontinuation because of adverse events when compared with other interleukin inhibitors. Here, the presence of spin in the abstract may mislead the reader to accept the “low risk” of risankizumab without understanding the study’s full results.³²

Another example of selective reporting of harm outcomes in a systematic review can be found in the article by Wu et al,³³ which focused on assessing IL-17 antagonists for the treatment of plaque psoriasis. The conclusion of the abstract indicated that IL-17 antagonists should be accepted as safe; however, in the results section, the authors discussed serious safety concerns with brodalumab, including the death of 4 patients from suicide.³³ This example of spin type 6 highlights how the overgeneralization of a drug’s safety profile neglects serious harm outcomes that are critical to patient safety. In fact, against the safety claims of Wu et al,³³ brodalumab later received a boxed warning from the US Food and Drug Administration after 6 patients died from suicide while receiving the drug, which led to early discontinuation of the trials.^34,35 Although studies suggest this relationship is not causal,^34-36 the purpose of our study was not to investigate this association but to highlight the importance of this finding. Thus, with this example of spin in mind, we offer recommendations that we believe will improve reporting in abstracts as well as quality of patient care.

Recommendations for Reporting in Abstracts—Regarding the boxed warning³⁷ for brodalumab because of suicidal ideation and behavior, the US Food and Drug Administration recommends that prior to prescribing brodalumab, clinicians consider the potential benefits and risks in patients with a history of depression and/or suicidal ideation or behavior. However, a clinician would not adequately assess the full risks and benefits when an abstract, such as that for the article by Wu et al,³³ contains spin through selectively reporting harm outcomes. Arguably, clinicians could just read the full text; however, research confirms that abstracts often are utilized by clinicians and commonly are used to guide clinical decisions.^7,38 It is reasonable that clinicians would use abstracts in this fashion because they provide a quick synopsis of the full article’s findings and are widely available to clinicians who may not have access to article databases. Initiatives are in place to improve the quality of reporting in an abstract, such as PRISMA-A,²⁰ but even this fails to address spin. In fact, it may suggest spin because checklist item 10 of PRISMA-A advises authors of systematic reviews to provide a “general interpretation of the results and important implications.” This item is concerning because it suggests that the authors interpret importance rather than the clinician who prescribes the drug and is ultimately responsible for patient safety. Therefore, we recommend a reform to abstract reporting and an update to PRISMA-A that leads authors to report all benefits and risks encountered instead of reporting what the authors define as important.

Strengths and Limitations—Our study has several strengths as well as limitations. One of these strengths is that our protocol was strictly adhered to; any deviations were noted and added as an amendment. Our protocol, data, and all study artifacts were made freely available online on the Open Science Framework to strengthen reproducibility (https://osf.io/zrxh8/). Investigators underwent training to ensure comprehension of spin and systematic review designs. All data were extracted in masked duplicate fashion per the Cochrane Handbook for Systematic Reviews of Interventions.³⁹

Regarding limitations, only 2 databases were searched—MEDLINE and Embase. Therefore, our screening process may not have included every available systematic review on the treatment of psoriasis. Journal impact factors may be inaccurate for the systematic reviews that were published earlier in our data date range; however, we attempted to negate this limitation by using a 5-year average. Our study characteristic regarding PRISMA adherence did not account for studies published before the PRISMA statement release; we also could not access prior submission guidelines to determine when a journal began recommending PRISMA adherence. Another limitation of our study was the intrinsic subjectivity behind spin. Some may disagree with our classifications. Finally, our cross-sectional design should not be generalized to study types that are not systematic reviews or published in other journals during different periods.

Conclusion

Evidence of spin was present in many of the abstracts of systematic reviews pertaining to the treatment of psoriasis. Future clinical research should investigate any reporting of spin and search for ways to better reduce spin within literature. Continued research is necessary to evaluate the presence of spin within dermatology and other specialties.

Psoriasis is an inflammatory autoimmune skin condition that affects approximately 125 million individuals worldwide, with approximately 8 million patients in the United States.¹ Psoriasis not only involves a cosmetic component but also comprises other comorbidities, such as psoriatic arthritis, cardiovascular disease, and psychiatric disorders, that can influence patient quality of life.^2-4 In addition, the costs associated with psoriasis are substantial, with an estimated economic burden of $35.2 billion in the United States in 2015.⁵ Given the prevalence of psoriasis and its many effects on patients, it is important that providers have high-quality evidence regarding efficacious treatment options.

Systematic reviews, which compile all available evidence on a subject to answer a specific question, represent the gold standard of research.⁶ However, studies have demonstrated that when referencing research literature, physicians tend to read only the abstract of a study rather than the entire article.^7,8 A study by Marcelo et al⁸ showed that residents at a tertiary care center answered clinical questions using only the abstract of a paper 69% of the time. Based on these findings, it is imperative that the results of systematic reviews be accurately reported in their abstracts because they can influence patient care.

Referencing only the abstracts of systematic reviews can be problematic if the abstract contains spin. Spin is a form of reporting that inappropriately highlights the benefits of a treatment with greater emphasis than what is shown by the results.⁹ Research has identified the presence of spin in the abstracts of randomized controlled trials.^10-12 For example, Cooper et al¹⁰ found that 70% (33/47) of abstracts in otolaryngology randomized controlled trials contained spin. Additionally, Arthur et al¹¹ and Austin et al¹² had similar findings within abstracts of orthopedic and obesity trials, where 44.8% (112/250) and 46.7% (21/45) contained spin, respectively. Ottwell et al¹³ found that the presence of spin in abstracts is not limited to randomized controlled trials; they demonstrated that the abstracts of nearly one-third (31% [11/36]) of systematic reviews focused on the treatment of acne vulgaris contained spin.

In our study, we aimed to evaluate the presence of spin in the abstracts of systematic reviews focused on the treatment of psoriasis.

Methods

Reproducibility and Reporting—Our study did not meet the regulatory definition for human subjects research per the US Code of Federal Regulations because the study did not involve human research subjects. The study also was not subject to review by the institutional review board. Our protocol, data set, analysis scripts, extraction forms, and other material related to the study have been placed on Open Science Framework to provide transparency and ensure reproducibility. To further allow for analytic reproducibility, our data set was given to an independent laboratory and reanalyzed with a masked approach. Our study was carried out alongside other studies assessing spin in systematic reviews regarding different specialties and disease states. Because these studies were similar in design, this methodology also has been reported elsewhere. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)¹⁴ and the guidelines for meta-epidemiological studies developed by Murad and Wang¹⁵ were used in drafting this article.

Search Strategy—The search strategies for the MEDLINE (Ovid) and Embase (Ovid) databases were created by a systematic review librarian (D.N.W.) to identify systematic reviews and meta-analyses regarding treatments for psoriasis (Figure 1). The searches were performed on June 2, 2020, and uploaded to Rayyan, a systematic review screening platform.¹⁶ After duplicates were removed, the records were screened for eligibility by 2 authors (C.H. and A.L.) using the titles and abstracts. Screening was conducted independently while each of these authors was masked to the other’s results; disagreements were resolved through discussion.

Eligibility Criteria—An article had to meet the following criteria for inclusion in our study: (1) be a systematic review with or without a meta-analysis; (2) relate to the treatment of psoriasis; and (3) be written in English and include human patients only. The PRISMA definition of systematic reviews and meta-analyses was applied.¹⁷

Training—Various training occurred throughout our study to ensure understanding of each step and mitigate subjectivity. Before beginning screening, 2 investigators (C.H. and A.L.) completed the Introduction to Systematic Review and Meta-Analysis course offered by Johns Hopkins University.¹⁸ They also underwent 2 days of online and in-person training on the definition and interpretation of the 9 most severe types of spin found in the abstracts of systematic reviews as defined by Yavchitz et al.⁹ Finally, they were trained to use A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) to appraise the methodological quality of each systematic review. Our protocol contained an outline of all training modules used.

Data Extraction—The investigators (C.H. and A.L.) analyzed included abstracts for the 9 most severe types of spin (Table 1). Data were extracted in a masked duplicate fashion using the Google form. AMSTAR-2 was used to assess systematic reviews for methodological quality. AMSTAR-2 is an appraisal tool consisting of a 16-item checklist for systematic reviews or meta-analyses. Scores range from critically low to high based on the methodological quality of the review. Interrater reliability of AMSTAR-2 scores has been moderate to high across studies. Construct validity coefficients have been high with the original AMSTAR instrument (r=0.91) and the Risk of Bias in Systematic Reviews instrument (r=0.84).¹⁹

During data extraction from each included systematic review, the following additional items were obtained: (1) the date the review was received; (2) intervention type (ie, pharmacologic, nonpharmacologic, surgery, light therapy, mixed); (3) the funding source(s) for each systematic review (ie, industry, private, public, none, not mentioned, hospital, a combination of funding not including industry, a combination of funding including industry, other); (4) whether the journal submission guidelines suggested adherence to PRISMA guidelines; (5) whether the review discussed adherence to PRISMA¹⁴ or PRISMA for Abstracts²⁰ (PRISMA-A); (6) the publishing journal’s 5-year impact factor; and (6) the country of the systematic review’s origin. When data extraction was complete, investigators (C.H. and A.L.) were unmasked and met to resolve any disagreements by discussion. Two authors (R.O. or M.V.) served as arbiters in the case that an agreement between C.H. and A.L. could not be reached.

Statistical Analysis—Frequencies and percentages were calculated to evaluate the most common types of spin found within systematic reviews and meta-analyses. One author (M.H.) prespecified the possibility of a binary logistic regression and calculated a power analysis to determine sample size, as stated in our protocol. Our final sample size of 173 was not powered to perform the multivariable logistic regression; therefore, we calculated unadjusted odds ratios to enable assessing relationships between the presence of spin in abstracts and the various study characteristics. We used Stata 16.1 for all analyses, and all analytic decisions can be found in our protocol.

Results

General Characteristics—Our systematic search of MEDLINE and Embase returned 3200 articles, of which 665 were duplicates that were removed. An additional 2253 articles were excluded during initial abstract and title screening, and full-text screening led to the exclusion of another 109 articles. In total, 173 systematic reviews were included for data extraction. Figure 2 illustrates the screening process with the rationale for all exclusions.

Of the 173 included systematic reviews and meta-analyses, 150 (86.7%) focused on pharmacologic interventions. The majority of studies did not mention adhering to PRISMA guidelines (125/173 [72.3%]), and the publishing journals recommended their authors adhere to PRISMA for only 66 (38.2%) of the included articles. For the articles that received funding (90/173 [52.0%]), industry sources were the most common funding source (40/90 [44.4%]), followed by private (27/90 [30%]) and public funding sources (23/90 [25.6%]). Of the remaining studies, 46 articles did not include a funding statement (46/83 [55.4%]), and 37 studies were not funded (37/83 [44.6%]). The average (SD) 5-year impact factor of our included journals was 4.68 (4.64). Systematic reviews were from 31 different countries. All studies were received by their respective journals between the years 2000 and 2020 (Table 2).

Abstracts Containing Spin—We found that 37 (21.4%) of the abstracts of systematic reviews focused on psoriasis treatments contained at least 1 type of spin. Some abstracts had more than 1 type; thus, a total of 51 different instances of spin were detected. Spin type 6—selective reporting of or overemphasis on harm outcomes or analysis favoring the safety of the experimental intervention—was the most common type ofspin, found in 19 of 173 abstracts (11.0%). The most severe type of spin—type 1 (conclusion contains recommendations for clinical practice not supported by the findings)—occurred in only 1 abstract (0.6%). Spin type 8 did not occur in any of the abstracts (Table 1). There was no statistically significant association between the presence of spin and any of the study characteristics (Table 2).

AMSTAR Ratings—After using AMSTAR-2 to appraise the included systematic reviews, we found that 6 (3.5%) of the 173 studies could be rated as high; 36 (20.8%) as moderate; 25 (14.5%) as low; and 106 (61.3%) as critically low. Of the 37 abstracts containing spin, 2 (5.4%) had an AMSTAR-2 rating of high, 10 (27%) had a rating of moderate, 6 (16.2%) had a rating of low, and 19 (51.4%) had a rating of critically low (Table 2). No statistically significant associations were seen between abstracts found to have spin and the AMSTAR-2 rating of the review.

Nearly all (160/173 [92.5%]) of the included reviews were compliant with the inclusion of Population, Intervention, Comparison, and Outcome (PICO) method. Only 17 of 173 (9.8%) reviews reported funding sources for the studies included. See Table 3 for all AMSTAR-2 items.

Comment

Primary Findings—We evaluated the abstracts of systematic reviews for the treatment of psoriasis and found that more than one-fifth of them contained spin. Our study contributes to the existing literature surrounding spin. Spin in randomized controlled trials is well documented across several fields of medicine, including otolaryngology,¹⁰ obesity medicine,¹² dermatology,²¹ anesthesiology,²² psychiatry,²³ orthopedics,²⁴ emergency medicine,²⁵ oncology,²⁶ and cardiology.²⁷ More recently, studies have emerged evaluating the presence of spin in systematic reviews. Specific to dermatology, one study found that 74% (84/113) of systematic reviews related to atopic dermatitis treatment contained spin.²⁸ Additionally, Ottwell et al¹³ identified spin in 31% (11/36) of the systematic reviews related to the treatment of acne vulgaris, which is similar to our results for systematic reviews focused on psoriasis treatments. When comparing the presence of spin in abstracts of systematic reviews from the field of dermatology with other specialties, dermatology-focused systematic reviews appear to contain more spin in the abstract than systematic reviews focused on tinnitus and glaucoma therapies.^29,30 However, systematic reviews from the field of dermatology appear to contain less spin than systematic reviews focused on therapies for lower back pain.³¹ For example, Nascimento et al³¹ found that 80% (53/66) of systematic reviews focused on low-back pain treatments contained spin.

Examples of Spin—The most common type of spin found in our study was type 6.⁹ An example of spin type 6 can be found in an article by Bai et al³² that investigated the short-term efficacy and safety of multiple interleukin inhibitors for the treatment of plaque psoriasis. The conclusion of the abstract states, “Risankizumab appeared to have relatively high efficacy and low risk.” However, in the results section, the authors showed that risankizumab had the highest risk of serious adverse events and was ranked highest for discontinuation because of adverse events when compared with other interleukin inhibitors. Here, the presence of spin in the abstract may mislead the reader to accept the “low risk” of risankizumab without understanding the study’s full results.³²

Another example of selective reporting of harm outcomes in a systematic review can be found in the article by Wu et al,³³ which focused on assessing IL-17 antagonists for the treatment of plaque psoriasis. The conclusion of the abstract indicated that IL-17 antagonists should be accepted as safe; however, in the results section, the authors discussed serious safety concerns with brodalumab, including the death of 4 patients from suicide.³³ This example of spin type 6 highlights how the overgeneralization of a drug’s safety profile neglects serious harm outcomes that are critical to patient safety. In fact, against the safety claims of Wu et al,³³ brodalumab later received a boxed warning from the US Food and Drug Administration after 6 patients died from suicide while receiving the drug, which led to early discontinuation of the trials.^34,35 Although studies suggest this relationship is not causal,^34-36 the purpose of our study was not to investigate this association but to highlight the importance of this finding. Thus, with this example of spin in mind, we offer recommendations that we believe will improve reporting in abstracts as well as quality of patient care.

Recommendations for Reporting in Abstracts—Regarding the boxed warning³⁷ for brodalumab because of suicidal ideation and behavior, the US Food and Drug Administration recommends that prior to prescribing brodalumab, clinicians consider the potential benefits and risks in patients with a history of depression and/or suicidal ideation or behavior. However, a clinician would not adequately assess the full risks and benefits when an abstract, such as that for the article by Wu et al,³³ contains spin through selectively reporting harm outcomes. Arguably, clinicians could just read the full text; however, research confirms that abstracts often are utilized by clinicians and commonly are used to guide clinical decisions.^7,38 It is reasonable that clinicians would use abstracts in this fashion because they provide a quick synopsis of the full article’s findings and are widely available to clinicians who may not have access to article databases. Initiatives are in place to improve the quality of reporting in an abstract, such as PRISMA-A,²⁰ but even this fails to address spin. In fact, it may suggest spin because checklist item 10 of PRISMA-A advises authors of systematic reviews to provide a “general interpretation of the results and important implications.” This item is concerning because it suggests that the authors interpret importance rather than the clinician who prescribes the drug and is ultimately responsible for patient safety. Therefore, we recommend a reform to abstract reporting and an update to PRISMA-A that leads authors to report all benefits and risks encountered instead of reporting what the authors define as important.

Strengths and Limitations—Our study has several strengths as well as limitations. One of these strengths is that our protocol was strictly adhered to; any deviations were noted and added as an amendment. Our protocol, data, and all study artifacts were made freely available online on the Open Science Framework to strengthen reproducibility (https://osf.io/zrxh8/). Investigators underwent training to ensure comprehension of spin and systematic review designs. All data were extracted in masked duplicate fashion per the Cochrane Handbook for Systematic Reviews of Interventions.³⁹

Regarding limitations, only 2 databases were searched—MEDLINE and Embase. Therefore, our screening process may not have included every available systematic review on the treatment of psoriasis. Journal impact factors may be inaccurate for the systematic reviews that were published earlier in our data date range; however, we attempted to negate this limitation by using a 5-year average. Our study characteristic regarding PRISMA adherence did not account for studies published before the PRISMA statement release; we also could not access prior submission guidelines to determine when a journal began recommending PRISMA adherence. Another limitation of our study was the intrinsic subjectivity behind spin. Some may disagree with our classifications. Finally, our cross-sectional design should not be generalized to study types that are not systematic reviews or published in other journals during different periods.

Conclusion

Evidence of spin was present in many of the abstracts of systematic reviews pertaining to the treatment of psoriasis. Future clinical research should investigate any reporting of spin and search for ways to better reduce spin within literature. Continued research is necessary to evaluate the presence of spin within dermatology and other specialties.

The U.S. Food and Drug Administration on May 22 approved a new autoinjection option for adalimumab-adbm (Cyltezo), a biosimilar to AbbVie’s adalimumab (Humira), ahead of Cyltezo’s commercial launch on July 1, 2023.

Cyltezo was approved by the FDA in 2017 as a prefilled syringe and was the first biosimilar deemed to be interchangeable with Humira in 2021. It is indicated to treat multiple chronic inflammatory conditions, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and hidradenitis suppurativa. This new design, which features one-button, three-step activation, has been certified as an “Ease of Use” product by the Arthritis Foundation, Boehringer Ingelheim said in a press release. The 40-mg, prefilled Cyltezo Pen will be available in two-, four-, and six-pack options.

“The FDA approval of the Cyltezo Pen is great news for patients living with chronic inflammatory diseases who may prefer administering the medication needed to manage their conditions via an autoinjector,” said Stephen Pagnotta, the executive director and biosimilar commercial lead at Boehringer Ingelheim in a statement; “we’re excited to be able to offer the Cyltezo Pen as an additional option to patients at Cyltezo’s launch on July 1.”

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration on May 22 approved a new autoinjection option for adalimumab-adbm (Cyltezo), a biosimilar to AbbVie’s adalimumab (Humira), ahead of Cyltezo’s commercial launch on July 1, 2023.

Cyltezo was approved by the FDA in 2017 as a prefilled syringe and was the first biosimilar deemed to be interchangeable with Humira in 2021. It is indicated to treat multiple chronic inflammatory conditions, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and hidradenitis suppurativa. This new design, which features one-button, three-step activation, has been certified as an “Ease of Use” product by the Arthritis Foundation, Boehringer Ingelheim said in a press release. The 40-mg, prefilled Cyltezo Pen will be available in two-, four-, and six-pack options.

“The FDA approval of the Cyltezo Pen is great news for patients living with chronic inflammatory diseases who may prefer administering the medication needed to manage their conditions via an autoinjector,” said Stephen Pagnotta, the executive director and biosimilar commercial lead at Boehringer Ingelheim in a statement; “we’re excited to be able to offer the Cyltezo Pen as an additional option to patients at Cyltezo’s launch on July 1.”

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration on May 22 approved a new autoinjection option for adalimumab-adbm (Cyltezo), a biosimilar to AbbVie’s adalimumab (Humira), ahead of Cyltezo’s commercial launch on July 1, 2023.

Cyltezo was approved by the FDA in 2017 as a prefilled syringe and was the first biosimilar deemed to be interchangeable with Humira in 2021. It is indicated to treat multiple chronic inflammatory conditions, including rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and hidradenitis suppurativa. This new design, which features one-button, three-step activation, has been certified as an “Ease of Use” product by the Arthritis Foundation, Boehringer Ingelheim said in a press release. The 40-mg, prefilled Cyltezo Pen will be available in two-, four-, and six-pack options.

“The FDA approval of the Cyltezo Pen is great news for patients living with chronic inflammatory diseases who may prefer administering the medication needed to manage their conditions via an autoinjector,” said Stephen Pagnotta, the executive director and biosimilar commercial lead at Boehringer Ingelheim in a statement; “we’re excited to be able to offer the Cyltezo Pen as an additional option to patients at Cyltezo’s launch on July 1.”

A version of this article first appeared on Medscape.com.

Are there clinically significant differences between axial spondyloarthritis with psoriasis and psoriatic arthritis with axial symptoms? Does it matter?

It all depends on whom you ask, but right now the evidence seems to be tipping in favor of the “splitters” who cite evidence supporting their contention that axial spondyloarthritis (axSpA)/ankylosing spondylitis (AS) with psoriasis and psoriatic arthritis (PsA) with axial symptoms are distinct clinical entities that require more precise diagnosis and treatment.

“Lumpers,” in contrast, argue that they are different points on the same clinical spectrum.

The debate is not just of academic interest, but has real consequences for patients, say specialists on both sides of the aisle.
 

Overlapping features, different presentations

“Axial SpA and axPsA have overlapping features but also meaningful differences in genetics, clinical presentation, imaging, and immunophenotype. Efforts are underway to develop classification criteria for axPsA to aid research efforts as well as clinical diagnosis and management,” Philip J. Mease, MD, director of rheumatology research at Swedish Medical Center/Providence–St. Joseph Health in Seattle, and colleagues contend.

In an editorial published in the International Journal of Rheumatic Diseases, Dr. Mease and colleagues noted that, although HLA-B*27 is a genetic risk factor for both axPsA and axSpA, some HLA-B alleles are significantly associated with axPsA, whereas other alleles are associated with axSpA.

In addition, while genes in the interleukin-23 and IL-17 pathway are associated with increased risk for axSpA, genes in the IL-13 pathway have been identified as risk markers for axPsA, they noted.
 

Two cohorts better than one?

Dafna Gladman, MD, professor of medicine at the University of Toronto and senior scientist at the Schroeder Arthritis Institute at Toronto Western Hospital, and colleagues have a unique perspective on the similarities and differences between the disease entities.

Her group’s research uses data on cohorts of patients treated in two separate clinics at Toronto Western Hospital: one for patients with PsA, and one for patients with axial spondyloarthritis, including those with ankylosing spondylitis, nonradiographic axSpA, and spondylitis associated with inflammatory bowel disease.

“Our work has shown that there are differences, and one of the reasons that it’s now important is that the anti–IL-23 medications, both the IL-12/23 inhibitor ustekinumab [Stelara] and the IL-23 inhibitor guselkumab [Tremfya] work for psoriatic arthritis, whereas IL-23 did not work in ankylosing spondylitis, so that provided further impetus to look into the distinction between the two groups,” Dr. Gladman said in an interview.

Dr. Gladman and colleagues published a study in Rheumatology in which they compared clinical presentations and features of patients with AS with or without psoriasis with patients with axPsA.

They found that patients with AS with or without psoriasis tended to be younger, had a higher proportion of males to females, and were more likely to be positive for HLA-B*27. Patients with AS also had more back pain at presentation, worse axial disease activity scores, worse global assessments by physicians, and higher grades of sacroiliitis, and they were more likely to be taking biologic agents.

“What that showed, right off the top, that whether we’re looking at the total group or we’re looking specifically at those patients who have psoriasis or don’t have psoriasis, they are different from those with psoriatic arthritis with axial disease,” she said.

They concluded that “axPsA seems to be a distinct entity.”
 

Two clinics, same presentation

Because the aforementioned study included all patients with PsA with or without peripheral disease, the investigators decided to filter out some of the background noise and conduct a second study in which they compared patients who presented to the two clinics with the same presentation, either with spinal disease and psoriasis to the spondylitis clinic, or with psoriasis and isolated axial disease to the PsA clinic.

The results, published in Annals of the Rheumatic Diseases, showed that just 2.03% of patients with PsA had isolated axial disease, and an additional 29.38% had axial and peripheral disease.

In this study, “you can see that even in that group there are distinct differences. The patients that are labeled psoriatic spondylitis are different from those that are labeled ankylosing spondylitis with psoriasis,” Dr. Gladman said.

Isolated axial disease in patients with PsA was associated with HLA-B*27 positivity and lower Health Assessment Questionnaire scores. In addition, patients who were HLA-B*27 positive also had a nearly eightfold higher risk for developing peripheral disease over time.

Patients with isolated axial PsA were significantly more likely to be diagnosed at an older age (mean, 37.44 vs. 29.65 years), had higher Psoriasis Area Severity Index scores and a higher likelihood of having psoriatic nail lesions than patients with AS with isolated axial disease and psoriasis.

In contrast, patients with isolated axSpA with psoriasis were more likely to have inflammatory back pain, spinal pain, joint pain/swelling, and areas of localized tenderness, and they had greater severity of morning stiffness.

Dr. Gladman noted that, although AS and PsA are associated with the same gene that encodes for the IL-23 receptor, each condition is associated with a different single-nucleotide polymorphism.

Same disease, different flavors?

But as Mark Twain said, it is difference of opinion that makes horse races, and some specialists in rheumatology say that axSpA amd axPsA are just two sides of the same coin.

Pramod Rathod

“There are always different schools of thought. I believe that they are not different diseases, but a spectrum of diseases,” said Shailendra Singh, MD, a rheumatologist at Unity Health Medical Center in Searcy, Ark., and past president of the Arkansas Rheumatology Association.

In an interview, Dr. Singh said that the spectrum ranges from diseases with primarily axial involvement, such as AS, to those with primarily peripheral involvement, such as reactive arthritis.

He pointed out that these conditions have overlapping symptoms, including enthesitis, dactylitis, and uveitis, and inflammatory arthritis.

Daniel Wendling, MD, PhD, from the Centre Hospitalier Régional Universitaire de Besançon (France), Université de Franche-Comté, and colleagues agreed.

“The criteria currently available for both SpA [ASAS (Assessment of Spondyloarthritis International Society) criteria] and PsA [CASPAR (Classification for Psoriatic Arthritis) criteria] are classification criteria, not diagnostic criteria. They are not very stringent and are not exclusive. Thus, the same patient can easily be classified simultaneously in both entities, making the distinction between axSpA with psoriasis and axPsA theoretical,” they wrote in an editorial published in Joint Bone Spine.

They cited as an example of the allegedly fuzzy criteria a prospective study conducted by the investigators in Bath, England, in which modified New York criteria for AS were met by 24% of patients with AS, and CASPAR criteria for PsA were met by an equal number of patients with AS.
 

Therapeutic implications

Dr. Wendling and colleagues acknowledge the differences cited in studies by Dr. Gladman, Dr. Mease, and others between patients with axPsA and those with axSpA, but argue that the differences are not that great and not so clear.

“It should also be emphasized that, although some differences between axPsA and axSpA reach statistical significance, they are mostly at the margin, with low odd ratios,” they wrote.

“It is also important to consider the variability in the definition of axPsA, sometimes simply ‘physician reported’ and elsewhere based on the modified New York radiographic criteria; the latter are only present late in the course of the disease, and this may induce bias,” they continued.

Dr. Singh agreed that, as noted by Dr. Gladman, some patients will respond to anti–IL-17, anti–IL-23, and anti–IL-12/23 agents, whereas others will have better responses with tumor necrosis factor (TNF) inhibitors, and still others, such as those with peripheral involvement in the hands and feet may fare better with nonbiologic disease-modifying antirheumatic drugs such as methotrexate.
 

Answers to come?

Dr. Gladman noted that the information available to date about the efficacy of IL-23 inhibition in axPsA is based on a post hoc analysis of the PSUMMIT 1 and 2 controlled trials in PsA, and is not definitive.

The randomized, controlled STAR trial, currently recruiting patients, is designed to see whether guselkumab can reduce axial symptoms and inflammation in patients with active axPsA.

“What I say is, there is a rationale for [anti–IL-23] to work in psoriatic arthritis, and not work in ankylosing spondylitis,” she said.

In contrast, IL-17 inhibitors, anti-TNF agents, and Janus kinase inhibitors show efficacy against both axPsA and AS. Rituximab is ineffective against PsA, but has shown efficacy against AS, especially in patients with neurologic complications from anti-TNF agents.

“There may be other medications that would work more specifically in axial psoriatic arthritis that don’t work in ankylosing spondylitis, but at least recognizing that there may be some differences, and that therefore a correct diagnosis should be obtained, might be important,” she said.

Ideally, the picture will become clearer with results from the ongoing Axial Involvement in Psoriatic Arthritis cohort, a joint project of ASAS and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. The multinational, cross-sectional study is designed “to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research.”

Stay tuned.

Dr. Gladman’s research is supported by a grant from the Krembil Foundation. Dr. Singh disclosed research support from various companies. Funding sources and conflict of interest disclosures from other works cited are contained in their respective references.

Are there clinically significant differences between axial spondyloarthritis with psoriasis and psoriatic arthritis with axial symptoms? Does it matter?

It all depends on whom you ask, but right now the evidence seems to be tipping in favor of the “splitters” who cite evidence supporting their contention that axial spondyloarthritis (axSpA)/ankylosing spondylitis (AS) with psoriasis and psoriatic arthritis (PsA) with axial symptoms are distinct clinical entities that require more precise diagnosis and treatment.

“Lumpers,” in contrast, argue that they are different points on the same clinical spectrum.

The debate is not just of academic interest, but has real consequences for patients, say specialists on both sides of the aisle.
 

Overlapping features, different presentations

“Axial SpA and axPsA have overlapping features but also meaningful differences in genetics, clinical presentation, imaging, and immunophenotype. Efforts are underway to develop classification criteria for axPsA to aid research efforts as well as clinical diagnosis and management,” Philip J. Mease, MD, director of rheumatology research at Swedish Medical Center/Providence–St. Joseph Health in Seattle, and colleagues contend.

In an editorial published in the International Journal of Rheumatic Diseases, Dr. Mease and colleagues noted that, although HLA-B*27 is a genetic risk factor for both axPsA and axSpA, some HLA-B alleles are significantly associated with axPsA, whereas other alleles are associated with axSpA.

In addition, while genes in the interleukin-23 and IL-17 pathway are associated with increased risk for axSpA, genes in the IL-13 pathway have been identified as risk markers for axPsA, they noted.
 

Two cohorts better than one?

Dafna Gladman, MD, professor of medicine at the University of Toronto and senior scientist at the Schroeder Arthritis Institute at Toronto Western Hospital, and colleagues have a unique perspective on the similarities and differences between the disease entities.

Her group’s research uses data on cohorts of patients treated in two separate clinics at Toronto Western Hospital: one for patients with PsA, and one for patients with axial spondyloarthritis, including those with ankylosing spondylitis, nonradiographic axSpA, and spondylitis associated with inflammatory bowel disease.

“Our work has shown that there are differences, and one of the reasons that it’s now important is that the anti–IL-23 medications, both the IL-12/23 inhibitor ustekinumab [Stelara] and the IL-23 inhibitor guselkumab [Tremfya] work for psoriatic arthritis, whereas IL-23 did not work in ankylosing spondylitis, so that provided further impetus to look into the distinction between the two groups,” Dr. Gladman said in an interview.

Dr. Gladman and colleagues published a study in Rheumatology in which they compared clinical presentations and features of patients with AS with or without psoriasis with patients with axPsA.

They found that patients with AS with or without psoriasis tended to be younger, had a higher proportion of males to females, and were more likely to be positive for HLA-B*27. Patients with AS also had more back pain at presentation, worse axial disease activity scores, worse global assessments by physicians, and higher grades of sacroiliitis, and they were more likely to be taking biologic agents.

“What that showed, right off the top, that whether we’re looking at the total group or we’re looking specifically at those patients who have psoriasis or don’t have psoriasis, they are different from those with psoriatic arthritis with axial disease,” she said.

They concluded that “axPsA seems to be a distinct entity.”
 

Two clinics, same presentation

Because the aforementioned study included all patients with PsA with or without peripheral disease, the investigators decided to filter out some of the background noise and conduct a second study in which they compared patients who presented to the two clinics with the same presentation, either with spinal disease and psoriasis to the spondylitis clinic, or with psoriasis and isolated axial disease to the PsA clinic.

The results, published in Annals of the Rheumatic Diseases, showed that just 2.03% of patients with PsA had isolated axial disease, and an additional 29.38% had axial and peripheral disease.

In this study, “you can see that even in that group there are distinct differences. The patients that are labeled psoriatic spondylitis are different from those that are labeled ankylosing spondylitis with psoriasis,” Dr. Gladman said.

Isolated axial disease in patients with PsA was associated with HLA-B*27 positivity and lower Health Assessment Questionnaire scores. In addition, patients who were HLA-B*27 positive also had a nearly eightfold higher risk for developing peripheral disease over time.

Patients with isolated axial PsA were significantly more likely to be diagnosed at an older age (mean, 37.44 vs. 29.65 years), had higher Psoriasis Area Severity Index scores and a higher likelihood of having psoriatic nail lesions than patients with AS with isolated axial disease and psoriasis.

In contrast, patients with isolated axSpA with psoriasis were more likely to have inflammatory back pain, spinal pain, joint pain/swelling, and areas of localized tenderness, and they had greater severity of morning stiffness.

Dr. Gladman noted that, although AS and PsA are associated with the same gene that encodes for the IL-23 receptor, each condition is associated with a different single-nucleotide polymorphism.

Same disease, different flavors?

But as Mark Twain said, it is difference of opinion that makes horse races, and some specialists in rheumatology say that axSpA amd axPsA are just two sides of the same coin.

Pramod Rathod

“There are always different schools of thought. I believe that they are not different diseases, but a spectrum of diseases,” said Shailendra Singh, MD, a rheumatologist at Unity Health Medical Center in Searcy, Ark., and past president of the Arkansas Rheumatology Association.

In an interview, Dr. Singh said that the spectrum ranges from diseases with primarily axial involvement, such as AS, to those with primarily peripheral involvement, such as reactive arthritis.

He pointed out that these conditions have overlapping symptoms, including enthesitis, dactylitis, and uveitis, and inflammatory arthritis.

Daniel Wendling, MD, PhD, from the Centre Hospitalier Régional Universitaire de Besançon (France), Université de Franche-Comté, and colleagues agreed.

“The criteria currently available for both SpA [ASAS (Assessment of Spondyloarthritis International Society) criteria] and PsA [CASPAR (Classification for Psoriatic Arthritis) criteria] are classification criteria, not diagnostic criteria. They are not very stringent and are not exclusive. Thus, the same patient can easily be classified simultaneously in both entities, making the distinction between axSpA with psoriasis and axPsA theoretical,” they wrote in an editorial published in Joint Bone Spine.

They cited as an example of the allegedly fuzzy criteria a prospective study conducted by the investigators in Bath, England, in which modified New York criteria for AS were met by 24% of patients with AS, and CASPAR criteria for PsA were met by an equal number of patients with AS.
 

Therapeutic implications

Dr. Wendling and colleagues acknowledge the differences cited in studies by Dr. Gladman, Dr. Mease, and others between patients with axPsA and those with axSpA, but argue that the differences are not that great and not so clear.

“It should also be emphasized that, although some differences between axPsA and axSpA reach statistical significance, they are mostly at the margin, with low odd ratios,” they wrote.

“It is also important to consider the variability in the definition of axPsA, sometimes simply ‘physician reported’ and elsewhere based on the modified New York radiographic criteria; the latter are only present late in the course of the disease, and this may induce bias,” they continued.

Dr. Singh agreed that, as noted by Dr. Gladman, some patients will respond to anti–IL-17, anti–IL-23, and anti–IL-12/23 agents, whereas others will have better responses with tumor necrosis factor (TNF) inhibitors, and still others, such as those with peripheral involvement in the hands and feet may fare better with nonbiologic disease-modifying antirheumatic drugs such as methotrexate.
 

Answers to come?

Dr. Gladman noted that the information available to date about the efficacy of IL-23 inhibition in axPsA is based on a post hoc analysis of the PSUMMIT 1 and 2 controlled trials in PsA, and is not definitive.

The randomized, controlled STAR trial, currently recruiting patients, is designed to see whether guselkumab can reduce axial symptoms and inflammation in patients with active axPsA.

“What I say is, there is a rationale for [anti–IL-23] to work in psoriatic arthritis, and not work in ankylosing spondylitis,” she said.

In contrast, IL-17 inhibitors, anti-TNF agents, and Janus kinase inhibitors show efficacy against both axPsA and AS. Rituximab is ineffective against PsA, but has shown efficacy against AS, especially in patients with neurologic complications from anti-TNF agents.

“There may be other medications that would work more specifically in axial psoriatic arthritis that don’t work in ankylosing spondylitis, but at least recognizing that there may be some differences, and that therefore a correct diagnosis should be obtained, might be important,” she said.

Ideally, the picture will become clearer with results from the ongoing Axial Involvement in Psoriatic Arthritis cohort, a joint project of ASAS and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. The multinational, cross-sectional study is designed “to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research.”

Stay tuned.

Dr. Gladman’s research is supported by a grant from the Krembil Foundation. Dr. Singh disclosed research support from various companies. Funding sources and conflict of interest disclosures from other works cited are contained in their respective references.

Are there clinically significant differences between axial spondyloarthritis with psoriasis and psoriatic arthritis with axial symptoms? Does it matter?

It all depends on whom you ask, but right now the evidence seems to be tipping in favor of the “splitters” who cite evidence supporting their contention that axial spondyloarthritis (axSpA)/ankylosing spondylitis (AS) with psoriasis and psoriatic arthritis (PsA) with axial symptoms are distinct clinical entities that require more precise diagnosis and treatment.

“Lumpers,” in contrast, argue that they are different points on the same clinical spectrum.

The debate is not just of academic interest, but has real consequences for patients, say specialists on both sides of the aisle.
 

Overlapping features, different presentations

“Axial SpA and axPsA have overlapping features but also meaningful differences in genetics, clinical presentation, imaging, and immunophenotype. Efforts are underway to develop classification criteria for axPsA to aid research efforts as well as clinical diagnosis and management,” Philip J. Mease, MD, director of rheumatology research at Swedish Medical Center/Providence–St. Joseph Health in Seattle, and colleagues contend.

In an editorial published in the International Journal of Rheumatic Diseases, Dr. Mease and colleagues noted that, although HLA-B*27 is a genetic risk factor for both axPsA and axSpA, some HLA-B alleles are significantly associated with axPsA, whereas other alleles are associated with axSpA.

In addition, while genes in the interleukin-23 and IL-17 pathway are associated with increased risk for axSpA, genes in the IL-13 pathway have been identified as risk markers for axPsA, they noted.
 

Two cohorts better than one?

Dafna Gladman, MD, professor of medicine at the University of Toronto and senior scientist at the Schroeder Arthritis Institute at Toronto Western Hospital, and colleagues have a unique perspective on the similarities and differences between the disease entities.

Her group’s research uses data on cohorts of patients treated in two separate clinics at Toronto Western Hospital: one for patients with PsA, and one for patients with axial spondyloarthritis, including those with ankylosing spondylitis, nonradiographic axSpA, and spondylitis associated with inflammatory bowel disease.

“Our work has shown that there are differences, and one of the reasons that it’s now important is that the anti–IL-23 medications, both the IL-12/23 inhibitor ustekinumab [Stelara] and the IL-23 inhibitor guselkumab [Tremfya] work for psoriatic arthritis, whereas IL-23 did not work in ankylosing spondylitis, so that provided further impetus to look into the distinction between the two groups,” Dr. Gladman said in an interview.

Dr. Gladman and colleagues published a study in Rheumatology in which they compared clinical presentations and features of patients with AS with or without psoriasis with patients with axPsA.

They found that patients with AS with or without psoriasis tended to be younger, had a higher proportion of males to females, and were more likely to be positive for HLA-B*27. Patients with AS also had more back pain at presentation, worse axial disease activity scores, worse global assessments by physicians, and higher grades of sacroiliitis, and they were more likely to be taking biologic agents.

“What that showed, right off the top, that whether we’re looking at the total group or we’re looking specifically at those patients who have psoriasis or don’t have psoriasis, they are different from those with psoriatic arthritis with axial disease,” she said.

They concluded that “axPsA seems to be a distinct entity.”
 

Two clinics, same presentation

Because the aforementioned study included all patients with PsA with or without peripheral disease, the investigators decided to filter out some of the background noise and conduct a second study in which they compared patients who presented to the two clinics with the same presentation, either with spinal disease and psoriasis to the spondylitis clinic, or with psoriasis and isolated axial disease to the PsA clinic.

The results, published in Annals of the Rheumatic Diseases, showed that just 2.03% of patients with PsA had isolated axial disease, and an additional 29.38% had axial and peripheral disease.

In this study, “you can see that even in that group there are distinct differences. The patients that are labeled psoriatic spondylitis are different from those that are labeled ankylosing spondylitis with psoriasis,” Dr. Gladman said.

Isolated axial disease in patients with PsA was associated with HLA-B*27 positivity and lower Health Assessment Questionnaire scores. In addition, patients who were HLA-B*27 positive also had a nearly eightfold higher risk for developing peripheral disease over time.

Patients with isolated axial PsA were significantly more likely to be diagnosed at an older age (mean, 37.44 vs. 29.65 years), had higher Psoriasis Area Severity Index scores and a higher likelihood of having psoriatic nail lesions than patients with AS with isolated axial disease and psoriasis.

In contrast, patients with isolated axSpA with psoriasis were more likely to have inflammatory back pain, spinal pain, joint pain/swelling, and areas of localized tenderness, and they had greater severity of morning stiffness.

Dr. Gladman noted that, although AS and PsA are associated with the same gene that encodes for the IL-23 receptor, each condition is associated with a different single-nucleotide polymorphism.

Same disease, different flavors?

But as Mark Twain said, it is difference of opinion that makes horse races, and some specialists in rheumatology say that axSpA amd axPsA are just two sides of the same coin.

Pramod Rathod

“There are always different schools of thought. I believe that they are not different diseases, but a spectrum of diseases,” said Shailendra Singh, MD, a rheumatologist at Unity Health Medical Center in Searcy, Ark., and past president of the Arkansas Rheumatology Association.

In an interview, Dr. Singh said that the spectrum ranges from diseases with primarily axial involvement, such as AS, to those with primarily peripheral involvement, such as reactive arthritis.

He pointed out that these conditions have overlapping symptoms, including enthesitis, dactylitis, and uveitis, and inflammatory arthritis.

Daniel Wendling, MD, PhD, from the Centre Hospitalier Régional Universitaire de Besançon (France), Université de Franche-Comté, and colleagues agreed.

“The criteria currently available for both SpA [ASAS (Assessment of Spondyloarthritis International Society) criteria] and PsA [CASPAR (Classification for Psoriatic Arthritis) criteria] are classification criteria, not diagnostic criteria. They are not very stringent and are not exclusive. Thus, the same patient can easily be classified simultaneously in both entities, making the distinction between axSpA with psoriasis and axPsA theoretical,” they wrote in an editorial published in Joint Bone Spine.

They cited as an example of the allegedly fuzzy criteria a prospective study conducted by the investigators in Bath, England, in which modified New York criteria for AS were met by 24% of patients with AS, and CASPAR criteria for PsA were met by an equal number of patients with AS.
 

Therapeutic implications

Dr. Wendling and colleagues acknowledge the differences cited in studies by Dr. Gladman, Dr. Mease, and others between patients with axPsA and those with axSpA, but argue that the differences are not that great and not so clear.

“It should also be emphasized that, although some differences between axPsA and axSpA reach statistical significance, they are mostly at the margin, with low odd ratios,” they wrote.

“It is also important to consider the variability in the definition of axPsA, sometimes simply ‘physician reported’ and elsewhere based on the modified New York radiographic criteria; the latter are only present late in the course of the disease, and this may induce bias,” they continued.

Dr. Singh agreed that, as noted by Dr. Gladman, some patients will respond to anti–IL-17, anti–IL-23, and anti–IL-12/23 agents, whereas others will have better responses with tumor necrosis factor (TNF) inhibitors, and still others, such as those with peripheral involvement in the hands and feet may fare better with nonbiologic disease-modifying antirheumatic drugs such as methotrexate.
 

Answers to come?

Dr. Gladman noted that the information available to date about the efficacy of IL-23 inhibition in axPsA is based on a post hoc analysis of the PSUMMIT 1 and 2 controlled trials in PsA, and is not definitive.

The randomized, controlled STAR trial, currently recruiting patients, is designed to see whether guselkumab can reduce axial symptoms and inflammation in patients with active axPsA.

“What I say is, there is a rationale for [anti–IL-23] to work in psoriatic arthritis, and not work in ankylosing spondylitis,” she said.

In contrast, IL-17 inhibitors, anti-TNF agents, and Janus kinase inhibitors show efficacy against both axPsA and AS. Rituximab is ineffective against PsA, but has shown efficacy against AS, especially in patients with neurologic complications from anti-TNF agents.

“There may be other medications that would work more specifically in axial psoriatic arthritis that don’t work in ankylosing spondylitis, but at least recognizing that there may be some differences, and that therefore a correct diagnosis should be obtained, might be important,” she said.

Ideally, the picture will become clearer with results from the ongoing Axial Involvement in Psoriatic Arthritis cohort, a joint project of ASAS and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. The multinational, cross-sectional study is designed “to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research.”

Stay tuned.

Dr. Gladman’s research is supported by a grant from the Krembil Foundation. Dr. Singh disclosed research support from various companies. Funding sources and conflict of interest disclosures from other works cited are contained in their respective references.

New research is shedding light on how an infection with COVID-19 may reactivate, or even cause, psoriasis. 

 Psoriasis has several well-established triggers, including stress, skin injury, cold or warm air, and allergies. Illnesses like strep throat can also cause a psoriasis flare in some people – and it appears COVID may also do so. “Psoriasis flares have long been associated with bacterial and viral infections, particularly a form of psoriasis called guttate, which is characterized by tons of tiny red scaly bumps all over the body,” said Joel M. Gelfand, MD, a professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia. “Infection with COVID-19 has been associated with flares of guttate and pustular psoriasis, and even psoriasis that affects 100% of the skin ... in many published case reports.”

Israeli researchers recently found that psoriasis patients have a slightly higher risk of getting COVID,  although they are not at higher risk of hospitalization or death, which could be related to treatment with immune-modulating therapy, which can increase their risk of infections.
 

How could COVID cause psoriasis to flare? 

Psoriasis is an autoimmune condition, and inflammation can cause symptoms.

Investigators for a study from Albany (N.Y.) Medical College and Weirton (Pa.) Medical Center found that people in the study who were already diagnosed with the skin condition had an unexpected flare within a week to a month after testing positive for COVID. New psoriasis after a COVID infection was also found. The researchers think this could be because COVID causes inflammation in the body, which negatively affects previously well-controlled psoriasis. They also think it’s possible that COVID-related inflammation could trigger a genetic tendency to have psoriasis, which may explain why it can appear for the first time after a positive test.

“A viral infection like COVID-19 can signal the release of proinflammatory factors that can appear as rashes, such as with psoriasis.” said Robert O. Carpenter, MD, director of wellness at Texas A&M University in Bryan.
 

What are the symptoms of COVID-related psoriasis?

The signs are the same as those of any form of psoriasis.
 

For a patient with psoriasis, will COVID automatically make it worse?

Not necessarily.

“Psoriasis is a common condition, so people should be aware that new psoriasis that develops may not be related to COVID-19,” said Esther Freeman MD, PhD, director of global health dermatology at Massachusetts General Hospital in Boston.

As with every aspect of COVID, doctors and scientists are still learning about how serious and widespread a problem psoriasis after COVID-19 may be. “We have seen case reports that psoriasis can flare after COVID-19,” said Dr. Freeman, who is also an associate professor of dermatology at Harvard Medical School. “I will say, this has not been a tidal wave – more like sporadic cases here and there. So I do not think psoriasis flares are a major post-COVID finding, nor do they necessarily mean you have long COVID. That being said, we know that many different infections can cause psoriasis flares, and so, in that respect, it’s not that surprising that SARS-CoV-2, like other infections, could trigger a psoriasis flare.”

Could getting COVID more than once cause psoriasis to flare? It’s possible.

“Your body can change after having COVID-19,” said Dr. Carpenter. “We don’t know the long-term implications, but having COVID-19 repeatedly can increase the risk of long COVID, which can cause many systemic changes in your body.” 

Another important point: For patients who take biologics for treating psoriasis, getting vaccinated and boosted for COVID is an important step to take to help protect themselves.
 

Is psoriasis itself a potential symptom of COVID? 

“Yes, but we don’t know the frequency at which this may occur, and a causal relationship is difficult to establish from just case reports,” said Dr. Gelfand, who’s also medical director of the clinical studies unit in the department of dermatology at his university. “Typically, if a patient presents with a flare of psoriasis, particularly guttate, pustular, or erythrodermic forms, an infectious trigger should be considered, and testing for strep and possibly COVID-19 may be appropriate.”
 

A version of this article first appeared on Medscape.com.

New research is shedding light on how an infection with COVID-19 may reactivate, or even cause, psoriasis. 

 Psoriasis has several well-established triggers, including stress, skin injury, cold or warm air, and allergies. Illnesses like strep throat can also cause a psoriasis flare in some people – and it appears COVID may also do so. “Psoriasis flares have long been associated with bacterial and viral infections, particularly a form of psoriasis called guttate, which is characterized by tons of tiny red scaly bumps all over the body,” said Joel M. Gelfand, MD, a professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia. “Infection with COVID-19 has been associated with flares of guttate and pustular psoriasis, and even psoriasis that affects 100% of the skin ... in many published case reports.”

Israeli researchers recently found that psoriasis patients have a slightly higher risk of getting COVID,  although they are not at higher risk of hospitalization or death, which could be related to treatment with immune-modulating therapy, which can increase their risk of infections.
 

How could COVID cause psoriasis to flare? 

Psoriasis is an autoimmune condition, and inflammation can cause symptoms.

Investigators for a study from Albany (N.Y.) Medical College and Weirton (Pa.) Medical Center found that people in the study who were already diagnosed with the skin condition had an unexpected flare within a week to a month after testing positive for COVID. New psoriasis after a COVID infection was also found. The researchers think this could be because COVID causes inflammation in the body, which negatively affects previously well-controlled psoriasis. They also think it’s possible that COVID-related inflammation could trigger a genetic tendency to have psoriasis, which may explain why it can appear for the first time after a positive test.

“A viral infection like COVID-19 can signal the release of proinflammatory factors that can appear as rashes, such as with psoriasis.” said Robert O. Carpenter, MD, director of wellness at Texas A&M University in Bryan.
 

What are the symptoms of COVID-related psoriasis?

The signs are the same as those of any form of psoriasis.
 

For a patient with psoriasis, will COVID automatically make it worse?

Not necessarily.

“Psoriasis is a common condition, so people should be aware that new psoriasis that develops may not be related to COVID-19,” said Esther Freeman MD, PhD, director of global health dermatology at Massachusetts General Hospital in Boston.

As with every aspect of COVID, doctors and scientists are still learning about how serious and widespread a problem psoriasis after COVID-19 may be. “We have seen case reports that psoriasis can flare after COVID-19,” said Dr. Freeman, who is also an associate professor of dermatology at Harvard Medical School. “I will say, this has not been a tidal wave – more like sporadic cases here and there. So I do not think psoriasis flares are a major post-COVID finding, nor do they necessarily mean you have long COVID. That being said, we know that many different infections can cause psoriasis flares, and so, in that respect, it’s not that surprising that SARS-CoV-2, like other infections, could trigger a psoriasis flare.”

Could getting COVID more than once cause psoriasis to flare? It’s possible.

“Your body can change after having COVID-19,” said Dr. Carpenter. “We don’t know the long-term implications, but having COVID-19 repeatedly can increase the risk of long COVID, which can cause many systemic changes in your body.” 

Another important point: For patients who take biologics for treating psoriasis, getting vaccinated and boosted for COVID is an important step to take to help protect themselves.
 

Is psoriasis itself a potential symptom of COVID? 

“Yes, but we don’t know the frequency at which this may occur, and a causal relationship is difficult to establish from just case reports,” said Dr. Gelfand, who’s also medical director of the clinical studies unit in the department of dermatology at his university. “Typically, if a patient presents with a flare of psoriasis, particularly guttate, pustular, or erythrodermic forms, an infectious trigger should be considered, and testing for strep and possibly COVID-19 may be appropriate.”
 

A version of this article first appeared on Medscape.com.

New research is shedding light on how an infection with COVID-19 may reactivate, or even cause, psoriasis. 

 Psoriasis has several well-established triggers, including stress, skin injury, cold or warm air, and allergies. Illnesses like strep throat can also cause a psoriasis flare in some people – and it appears COVID may also do so. “Psoriasis flares have long been associated with bacterial and viral infections, particularly a form of psoriasis called guttate, which is characterized by tons of tiny red scaly bumps all over the body,” said Joel M. Gelfand, MD, a professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia. “Infection with COVID-19 has been associated with flares of guttate and pustular psoriasis, and even psoriasis that affects 100% of the skin ... in many published case reports.”

Israeli researchers recently found that psoriasis patients have a slightly higher risk of getting COVID,  although they are not at higher risk of hospitalization or death, which could be related to treatment with immune-modulating therapy, which can increase their risk of infections.
 

How could COVID cause psoriasis to flare? 

Psoriasis is an autoimmune condition, and inflammation can cause symptoms.

Investigators for a study from Albany (N.Y.) Medical College and Weirton (Pa.) Medical Center found that people in the study who were already diagnosed with the skin condition had an unexpected flare within a week to a month after testing positive for COVID. New psoriasis after a COVID infection was also found. The researchers think this could be because COVID causes inflammation in the body, which negatively affects previously well-controlled psoriasis. They also think it’s possible that COVID-related inflammation could trigger a genetic tendency to have psoriasis, which may explain why it can appear for the first time after a positive test.

“A viral infection like COVID-19 can signal the release of proinflammatory factors that can appear as rashes, such as with psoriasis.” said Robert O. Carpenter, MD, director of wellness at Texas A&M University in Bryan.
 

What are the symptoms of COVID-related psoriasis?

The signs are the same as those of any form of psoriasis.
 

For a patient with psoriasis, will COVID automatically make it worse?

Not necessarily.

“Psoriasis is a common condition, so people should be aware that new psoriasis that develops may not be related to COVID-19,” said Esther Freeman MD, PhD, director of global health dermatology at Massachusetts General Hospital in Boston.

As with every aspect of COVID, doctors and scientists are still learning about how serious and widespread a problem psoriasis after COVID-19 may be. “We have seen case reports that psoriasis can flare after COVID-19,” said Dr. Freeman, who is also an associate professor of dermatology at Harvard Medical School. “I will say, this has not been a tidal wave – more like sporadic cases here and there. So I do not think psoriasis flares are a major post-COVID finding, nor do they necessarily mean you have long COVID. That being said, we know that many different infections can cause psoriasis flares, and so, in that respect, it’s not that surprising that SARS-CoV-2, like other infections, could trigger a psoriasis flare.”

Could getting COVID more than once cause psoriasis to flare? It’s possible.

“Your body can change after having COVID-19,” said Dr. Carpenter. “We don’t know the long-term implications, but having COVID-19 repeatedly can increase the risk of long COVID, which can cause many systemic changes in your body.” 

Another important point: For patients who take biologics for treating psoriasis, getting vaccinated and boosted for COVID is an important step to take to help protect themselves.
 

Is psoriasis itself a potential symptom of COVID? 

“Yes, but we don’t know the frequency at which this may occur, and a causal relationship is difficult to establish from just case reports,” said Dr. Gelfand, who’s also medical director of the clinical studies unit in the department of dermatology at his university. “Typically, if a patient presents with a flare of psoriasis, particularly guttate, pustular, or erythrodermic forms, an infectious trigger should be considered, and testing for strep and possibly COVID-19 may be appropriate.”
 

A version of this article first appeared on Medscape.com.

Since the COVID-19 pandemic started more than 3 years ago, the longer-lasting effects of SARS-CoV-2 infection have continued to reveal themselves. Approximately 28% of Americans report having ever experienced post-COVID conditions, such as brain fog, postexertional malaise, and joint pain, and 11% say they are still experiencing these long-term effects. Now, new research is showing that people who have had COVID are more likely to newly develop an autoimmune disease. Exactly why this is happening is less clear, experts say.

Two preprint studies and one study published in a peer-reviewed journal provide strong evidence that patients who have been infected with SARS-CoV-2 are at elevated risk of developing an autoimmune disease. The studies retrospectively reviewed medical records from three countries and compared the incidence of new-onset autoimmune disease among patients who had polymerase chain reaction–confirmed COVID-19 and those who had never been diagnosed with the virus.

A study analyzing the health records of 3.8 million U.S. patients – more than 888,460 with confirmed COVID-19 – found that the COVID-19 group was two to three times as likely to develop various autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. A U.K. preprint study that included more than 458,000 people with confirmed COVID found that those who had previously been infected with SARS-CoV-2 were 22% more likely to develop an autoimmune disease compared with the control group. In this cohort, the diseases most strongly associated with COVID-19 were type 1 diabetes, inflammatory bowel disease, and psoriasis. A preprint study from German researchers found that COVID-19 patients were almost 43% more likely to develop an autoimmune disease, compared with those who had never been infected. COVID-19 was most strongly linked to vasculitis.
 

These large studies are telling us, “Yes, this link is there, so we have to accept it,” Sonia Sharma, PhD, of the Center for Autoimmunity and Inflammation at the La Jolla (Calif.) Institute for Immunology, told this news organization. But this is not the first time that autoimmune diseases have been linked to previous infections.

La Jolla Institute for Immunology

Researchers have known for decades that Epstein-Barr virus infection is linked to several autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. More recent research suggests the virus may activate certain genes associated with these immune disorders. Hepatitis C virus can induce cryoglobulinemia, and infection with cytomegalovirus has been implicated in several autoimmune diseases. Bacterial infections have also been linked to autoimmunity, such as group A streptococcus and rheumatic fever, as well as salmonella and reactive arthritis, to name only a few.

“In a way, this isn’t necessarily a new concept to physicians, particularly rheumatologists,” said Jeffrey A. Sparks, MD, a rheumatologist at Brigham and Women’s Hospital in Boston. “There’s a fine line between appropriately clearing an infection and the body overreacting and setting off a cascade where the immune system is chronically overactive that can manifest as an autoimmune disease,” he told this news organization.

A dysregulated response to infection

It takes the immune system a week or two to develop antigen-specific antibodies to a new pathogen. But for patients with serious infections – in this instance, COVID-19 – that’s time they don’t have. Therefore, the immune system has an alternative pathway, called extrafollicular activation, that creates fast-acting antibodies, explained Matthew Woodruff, PhD, an instructor of immunology and rheumatology at Emory University, Atlanta.

Emory University School of Medicine

The trade-off is that these antibodies are not as specific and can target the body’s own tissues. This dysregulation of antibody selection is generally short lived and fades when more targeted antibodies are produced and take over, but in some cases, this process can lead to high levels of self-targeting antibodies that can harm the body’s organs and tissues. Research also suggests that for patients who experience long COVID, the same autoantibodies that drive the initial immune response are detectable in the body months after infection, though it is not known whether these lingering immune cells cause these longer-lasting symptoms.

“If you have a virus that causes hyperinflammation plus organ damage, that is a recipe for disaster,” Dr. Sharma said. “It’s a recipe for autoantibodies and autoreactive T cells that down the road can attack the body’s own tissues, especially in people whose immune system is trained in such a way to cause self-reactivity,” she added.

This hyperinflammation can result in rare but serious complications, such as multisystem inflammatory syndrome in children and adults, which can occur 2-6 weeks after SARS-CoV-2 infection. But even in these patients with severe illness, organ-specific complications tend to resolve in 6 months with “no significant sequelae 1 year after diagnosis,” according to the Centers for Disease Control and Prevention. And while long COVID can last for a year or longer, data suggest that symptoms do eventually resolve for most people. What is not clear is why acute autoimmunity triggered by COVID-19 can become a chronic condition in certain patients.
 

Predisposition to autoimmunity

P. J. Utz, MD, PhD, professor of immunology and rheumatology at Stanford (Calif.) University, said that people who develop autoimmune disease after SARS-CoV-2 infection may have already been predisposed toward autoimmunity. Especially for autoimmune diseases such as type 1 diabetes and lupus, autoantibodies can appear and circulate in the body for more than a decade in some people before they present with any clinical symptoms. “Their immune system is primed such that if they get infected with something – or they have some other environmental trigger that maybe we don’t know about yet – that is enough to then push them over the edge so that they get full-blown autoimmunity,” he said. What is not known is whether these patients’ conditions would have advanced to true clinical disease had they not been infected, he said.

Steve Fisch

He also noted that the presence of autoantibodies does not necessarily mean someone has autoimmune disease; healthy people can also have autoantibodies, and everyone develops them with age. “My advice would be, ‘Don’t lose sleep over this,’ “ he said.

Dr. Sparks agreed that while these retrospective studies did show an elevated risk of autoimmune disease after COVID-19, that risk appears to be relatively small. “As a practicing rheumatologist, we aren’t seeing a stampede of patients with new-onset rheumatic diseases,” he said. “It’s not like we’re overwhelmed with autoimmune patients, even though almost everyone’s had COVID. So, if there is a risk, it’s very modest.”

Dr. Sparks is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care. Dr. Utz receives research funding from Pfizer. Dr. Sharma and Dr. Woodruff have disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Since the COVID-19 pandemic started more than 3 years ago, the longer-lasting effects of SARS-CoV-2 infection have continued to reveal themselves. Approximately 28% of Americans report having ever experienced post-COVID conditions, such as brain fog, postexertional malaise, and joint pain, and 11% say they are still experiencing these long-term effects. Now, new research is showing that people who have had COVID are more likely to newly develop an autoimmune disease. Exactly why this is happening is less clear, experts say.

Two preprint studies and one study published in a peer-reviewed journal provide strong evidence that patients who have been infected with SARS-CoV-2 are at elevated risk of developing an autoimmune disease. The studies retrospectively reviewed medical records from three countries and compared the incidence of new-onset autoimmune disease among patients who had polymerase chain reaction–confirmed COVID-19 and those who had never been diagnosed with the virus.

A study analyzing the health records of 3.8 million U.S. patients – more than 888,460 with confirmed COVID-19 – found that the COVID-19 group was two to three times as likely to develop various autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. A U.K. preprint study that included more than 458,000 people with confirmed COVID found that those who had previously been infected with SARS-CoV-2 were 22% more likely to develop an autoimmune disease compared with the control group. In this cohort, the diseases most strongly associated with COVID-19 were type 1 diabetes, inflammatory bowel disease, and psoriasis. A preprint study from German researchers found that COVID-19 patients were almost 43% more likely to develop an autoimmune disease, compared with those who had never been infected. COVID-19 was most strongly linked to vasculitis.
 

These large studies are telling us, “Yes, this link is there, so we have to accept it,” Sonia Sharma, PhD, of the Center for Autoimmunity and Inflammation at the La Jolla (Calif.) Institute for Immunology, told this news organization. But this is not the first time that autoimmune diseases have been linked to previous infections.

La Jolla Institute for Immunology

Researchers have known for decades that Epstein-Barr virus infection is linked to several autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. More recent research suggests the virus may activate certain genes associated with these immune disorders. Hepatitis C virus can induce cryoglobulinemia, and infection with cytomegalovirus has been implicated in several autoimmune diseases. Bacterial infections have also been linked to autoimmunity, such as group A streptococcus and rheumatic fever, as well as salmonella and reactive arthritis, to name only a few.

“In a way, this isn’t necessarily a new concept to physicians, particularly rheumatologists,” said Jeffrey A. Sparks, MD, a rheumatologist at Brigham and Women’s Hospital in Boston. “There’s a fine line between appropriately clearing an infection and the body overreacting and setting off a cascade where the immune system is chronically overactive that can manifest as an autoimmune disease,” he told this news organization.

A dysregulated response to infection

It takes the immune system a week or two to develop antigen-specific antibodies to a new pathogen. But for patients with serious infections – in this instance, COVID-19 – that’s time they don’t have. Therefore, the immune system has an alternative pathway, called extrafollicular activation, that creates fast-acting antibodies, explained Matthew Woodruff, PhD, an instructor of immunology and rheumatology at Emory University, Atlanta.

Emory University School of Medicine

The trade-off is that these antibodies are not as specific and can target the body’s own tissues. This dysregulation of antibody selection is generally short lived and fades when more targeted antibodies are produced and take over, but in some cases, this process can lead to high levels of self-targeting antibodies that can harm the body’s organs and tissues. Research also suggests that for patients who experience long COVID, the same autoantibodies that drive the initial immune response are detectable in the body months after infection, though it is not known whether these lingering immune cells cause these longer-lasting symptoms.

“If you have a virus that causes hyperinflammation plus organ damage, that is a recipe for disaster,” Dr. Sharma said. “It’s a recipe for autoantibodies and autoreactive T cells that down the road can attack the body’s own tissues, especially in people whose immune system is trained in such a way to cause self-reactivity,” she added.

This hyperinflammation can result in rare but serious complications, such as multisystem inflammatory syndrome in children and adults, which can occur 2-6 weeks after SARS-CoV-2 infection. But even in these patients with severe illness, organ-specific complications tend to resolve in 6 months with “no significant sequelae 1 year after diagnosis,” according to the Centers for Disease Control and Prevention. And while long COVID can last for a year or longer, data suggest that symptoms do eventually resolve for most people. What is not clear is why acute autoimmunity triggered by COVID-19 can become a chronic condition in certain patients.
 

Predisposition to autoimmunity

P. J. Utz, MD, PhD, professor of immunology and rheumatology at Stanford (Calif.) University, said that people who develop autoimmune disease after SARS-CoV-2 infection may have already been predisposed toward autoimmunity. Especially for autoimmune diseases such as type 1 diabetes and lupus, autoantibodies can appear and circulate in the body for more than a decade in some people before they present with any clinical symptoms. “Their immune system is primed such that if they get infected with something – or they have some other environmental trigger that maybe we don’t know about yet – that is enough to then push them over the edge so that they get full-blown autoimmunity,” he said. What is not known is whether these patients’ conditions would have advanced to true clinical disease had they not been infected, he said.

Steve Fisch

He also noted that the presence of autoantibodies does not necessarily mean someone has autoimmune disease; healthy people can also have autoantibodies, and everyone develops them with age. “My advice would be, ‘Don’t lose sleep over this,’ “ he said.

Dr. Sparks agreed that while these retrospective studies did show an elevated risk of autoimmune disease after COVID-19, that risk appears to be relatively small. “As a practicing rheumatologist, we aren’t seeing a stampede of patients with new-onset rheumatic diseases,” he said. “It’s not like we’re overwhelmed with autoimmune patients, even though almost everyone’s had COVID. So, if there is a risk, it’s very modest.”

Dr. Sparks is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care. Dr. Utz receives research funding from Pfizer. Dr. Sharma and Dr. Woodruff have disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Since the COVID-19 pandemic started more than 3 years ago, the longer-lasting effects of SARS-CoV-2 infection have continued to reveal themselves. Approximately 28% of Americans report having ever experienced post-COVID conditions, such as brain fog, postexertional malaise, and joint pain, and 11% say they are still experiencing these long-term effects. Now, new research is showing that people who have had COVID are more likely to newly develop an autoimmune disease. Exactly why this is happening is less clear, experts say.

Two preprint studies and one study published in a peer-reviewed journal provide strong evidence that patients who have been infected with SARS-CoV-2 are at elevated risk of developing an autoimmune disease. The studies retrospectively reviewed medical records from three countries and compared the incidence of new-onset autoimmune disease among patients who had polymerase chain reaction–confirmed COVID-19 and those who had never been diagnosed with the virus.

A study analyzing the health records of 3.8 million U.S. patients – more than 888,460 with confirmed COVID-19 – found that the COVID-19 group was two to three times as likely to develop various autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. A U.K. preprint study that included more than 458,000 people with confirmed COVID found that those who had previously been infected with SARS-CoV-2 were 22% more likely to develop an autoimmune disease compared with the control group. In this cohort, the diseases most strongly associated with COVID-19 were type 1 diabetes, inflammatory bowel disease, and psoriasis. A preprint study from German researchers found that COVID-19 patients were almost 43% more likely to develop an autoimmune disease, compared with those who had never been infected. COVID-19 was most strongly linked to vasculitis.
 

These large studies are telling us, “Yes, this link is there, so we have to accept it,” Sonia Sharma, PhD, of the Center for Autoimmunity and Inflammation at the La Jolla (Calif.) Institute for Immunology, told this news organization. But this is not the first time that autoimmune diseases have been linked to previous infections.

La Jolla Institute for Immunology

Researchers have known for decades that Epstein-Barr virus infection is linked to several autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. More recent research suggests the virus may activate certain genes associated with these immune disorders. Hepatitis C virus can induce cryoglobulinemia, and infection with cytomegalovirus has been implicated in several autoimmune diseases. Bacterial infections have also been linked to autoimmunity, such as group A streptococcus and rheumatic fever, as well as salmonella and reactive arthritis, to name only a few.

“In a way, this isn’t necessarily a new concept to physicians, particularly rheumatologists,” said Jeffrey A. Sparks, MD, a rheumatologist at Brigham and Women’s Hospital in Boston. “There’s a fine line between appropriately clearing an infection and the body overreacting and setting off a cascade where the immune system is chronically overactive that can manifest as an autoimmune disease,” he told this news organization.

A dysregulated response to infection

It takes the immune system a week or two to develop antigen-specific antibodies to a new pathogen. But for patients with serious infections – in this instance, COVID-19 – that’s time they don’t have. Therefore, the immune system has an alternative pathway, called extrafollicular activation, that creates fast-acting antibodies, explained Matthew Woodruff, PhD, an instructor of immunology and rheumatology at Emory University, Atlanta.

Emory University School of Medicine

The trade-off is that these antibodies are not as specific and can target the body’s own tissues. This dysregulation of antibody selection is generally short lived and fades when more targeted antibodies are produced and take over, but in some cases, this process can lead to high levels of self-targeting antibodies that can harm the body’s organs and tissues. Research also suggests that for patients who experience long COVID, the same autoantibodies that drive the initial immune response are detectable in the body months after infection, though it is not known whether these lingering immune cells cause these longer-lasting symptoms.

“If you have a virus that causes hyperinflammation plus organ damage, that is a recipe for disaster,” Dr. Sharma said. “It’s a recipe for autoantibodies and autoreactive T cells that down the road can attack the body’s own tissues, especially in people whose immune system is trained in such a way to cause self-reactivity,” she added.

This hyperinflammation can result in rare but serious complications, such as multisystem inflammatory syndrome in children and adults, which can occur 2-6 weeks after SARS-CoV-2 infection. But even in these patients with severe illness, organ-specific complications tend to resolve in 6 months with “no significant sequelae 1 year after diagnosis,” according to the Centers for Disease Control and Prevention. And while long COVID can last for a year or longer, data suggest that symptoms do eventually resolve for most people. What is not clear is why acute autoimmunity triggered by COVID-19 can become a chronic condition in certain patients.
 

Predisposition to autoimmunity

P. J. Utz, MD, PhD, professor of immunology and rheumatology at Stanford (Calif.) University, said that people who develop autoimmune disease after SARS-CoV-2 infection may have already been predisposed toward autoimmunity. Especially for autoimmune diseases such as type 1 diabetes and lupus, autoantibodies can appear and circulate in the body for more than a decade in some people before they present with any clinical symptoms. “Their immune system is primed such that if they get infected with something – or they have some other environmental trigger that maybe we don’t know about yet – that is enough to then push them over the edge so that they get full-blown autoimmunity,” he said. What is not known is whether these patients’ conditions would have advanced to true clinical disease had they not been infected, he said.

Steve Fisch

He also noted that the presence of autoantibodies does not necessarily mean someone has autoimmune disease; healthy people can also have autoantibodies, and everyone develops them with age. “My advice would be, ‘Don’t lose sleep over this,’ “ he said.

Dr. Sparks agreed that while these retrospective studies did show an elevated risk of autoimmune disease after COVID-19, that risk appears to be relatively small. “As a practicing rheumatologist, we aren’t seeing a stampede of patients with new-onset rheumatic diseases,” he said. “It’s not like we’re overwhelmed with autoimmune patients, even though almost everyone’s had COVID. So, if there is a risk, it’s very modest.”

Dr. Sparks is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care. Dr. Utz receives research funding from Pfizer. Dr. Sharma and Dr. Woodruff have disclosed no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

MANCHESTER, ENGLAND – Janus kinase (JAK) inhibitors may be associated with a higher risk for cancer relative to tumor necrosis factor (TNF) inhibitors, according to a meta-analysis reported at the annual meeting of the British Society for Rheumatology.

Looking at all phase 2, 3, and 4 trials and long-term extension studies across the indications of rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, and atopic dermatitis, the risk ratio for any cancer developing was 1.63 when compared with anti-TNF therapy (95% confidence interval, 1.27-2.09).

Sara Freeman/MDedge News

By comparison, JAK inhibitor use was not significantly associated with any greater risk for cancer than methotrexate (RR, 1.06; 95% confidence interval, 0.58-1.94) or placebo (RR, 1.16; 95% CI, 0.75-1.80).

“Our data suggests that rather than JAK inhibitors necessarily being harmful, it could be more a case of TNF inhibitors being protective,” said Christopher Stovin, MBChB, a specialist registrar in rheumatology at the Princess Royal University Hospital, King’s College Hospital NHS Trust, London.

“We should stress that these are rare events in our study, roughly around 1 in every 100 patient-years of exposure,” Dr. Stovin said.

“Despite having over 80,000 years of patient exposure, the median follow-up duration for JAK inhibitors was still only 118 weeks, which for cancers [that] obviously have long latency periods is still a relatively small duration of time,” the researcher added.

“People worry about the drugs. But there is a possibility that [a] disturbed immune system plays a role per se in development of cancers,” consultant rheumatologist Anurag Bharadwaj, MD, DM, said in an interview.

“Although there are studies which attribute increased risk of cancer to different DMARDs [disease-modifying antirheumatic drugs] and biologics like TNF, but on other hand, it’s maybe that we are giving these drugs to patients who have got more serious immunological disease,” suggested Bharadwaj, who serves as the clinical lead for rheumatology at Basildon (England) Hospital, Mid & South Essex Foundation Trust.

“So, a possibility may be that the more severe or the more active the immunological inflammatory disease, the higher the chance of cancer, and these are the patients who go for the stronger medications,” Dr. Bharadwaj said.

There is an “immunological window of opportunity” when treating these inflammatory diseases, said Dr. Bharadwaj, noting that the first few months of treatment are vital. “For all immunological diseases, the more quickly you bring the immunological abnormality down, the chances of long-term complications go down, including [possibly that the] chances of cancer go down, chances of cardiovascular disease go down, and chances of lung disease go down. Hit it early, hit it hard.”

Concern over a possible higher risk for cancer with JAK inhibitors than with TNF inhibitors was raised following the release of data from the ORAL Surveillance trial, a postmarketing trial of tofacitinib (Xeljanz) that had been mandated by the Food and Drug Administration.

“This was a study looking at the coprimary endpoints of malignancy and major adverse cardiovascular events, and it was enriched with patients over the age of 50, with one additional cardiac risk factor, designed to amplify the detection of these rare events,” Dr. Stovin said.

“There was a signal of an increased risk of malignancy in the tofacitinib group, and this led to the FDA issuing a [boxed warning for all licensed JAK inhibitors] at that time,” he added.

Dr. Stovin and colleagues aimed to determine what, if any, cancer risk was associated with all available JAK inhibitors relative to placebo, TNF inhibitors, and methotrexate.

In all, data from 62 randomized controlled trials and 14 long-term extension studies were included in the meta-analysis, accounting for 82,366 patient years of follow-up. The JAK inhibitors analyzed included tofacitinib, baricitinib (Olumiant), upadacitinib (Rinvoq), filgotinib (Jyseleca), and peficitinib (Smyraf). (Filgotinib and peficitinib have not been approved by the FDA.)

The researchers performed sensitivity analyses that excluded cancers detected within the first 6 months of treatment, the use of higher than licensed JAK inhibitor doses, and patients with non-rheumatoid arthritis diagnoses, but the results remained largely unchanged, Dr. Stovin reported.  

“Perhaps not surprisingly, when we removed ORAL Surveillance” from the analysis comparing JAK inhibitors and TNF inhibitors, “we lost statistical significance,” he said.

“Longitudinal observational data is needed but currently remains limited,” Dr. Stovin concluded.

Dr. Stovin and Dr. Bharadwaj reported no relevant financial relationships. The meta-analysis was independently supported. Dr. Bharadwaj was not involved in the study and provided comment ahead of the presentation.

A version of this article first appeared on Medscape.com.

MANCHESTER, ENGLAND – Janus kinase (JAK) inhibitors may be associated with a higher risk for cancer relative to tumor necrosis factor (TNF) inhibitors, according to a meta-analysis reported at the annual meeting of the British Society for Rheumatology.

Looking at all phase 2, 3, and 4 trials and long-term extension studies across the indications of rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, and atopic dermatitis, the risk ratio for any cancer developing was 1.63 when compared with anti-TNF therapy (95% confidence interval, 1.27-2.09).

Sara Freeman/MDedge News

By comparison, JAK inhibitor use was not significantly associated with any greater risk for cancer than methotrexate (RR, 1.06; 95% confidence interval, 0.58-1.94) or placebo (RR, 1.16; 95% CI, 0.75-1.80).

“Our data suggests that rather than JAK inhibitors necessarily being harmful, it could be more a case of TNF inhibitors being protective,” said Christopher Stovin, MBChB, a specialist registrar in rheumatology at the Princess Royal University Hospital, King’s College Hospital NHS Trust, London.

“We should stress that these are rare events in our study, roughly around 1 in every 100 patient-years of exposure,” Dr. Stovin said.

“Despite having over 80,000 years of patient exposure, the median follow-up duration for JAK inhibitors was still only 118 weeks, which for cancers [that] obviously have long latency periods is still a relatively small duration of time,” the researcher added.

“People worry about the drugs. But there is a possibility that [a] disturbed immune system plays a role per se in development of cancers,” consultant rheumatologist Anurag Bharadwaj, MD, DM, said in an interview.

“Although there are studies which attribute increased risk of cancer to different DMARDs [disease-modifying antirheumatic drugs] and biologics like TNF, but on other hand, it’s maybe that we are giving these drugs to patients who have got more serious immunological disease,” suggested Bharadwaj, who serves as the clinical lead for rheumatology at Basildon (England) Hospital, Mid & South Essex Foundation Trust.

“So, a possibility may be that the more severe or the more active the immunological inflammatory disease, the higher the chance of cancer, and these are the patients who go for the stronger medications,” Dr. Bharadwaj said.

There is an “immunological window of opportunity” when treating these inflammatory diseases, said Dr. Bharadwaj, noting that the first few months of treatment are vital. “For all immunological diseases, the more quickly you bring the immunological abnormality down, the chances of long-term complications go down, including [possibly that the] chances of cancer go down, chances of cardiovascular disease go down, and chances of lung disease go down. Hit it early, hit it hard.”

Concern over a possible higher risk for cancer with JAK inhibitors than with TNF inhibitors was raised following the release of data from the ORAL Surveillance trial, a postmarketing trial of tofacitinib (Xeljanz) that had been mandated by the Food and Drug Administration.

“This was a study looking at the coprimary endpoints of malignancy and major adverse cardiovascular events, and it was enriched with patients over the age of 50, with one additional cardiac risk factor, designed to amplify the detection of these rare events,” Dr. Stovin said.

“There was a signal of an increased risk of malignancy in the tofacitinib group, and this led to the FDA issuing a [boxed warning for all licensed JAK inhibitors] at that time,” he added.

Dr. Stovin and colleagues aimed to determine what, if any, cancer risk was associated with all available JAK inhibitors relative to placebo, TNF inhibitors, and methotrexate.

In all, data from 62 randomized controlled trials and 14 long-term extension studies were included in the meta-analysis, accounting for 82,366 patient years of follow-up. The JAK inhibitors analyzed included tofacitinib, baricitinib (Olumiant), upadacitinib (Rinvoq), filgotinib (Jyseleca), and peficitinib (Smyraf). (Filgotinib and peficitinib have not been approved by the FDA.)

The researchers performed sensitivity analyses that excluded cancers detected within the first 6 months of treatment, the use of higher than licensed JAK inhibitor doses, and patients with non-rheumatoid arthritis diagnoses, but the results remained largely unchanged, Dr. Stovin reported.  

“Perhaps not surprisingly, when we removed ORAL Surveillance” from the analysis comparing JAK inhibitors and TNF inhibitors, “we lost statistical significance,” he said.

“Longitudinal observational data is needed but currently remains limited,” Dr. Stovin concluded.

Dr. Stovin and Dr. Bharadwaj reported no relevant financial relationships. The meta-analysis was independently supported. Dr. Bharadwaj was not involved in the study and provided comment ahead of the presentation.

A version of this article first appeared on Medscape.com.

MANCHESTER, ENGLAND – Janus kinase (JAK) inhibitors may be associated with a higher risk for cancer relative to tumor necrosis factor (TNF) inhibitors, according to a meta-analysis reported at the annual meeting of the British Society for Rheumatology.

Looking at all phase 2, 3, and 4 trials and long-term extension studies across the indications of rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, and atopic dermatitis, the risk ratio for any cancer developing was 1.63 when compared with anti-TNF therapy (95% confidence interval, 1.27-2.09).

Sara Freeman/MDedge News

By comparison, JAK inhibitor use was not significantly associated with any greater risk for cancer than methotrexate (RR, 1.06; 95% confidence interval, 0.58-1.94) or placebo (RR, 1.16; 95% CI, 0.75-1.80).

“Our data suggests that rather than JAK inhibitors necessarily being harmful, it could be more a case of TNF inhibitors being protective,” said Christopher Stovin, MBChB, a specialist registrar in rheumatology at the Princess Royal University Hospital, King’s College Hospital NHS Trust, London.

“We should stress that these are rare events in our study, roughly around 1 in every 100 patient-years of exposure,” Dr. Stovin said.

“Despite having over 80,000 years of patient exposure, the median follow-up duration for JAK inhibitors was still only 118 weeks, which for cancers [that] obviously have long latency periods is still a relatively small duration of time,” the researcher added.

“People worry about the drugs. But there is a possibility that [a] disturbed immune system plays a role per se in development of cancers,” consultant rheumatologist Anurag Bharadwaj, MD, DM, said in an interview.

“Although there are studies which attribute increased risk of cancer to different DMARDs [disease-modifying antirheumatic drugs] and biologics like TNF, but on other hand, it’s maybe that we are giving these drugs to patients who have got more serious immunological disease,” suggested Bharadwaj, who serves as the clinical lead for rheumatology at Basildon (England) Hospital, Mid & South Essex Foundation Trust.

“So, a possibility may be that the more severe or the more active the immunological inflammatory disease, the higher the chance of cancer, and these are the patients who go for the stronger medications,” Dr. Bharadwaj said.

There is an “immunological window of opportunity” when treating these inflammatory diseases, said Dr. Bharadwaj, noting that the first few months of treatment are vital. “For all immunological diseases, the more quickly you bring the immunological abnormality down, the chances of long-term complications go down, including [possibly that the] chances of cancer go down, chances of cardiovascular disease go down, and chances of lung disease go down. Hit it early, hit it hard.”

Concern over a possible higher risk for cancer with JAK inhibitors than with TNF inhibitors was raised following the release of data from the ORAL Surveillance trial, a postmarketing trial of tofacitinib (Xeljanz) that had been mandated by the Food and Drug Administration.

“This was a study looking at the coprimary endpoints of malignancy and major adverse cardiovascular events, and it was enriched with patients over the age of 50, with one additional cardiac risk factor, designed to amplify the detection of these rare events,” Dr. Stovin said.

“There was a signal of an increased risk of malignancy in the tofacitinib group, and this led to the FDA issuing a [boxed warning for all licensed JAK inhibitors] at that time,” he added.

Dr. Stovin and colleagues aimed to determine what, if any, cancer risk was associated with all available JAK inhibitors relative to placebo, TNF inhibitors, and methotrexate.

In all, data from 62 randomized controlled trials and 14 long-term extension studies were included in the meta-analysis, accounting for 82,366 patient years of follow-up. The JAK inhibitors analyzed included tofacitinib, baricitinib (Olumiant), upadacitinib (Rinvoq), filgotinib (Jyseleca), and peficitinib (Smyraf). (Filgotinib and peficitinib have not been approved by the FDA.)

The researchers performed sensitivity analyses that excluded cancers detected within the first 6 months of treatment, the use of higher than licensed JAK inhibitor doses, and patients with non-rheumatoid arthritis diagnoses, but the results remained largely unchanged, Dr. Stovin reported.  

“Perhaps not surprisingly, when we removed ORAL Surveillance” from the analysis comparing JAK inhibitors and TNF inhibitors, “we lost statistical significance,” he said.

“Longitudinal observational data is needed but currently remains limited,” Dr. Stovin concluded.

Dr. Stovin and Dr. Bharadwaj reported no relevant financial relationships. The meta-analysis was independently supported. Dr. Bharadwaj was not involved in the study and provided comment ahead of the presentation.

A version of this article first appeared on Medscape.com.

A position paper by the National Psoriasis Foundation’s Telemedicine Task Force outlines key principles and practices for managing psoriatic disease via telemedicine.

The success of telemedicine in managing chronic inflammatory skin conditions including psoriasis during the COVID-19 pandemic “highlighted that teledermatology can be used beyond the context of a global health crisis to provide continuity of care and improve access to health care more broadly,” the task force wrote in a paper published online in JAAD International.

Jean-philippe WALLET/Getty Images

Co–senior author George Han, MD, PhD, said in an interview that the impetus for the guidelines came from NPF patient advocates, who realized that the organization needed something to take to payers and governmental agencies to advocate for better access to dermatologic care. He is associate professor of dermatology and director of teledermatology at the Hofstra/Northwell department of dermatology, Hyde Park, New York.

“We realized that, in many places around the country, people don’t have access to dermatology.” In upstate New York, said Dr. Han, his anecdotal research has revealed wait times of 6 months or more.

As a guiding principle, the authors pronounce teledermatology “a reasonable alternative for providing long-term management of patients with psoriasis.” Research shows that nearly all dermatologists used teledermatology during the pandemic, the authors noted, and that well-run programs improve Psoriasis Area and Severity Index (PASI) scores and other measures on par with in-person care. Telemedicine may be especially useful for initial visits, they added, particularly when distance, patient incapacity, and circumstances prevent face-to-face evaluation.

Additional position statements emphasize that teledermatology should support rather than supplant in-person visits, and that this balance may be particularly important in cases involving psoriatic arthritis (PsA). “Even though we can’t do a physical exam and palpate some of those joints in person,” said Dr. Han, “tools have been developed that, through a series of questions the patient can answer, can guide you towards whether there is a high index of suspicion for psoriatic arthritis.” Such patients require in-person evaluation with urgency, he said, because delays in PsA diagnosis and treatment can lead to irreversible joint damage and significant functional impairment.

Another motivation for producing the guidelines, said Dr. Han, was that, even when underserved patients get a dermatology appointment, some providers may not have all the latest tools or medicines available for treating psoriasis. In such cases, telemedicine may allow dermatologists specializing in psoriasis care to extend their reach in comanaging patients with primary care physicians and community dermatologists.

Before the appointment, guidelines suggest determining what form of teledermatology will best suit each patient. Authors recommended gauging patients’ savviness with computers and cameras, and counseling patients regarding available virtual evaluation tools – such as live video visits, store-and-forward photo strategies, and assessment-tool training videos.

A subsequent guideline underscores the importance of continuously improving technology to support expeditious image capture and workflows that emulate in-person practice. Dr. Han explained, “we wanted to make sure that on the back end there’s adequate support such that – if through teledermatology, we determine that the patient should get, say, a systemic treatment – the patient is able to get the appropriate lab tests, get the medicine, and know how to inject it.”

Regarding reimbursement, Dr. Han said that policies varied prepandemic, but many commercial insurers covered telemedicine at a rate 20% lower than the in-person rate. During the pandemic, he said, insurers shifted to provide the higher rate for telemedicine, consistent with policies adopted by the Centers for Medicare & Medicaid Services.

“There are differences in coverage and reimbursement from plan to plan,” Dr. Han added. “And even within the same plan, there are carve-outs so that some plans don’t allow certain services. The big picture is that for the most part these services are covered at a level comparable to an in-person visit at present.”

With the Department of Health & Human Services’ public health emergency declaration expiring in May, he said, physicians have worried that some of the allowances made by CMS – such as lifting requirements that Medicare patients in rural areas be seen at care sites – will expire. “It seems that some of those limitations have been addressed, and those allowances are going to be extended until Congress is able to pass something that gives us durable access to telemedicine care. We think that based on the current environment telemedicine is here to stay.”

The study was funded by the NPF. Dr. Han has been an investigator, adviser, speaker, or researcher for AbbVie, Amgen, Apogee Therapeutics, Arcutis, Athenex, Bausch Health, Beiersdorf, Boehringer Ingelheim, Bond Avillion, Bristol Myers Squibb, Celgene, CeraVe, Dermavant, DermTech, Eli Lilly, EPI Health, Janssen Pharmaceuticals, LEO Pharma, L’Oreal, MC2 Therapeutics, Novartis, Ortho Dermatologics, PellePharm, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, SUN Pharmaceuticals, and UCB.

A position paper by the National Psoriasis Foundation’s Telemedicine Task Force outlines key principles and practices for managing psoriatic disease via telemedicine.

The success of telemedicine in managing chronic inflammatory skin conditions including psoriasis during the COVID-19 pandemic “highlighted that teledermatology can be used beyond the context of a global health crisis to provide continuity of care and improve access to health care more broadly,” the task force wrote in a paper published online in JAAD International.

Jean-philippe WALLET/Getty Images

Co–senior author George Han, MD, PhD, said in an interview that the impetus for the guidelines came from NPF patient advocates, who realized that the organization needed something to take to payers and governmental agencies to advocate for better access to dermatologic care. He is associate professor of dermatology and director of teledermatology at the Hofstra/Northwell department of dermatology, Hyde Park, New York.

“We realized that, in many places around the country, people don’t have access to dermatology.” In upstate New York, said Dr. Han, his anecdotal research has revealed wait times of 6 months or more.

As a guiding principle, the authors pronounce teledermatology “a reasonable alternative for providing long-term management of patients with psoriasis.” Research shows that nearly all dermatologists used teledermatology during the pandemic, the authors noted, and that well-run programs improve Psoriasis Area and Severity Index (PASI) scores and other measures on par with in-person care. Telemedicine may be especially useful for initial visits, they added, particularly when distance, patient incapacity, and circumstances prevent face-to-face evaluation.

Additional position statements emphasize that teledermatology should support rather than supplant in-person visits, and that this balance may be particularly important in cases involving psoriatic arthritis (PsA). “Even though we can’t do a physical exam and palpate some of those joints in person,” said Dr. Han, “tools have been developed that, through a series of questions the patient can answer, can guide you towards whether there is a high index of suspicion for psoriatic arthritis.” Such patients require in-person evaluation with urgency, he said, because delays in PsA diagnosis and treatment can lead to irreversible joint damage and significant functional impairment.

Another motivation for producing the guidelines, said Dr. Han, was that, even when underserved patients get a dermatology appointment, some providers may not have all the latest tools or medicines available for treating psoriasis. In such cases, telemedicine may allow dermatologists specializing in psoriasis care to extend their reach in comanaging patients with primary care physicians and community dermatologists.

Before the appointment, guidelines suggest determining what form of teledermatology will best suit each patient. Authors recommended gauging patients’ savviness with computers and cameras, and counseling patients regarding available virtual evaluation tools – such as live video visits, store-and-forward photo strategies, and assessment-tool training videos.

A subsequent guideline underscores the importance of continuously improving technology to support expeditious image capture and workflows that emulate in-person practice. Dr. Han explained, “we wanted to make sure that on the back end there’s adequate support such that – if through teledermatology, we determine that the patient should get, say, a systemic treatment – the patient is able to get the appropriate lab tests, get the medicine, and know how to inject it.”

Regarding reimbursement, Dr. Han said that policies varied prepandemic, but many commercial insurers covered telemedicine at a rate 20% lower than the in-person rate. During the pandemic, he said, insurers shifted to provide the higher rate for telemedicine, consistent with policies adopted by the Centers for Medicare & Medicaid Services.

“There are differences in coverage and reimbursement from plan to plan,” Dr. Han added. “And even within the same plan, there are carve-outs so that some plans don’t allow certain services. The big picture is that for the most part these services are covered at a level comparable to an in-person visit at present.”

With the Department of Health & Human Services’ public health emergency declaration expiring in May, he said, physicians have worried that some of the allowances made by CMS – such as lifting requirements that Medicare patients in rural areas be seen at care sites – will expire. “It seems that some of those limitations have been addressed, and those allowances are going to be extended until Congress is able to pass something that gives us durable access to telemedicine care. We think that based on the current environment telemedicine is here to stay.”

The study was funded by the NPF. Dr. Han has been an investigator, adviser, speaker, or researcher for AbbVie, Amgen, Apogee Therapeutics, Arcutis, Athenex, Bausch Health, Beiersdorf, Boehringer Ingelheim, Bond Avillion, Bristol Myers Squibb, Celgene, CeraVe, Dermavant, DermTech, Eli Lilly, EPI Health, Janssen Pharmaceuticals, LEO Pharma, L’Oreal, MC2 Therapeutics, Novartis, Ortho Dermatologics, PellePharm, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, SUN Pharmaceuticals, and UCB.

A position paper by the National Psoriasis Foundation’s Telemedicine Task Force outlines key principles and practices for managing psoriatic disease via telemedicine.

The success of telemedicine in managing chronic inflammatory skin conditions including psoriasis during the COVID-19 pandemic “highlighted that teledermatology can be used beyond the context of a global health crisis to provide continuity of care and improve access to health care more broadly,” the task force wrote in a paper published online in JAAD International.

Jean-philippe WALLET/Getty Images

Co–senior author George Han, MD, PhD, said in an interview that the impetus for the guidelines came from NPF patient advocates, who realized that the organization needed something to take to payers and governmental agencies to advocate for better access to dermatologic care. He is associate professor of dermatology and director of teledermatology at the Hofstra/Northwell department of dermatology, Hyde Park, New York.

“We realized that, in many places around the country, people don’t have access to dermatology.” In upstate New York, said Dr. Han, his anecdotal research has revealed wait times of 6 months or more.

As a guiding principle, the authors pronounce teledermatology “a reasonable alternative for providing long-term management of patients with psoriasis.” Research shows that nearly all dermatologists used teledermatology during the pandemic, the authors noted, and that well-run programs improve Psoriasis Area and Severity Index (PASI) scores and other measures on par with in-person care. Telemedicine may be especially useful for initial visits, they added, particularly when distance, patient incapacity, and circumstances prevent face-to-face evaluation.

Additional position statements emphasize that teledermatology should support rather than supplant in-person visits, and that this balance may be particularly important in cases involving psoriatic arthritis (PsA). “Even though we can’t do a physical exam and palpate some of those joints in person,” said Dr. Han, “tools have been developed that, through a series of questions the patient can answer, can guide you towards whether there is a high index of suspicion for psoriatic arthritis.” Such patients require in-person evaluation with urgency, he said, because delays in PsA diagnosis and treatment can lead to irreversible joint damage and significant functional impairment.

Another motivation for producing the guidelines, said Dr. Han, was that, even when underserved patients get a dermatology appointment, some providers may not have all the latest tools or medicines available for treating psoriasis. In such cases, telemedicine may allow dermatologists specializing in psoriasis care to extend their reach in comanaging patients with primary care physicians and community dermatologists.

Before the appointment, guidelines suggest determining what form of teledermatology will best suit each patient. Authors recommended gauging patients’ savviness with computers and cameras, and counseling patients regarding available virtual evaluation tools – such as live video visits, store-and-forward photo strategies, and assessment-tool training videos.

A subsequent guideline underscores the importance of continuously improving technology to support expeditious image capture and workflows that emulate in-person practice. Dr. Han explained, “we wanted to make sure that on the back end there’s adequate support such that – if through teledermatology, we determine that the patient should get, say, a systemic treatment – the patient is able to get the appropriate lab tests, get the medicine, and know how to inject it.”

Regarding reimbursement, Dr. Han said that policies varied prepandemic, but many commercial insurers covered telemedicine at a rate 20% lower than the in-person rate. During the pandemic, he said, insurers shifted to provide the higher rate for telemedicine, consistent with policies adopted by the Centers for Medicare & Medicaid Services.

“There are differences in coverage and reimbursement from plan to plan,” Dr. Han added. “And even within the same plan, there are carve-outs so that some plans don’t allow certain services. The big picture is that for the most part these services are covered at a level comparable to an in-person visit at present.”

With the Department of Health & Human Services’ public health emergency declaration expiring in May, he said, physicians have worried that some of the allowances made by CMS – such as lifting requirements that Medicare patients in rural areas be seen at care sites – will expire. “It seems that some of those limitations have been addressed, and those allowances are going to be extended until Congress is able to pass something that gives us durable access to telemedicine care. We think that based on the current environment telemedicine is here to stay.”

The study was funded by the NPF. Dr. Han has been an investigator, adviser, speaker, or researcher for AbbVie, Amgen, Apogee Therapeutics, Arcutis, Athenex, Bausch Health, Beiersdorf, Boehringer Ingelheim, Bond Avillion, Bristol Myers Squibb, Celgene, CeraVe, Dermavant, DermTech, Eli Lilly, EPI Health, Janssen Pharmaceuticals, LEO Pharma, L’Oreal, MC2 Therapeutics, Novartis, Ortho Dermatologics, PellePharm, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, SUN Pharmaceuticals, and UCB.

Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.¹ Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.^2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.⁴

Antibacterial, anti-inflammatory, hypolipemic, and anticancer properties have been associated with bergapten, which is primarily found in bergamot essential oil and used effectively as a photosensitizing agent.⁵ In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.⁶ In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.⁷ This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
 

Bergapten

In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.⁴

The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.⁵

Anti-inflammatory topical uses

In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.⁸

More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.³

Acne

In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.²

Psoriasis

In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.⁹

Vitiligo

In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.¹⁰

Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.⁶

Photoaging, photoprotection, and safety concerns

Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.¹¹

In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.¹²In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.¹³

Conclusion

As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at [email protected].

References

1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.

2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.

3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.

4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.

5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.

6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.

7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.

8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.

9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.

10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.

11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.

12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.

13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.

Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.¹ Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.^2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.⁴

Antibacterial, anti-inflammatory, hypolipemic, and anticancer properties have been associated with bergapten, which is primarily found in bergamot essential oil and used effectively as a photosensitizing agent.⁵ In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.⁶ In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.⁷ This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
 

Bergapten

In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.⁴

The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.⁵

Anti-inflammatory topical uses

In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.⁸

More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.³

Acne

In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.²

Psoriasis

In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.⁹

Vitiligo

In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.¹⁰

Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.⁶

Photoaging, photoprotection, and safety concerns

Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.¹¹

In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.¹²In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.¹³

Conclusion

As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at [email protected].

References

1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.

2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.

3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.

4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.

5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.

6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.

7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.

8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.

9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.

10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.

11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.

12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.

13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.

Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.¹ Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.^2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.⁴

Antibacterial, anti-inflammatory, hypolipemic, and anticancer properties have been associated with bergapten, which is primarily found in bergamot essential oil and used effectively as a photosensitizing agent.⁵ In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.⁶ In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.⁷ This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
 

Bergapten

In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.⁴

The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.⁵

Anti-inflammatory topical uses

In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.⁸

More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.³

Acne

In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.²

Psoriasis

In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.⁹

Vitiligo

In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.¹⁰

Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.⁶

Photoaging, photoprotection, and safety concerns

Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.¹¹

In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.¹²In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.¹³

Conclusion

As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at [email protected].

References

1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.

2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.

3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.

4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.

5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.

6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.

7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.

8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.

9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.

10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.

11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.

12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.

13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.

Just 16% of psoriasis-related visits to dermatology providers in the United States involve screening for cardiovascular (CV) risk factors, with screening lowest in the region with the highest CV disease burden, according to an analysis of 10 years of national survey data.

From 2007 to 2016, national screening rates for four CV risk factors at 14.8 million psoriasis-related visits to dermatology providers were 11% (body-mass index), 7.4% (blood pressure), 2.9% (cholesterol), and 1.7% (glucose). Data from the National Ambulatory Medical Care Survey showed that at least one of the four factors was screened at 16% of dermatology visits, said William B. Song, BS, of the department of dermatology, University of Pennsylvania, Philadelphia, and associates.

The main focus of their study, however, was regional differences. “CV risk factor screening by dermatology providers for patients with psoriasis is low across all regions of the United States and lowest in the South, the region that experiences the highest CVD burden in the United States,” they wrote in a letter to the editor.

Compared with the South, the adjusted odds of any CV screening were 0.98 in the West, 1.25 in the Northeast, and 1.92 in the Midwest. Blood pressure screening was significantly higher in all three regions, compared with the South, while BMI screening was actually lower in the West (0.74), the investigators reported. Odds ratios were not available for cholesterol and glucose screening because of sample size limitations.

The regional variation in screening rates “is not explained by patient demographics or disease severity,” they noted, adding that 2.8 million visits with BP screening would have been added over the 10-year study period “if providers in the South screened patients with psoriasis for high blood pressure at the same rate as providers in the Northeast.”

Guidelines published in 2019 by the American Academy of Dermatology and the National Psoriasis Foundation – which were cowritten by Joel M. Gelfand, MD, senior author of the current study – noted that dermatologists “play an important role in evidence-based screening of CV risk factors in patients with psoriasis,” the investigators wrote. But the regional variations suggest “that some regions experience barriers to appropriate screening or challenges in adhering to guidelines for managing psoriasis and CV risk.”

While the lack of data from after 2016 is one of the study limitations, they added, “continued efforts to develop effective interventions to improve CV screening and care for people with psoriasis in all regions of the U.S. are needed to more effectively address the burden of CV disease experienced by people with psoriasis.”

The study was partly funded by the National Psoriasis Foundation. Three of the seven investigators disclosed earnings from private companies in the form of consultant fees, research support, and honoraria. Dr. Gelfand is a deputy editor for the Journal of Investigative Dermatology.

Just 16% of psoriasis-related visits to dermatology providers in the United States involve screening for cardiovascular (CV) risk factors, with screening lowest in the region with the highest CV disease burden, according to an analysis of 10 years of national survey data.

From 2007 to 2016, national screening rates for four CV risk factors at 14.8 million psoriasis-related visits to dermatology providers were 11% (body-mass index), 7.4% (blood pressure), 2.9% (cholesterol), and 1.7% (glucose). Data from the National Ambulatory Medical Care Survey showed that at least one of the four factors was screened at 16% of dermatology visits, said William B. Song, BS, of the department of dermatology, University of Pennsylvania, Philadelphia, and associates.

The main focus of their study, however, was regional differences. “CV risk factor screening by dermatology providers for patients with psoriasis is low across all regions of the United States and lowest in the South, the region that experiences the highest CVD burden in the United States,” they wrote in a letter to the editor.

Compared with the South, the adjusted odds of any CV screening were 0.98 in the West, 1.25 in the Northeast, and 1.92 in the Midwest. Blood pressure screening was significantly higher in all three regions, compared with the South, while BMI screening was actually lower in the West (0.74), the investigators reported. Odds ratios were not available for cholesterol and glucose screening because of sample size limitations.

The regional variation in screening rates “is not explained by patient demographics or disease severity,” they noted, adding that 2.8 million visits with BP screening would have been added over the 10-year study period “if providers in the South screened patients with psoriasis for high blood pressure at the same rate as providers in the Northeast.”

Guidelines published in 2019 by the American Academy of Dermatology and the National Psoriasis Foundation – which were cowritten by Joel M. Gelfand, MD, senior author of the current study – noted that dermatologists “play an important role in evidence-based screening of CV risk factors in patients with psoriasis,” the investigators wrote. But the regional variations suggest “that some regions experience barriers to appropriate screening or challenges in adhering to guidelines for managing psoriasis and CV risk.”

While the lack of data from after 2016 is one of the study limitations, they added, “continued efforts to develop effective interventions to improve CV screening and care for people with psoriasis in all regions of the U.S. are needed to more effectively address the burden of CV disease experienced by people with psoriasis.”

The study was partly funded by the National Psoriasis Foundation. Three of the seven investigators disclosed earnings from private companies in the form of consultant fees, research support, and honoraria. Dr. Gelfand is a deputy editor for the Journal of Investigative Dermatology.

Just 16% of psoriasis-related visits to dermatology providers in the United States involve screening for cardiovascular (CV) risk factors, with screening lowest in the region with the highest CV disease burden, according to an analysis of 10 years of national survey data.

From 2007 to 2016, national screening rates for four CV risk factors at 14.8 million psoriasis-related visits to dermatology providers were 11% (body-mass index), 7.4% (blood pressure), 2.9% (cholesterol), and 1.7% (glucose). Data from the National Ambulatory Medical Care Survey showed that at least one of the four factors was screened at 16% of dermatology visits, said William B. Song, BS, of the department of dermatology, University of Pennsylvania, Philadelphia, and associates.

The main focus of their study, however, was regional differences. “CV risk factor screening by dermatology providers for patients with psoriasis is low across all regions of the United States and lowest in the South, the region that experiences the highest CVD burden in the United States,” they wrote in a letter to the editor.

Compared with the South, the adjusted odds of any CV screening were 0.98 in the West, 1.25 in the Northeast, and 1.92 in the Midwest. Blood pressure screening was significantly higher in all three regions, compared with the South, while BMI screening was actually lower in the West (0.74), the investigators reported. Odds ratios were not available for cholesterol and glucose screening because of sample size limitations.

The regional variation in screening rates “is not explained by patient demographics or disease severity,” they noted, adding that 2.8 million visits with BP screening would have been added over the 10-year study period “if providers in the South screened patients with psoriasis for high blood pressure at the same rate as providers in the Northeast.”

Guidelines published in 2019 by the American Academy of Dermatology and the National Psoriasis Foundation – which were cowritten by Joel M. Gelfand, MD, senior author of the current study – noted that dermatologists “play an important role in evidence-based screening of CV risk factors in patients with psoriasis,” the investigators wrote. But the regional variations suggest “that some regions experience barriers to appropriate screening or challenges in adhering to guidelines for managing psoriasis and CV risk.”

While the lack of data from after 2016 is one of the study limitations, they added, “continued efforts to develop effective interventions to improve CV screening and care for people with psoriasis in all regions of the U.S. are needed to more effectively address the burden of CV disease experienced by people with psoriasis.”

The study was partly funded by the National Psoriasis Foundation. Three of the seven investigators disclosed earnings from private companies in the form of consultant fees, research support, and honoraria. Dr. Gelfand is a deputy editor for the Journal of Investigative Dermatology.