Article Text

Treating the skin with biologics in patients with psoriasis decreases the incidence of psoriatic arthritis
  1. Maria Laura Acosta Felquer1,
  2. Luciano LoGiudice1,
  3. Maria Laura Galimberti2,
  4. Javier Rosa1,
  5. Luis Mazzuoccolo2,
  6. Enrique R Soriano1
  1. 1 Rheumatology Unit, Internal Medicine Service, Hospital Italiano de Buenos Aires and Instituto Universitario Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
  2. 2 Dermatology Service, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
  1. Correspondence to Dr Enrique R Soriano, Rheumatology Unit, Internal Medicine Service, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; enrique.soriano{at}hospitalitaliano.org.ar

Abstract

Objectives To compare the incidence of psoriatic arthritis (PsA) in patients with psoriasis (PsO) according to different treatments for their skin: topics/no treatment, conventional disease-modifying antirheumatic drugs (DMARDs) (cDMARDs) or biological DMARDs (bDMARDs).

Methods Patients with PsO without PsA followed at a university hospital were included in this retrospective cohort study. Patients were classified according to their treatment in topics (topics, phototherapy or no treatment), cDMARDs (methotrexate and cyclosporine) and bDMARDs (tumour necrosis factor inhibitors (TNFi), interleukin 17 inhibitors (IL-17i) and IL-12-23i ((interleukin (IL) 12/IL-23 inhibitor))) groups. Incident cases of PsA were attributed to one treatment if developed during the administration of that treatment. A Cox proportional hazards model was used to evaluate the adjusted risk of PsA development by treatment group.

Results 1719 patients with PsO contributed a total of 14 721 patient/years (py). 1387 (81%) patients were in the topics, 229 (13%) in cDMARDs and 103 (6%) in the bDMARDs group. During follow-up, 239 patients (14%) developed PsA (231 under topics, six under cDMARDs and two under bDMARDs). Global incidence was 1.6 per 100 py. The risk of developing PsA in patients with PsO treated with bDMARDs was significantly lower (incidence rate ratio (IRR)=0.26; 95% CI 0.03 to 0.94; p=0.0111), compared with topics, but not compared with cDMARDs (IRR=0.35; 95% CI 0.035 to 1.96; p=0.1007). Adjusted Cox proportional hazards regression analysis showed that male sex, nail involvement and higher body max index were associated with increased risk of developing PsA, while biologics use was protective (HR: 0.19; 95% CI 0.05 to 0.81).

Conclusion Treatment with biologics in patients with PsO reduced the risk of PsA development.

  • psoriatic arthritis
  • biological therapy
  • epidemiology

Data availability statement

Data are available upon reasonable request. Our data are not in a repository; data are available upon request to ERS.

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Key messages

What is already known about this subject?

  • Psoriasis usually precedes the development of psoriatic arthritis by many years, and it is the principal risk factor.

  • Subclinical enthesitis is another risk factor for the development of psoriatic arthritis.

  • Both psoriasis and subclinical enthesitis could be efficaciously treated with biological disease-modifying drugs, but it has not been shown that that could prevent the development of psoriatic arthritis.

What does this study add?

  • In this analysis of a single-centre cohort, treating psoriasis skin involvement with biologics was associated with lower risk of developing psoriatic arthritis.

  • Risk factors for the development of psoriatic arthritis in patients with psoriasis were male sex, higher body mass index and nail involvement.

How might this impact on clinical practice or future developments?

  • Preventing development of psoriatic arthritis could be another factor suggesting the use of biologics early on in the treatment of the skin in patients with psoriasis at increased risk of developing psoriatic arthritis.

Introduction

The prevalence of psoriasis (PsO) in the general population ranges between 0.1% and 2.8%, and between 6% and 42% of patients with PsO can develop psoriatic arthritis (PsA).1 2 Majority of patients develop PsO before articular involvement.3

PsO is a unique model for preventive medicine, as we have easy access to patients at high risk of developing PsA: patients with PsO. However, it is still not clear which patients with PsO will develop PsA, although several risk factors, such as extension of skin disease, obesity and subclinical enthesitis, have been described.4–6 Conceptually, one of the models proposed to explain the development of PsA in patients with PsO is that chronic skin inflammation expands systemically into synovio-entheseal tissues.7 Although biological therapies (TNF-α inhibitors (tumour necrosis factor α inhibitors) IL-12/23 (interleukin (IL) 12/IL-23), IL-17 (interleukin 17) and IL-23 (interleukin 23) inhibitors) have shown to be highly effective for PsO treatment,8 it has not been proven that effective treatment of the skin could prevent the development of PsA.4 On the other hand, a high percentage of subclinical enthesitis has been detected by ultrasound in asymptomatic patients with PsO9 10 and can be observed at early stages of the articular disease.11 Enthesitis has been implicated as the initial lesion in PsA,12 and there is some evidence that subclinical enthesitis in patients with PsO is a risk factor for the development of PsA.13–15 It has been shown that the use of biologics can improve the inflammatory component of subclinical enthesitis in patients with PsO.16 We can assume that biological treatment being effective in diminishing chronic skin inflammation, and solving subclinical enthesitis in patients with PsO, might prevent the development of PsA in those patients. With the hypothesis that biologics prescribed for treatment of the skin will be able to prevent the development of PsA, the objective of our study was to compare the incidence of PsA in patients with PsO according to their treatment (biological disease-modifying antirheumatic drugs (bDMARDs) or topical treatment or conventional disease-modifying antirheumatic drugs (cDMARDs)) in a large university hospital-based healthcare management organisation (HMO)

Patients and methods

Study design

Retrospective cohort study between 1 January 2000 and 31 December 2018

Setting

The study was performed at a prepaid HMO. This HMO provides comprehensive medical and health services to around 140 000 adult members primarily located in urban areas. Since the year 1999, the HMO has a problem-oriented electronic medical record (EMR) where all medical appointments, diagnoses and procedures are registered without exceptions.17 18

All patients with cutaneous PsO, over 18 years old at time of entering the cohort, diagnosed by a dermatologist, without musculoskeletal symptoms and without diagnosis of PsA at study entry treated with biologics (TNF-α inhibitors, IL-12/23 and IL-17 inhibitors) because of their skin disease were included as cases. All patients with cutaneous PsO, over 18 years old at time of entering the cohort, diagnosed by a dermatologist, without musculoskeletal symptoms and without diagnosis of PsA at study entry, without treatment and/or with topical treatment and/or with systemic non-biological treatment methotrexate (MTX) or cyclosporine (CycA), were included as controls.

Cases and controls ascertainment

Cases and controls were obtained from the EMR including all patients with diagnosis of PsO, with at least two medical appointments in the EMR. The absence of PsA at study entry was checked by manual review of each one of the EMR. All medical appointments were reviewed, with special attention to pain-related problems or musculoskeletal symptoms and orthopedists, physiotherapists and rheumatologists visit. The final diagnosis impression of each one of these appointments and the presence of signs and symptoms of CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria, even when the diagnosis was not recorded in the EMR, were considered to rule out the diagnosis of PsA. Also, special attention was paid to all medical appointments and signs and symptoms around the date of the prescription of a cDMARD or bDMARD looking for evidence of PsA.

A patient was considered not having PsA if the diagnosis of PsA was not recorded in the EMR, plus not fulfilling CASPAR criteria with the information collected from all the medical appointments manually reviewed from the EMR (including the evaluation by a rheumatologist ruling out PsA, when present)

Follow-up

All clinical, laboratory and diagnostic studies are recorded in the HMO EMR. In the primary analysis, incident cases were attributed to one treatment if developed during the administration of that treatment (at least 1 month of treatment should have elapsed). In this analysis, patients contributed time of exposure since the beginning of the corresponding treatment until diagnosis of PsA, loss of follow-up, end of that treatment or end of study (31 December 2018). In those patients that received more than one cDMARDs or more than one biologics, time on each one of the drugs was added to the specific treatment and to the corresponding treatment group. In the secondary analysis, it was considered that once cDMARDs or bDMARDs were received for at least 6 months, they would prevent the development of PsA forever (once the patient was exposed to a biologics, they were considered always exposed). In this secondary analysis, patients contributed time of exposure since the beginning of the corresponding treatment until diagnosis of PsA, loss of follow-up or end of the study (31 December 2018), independently of treatment discontinuation.

As treatment of PsO usually has a hierarchical order where patients are treated with topicals before cDMARDs and with cDMARDs before biologics, to avoid survival bias, time on topics (if received) was not added to that group in patients included in the cDMARDs group, and time on cDMARDs (if received) was not added to that group in patients who received biologics (by definition, these patients should not have PsA when starting cDMARDs or biologics, so by definition, all the time those patients spend on topics or cDMARDs would be free of PsA).

Definition of incident PsA

A patient was defined as developing PsA if she/he had the diagnosis of PsA confirmed by a rheumatologist and/or fulfilled CASPAR criteria19 (by review of the EMR, even if the diagnosis was not recorded in the EMR), at any time after 1 month of study entry. If the diagnosis was made within the first month of entering the cohort, it was considered a prevalent case and excluded from the study.

Data collection

The following data were collected by manual review of the EMR for each patient with PsO: sex, age at PsO diagnosis, date of incident diagnosis of PsA (if developed), PsO duration, ungueal involvement, type of PsO, main PsO localisation, current and previous treatments including biological therapy and start and end dates of each one of the treatments received.

Statistical analysis

Sample size

The incidence of PsA in patients with PsO was calculated in 2.7 per 100 py; with a mean follow-up of 10 years, we estimated a PsA incidence of 20%.6

A sample size of 398 patients was required, considering an expected incidence of 20% of PsA for the controls (confidence level of 80% and alpha of 5%) with a 60% reduction in incidence rate (IR) in those patients treated with biologics.

Statistical analysis

Descriptive statistics were computed for patients at risk, overall and stratified by treatment, mean±SD for continuous variables and number and percentage for categorical variables. Pearson’s χ2 test for categorical variables and the unpaired Student’ t-test for continuous variables with normal distribution or Wilcoxon rank-sum test for variables without normal distribution was used to compare baseline differences between patients that did or did not develop PsA.

IRs were calculated as the number of incident PsA events divided by the number of py at risk per 100 py, with their 95% CIs for each one of the treatment groups using exact (Clopper-Pearson) Poisson confidence limits: (1) those with topical/no treatment, (2) those treated with cDMARDs and (3) those treated with bDMARDs. Incidence rate ratio (IRR) between treatments was also calculated.

Associations between treatment group and incident PsA were analysed using a Cox proportional hazards model. Explanatory variables included all variables collected in most patients: age at PsO onset, sex, body mass index (BMI) and presence of nail involvement. All these variables were included in the model for the primary and a secondary analysis. All variables included in the model were significantly associated with the outcome or the treatment in univariable analysis. The effects of these variables on the risk of incident PsA were expressed in terms of HRs along with their 95% CI. The goodness of fit of the null proportional hazards assumption was tested with the proportional hazards assumption test based on Shoenfeld residuals.

We also estimated the average treatment effect (ATE) and ATE on the treated (ATET) by propensity score matching (PSM) by fitting a logistic regression model in which baseline gender, age, BMI, PsO localisation, type of PsO and nail involvement were used as matching variables and the treatment received (dichotomised to biologics vs other treatments) was the dependent variable. bDMARDs were matched with other treatments (cDMARDs plus topicals) using at least two controls per treatment with replacement and a calliper width of 0.1 of the SD of the propensity score.

All analyses were conducted using the STATA software (V.14.2, StataCorp, Collage Station, Texas, USA).

The study was conducted according to the Declaration of Helsinki and local regulations. Ethical approval for the study was obtained from the hospital local ethics committee.

Results

A total of 1719 patients with PsO that contributed a total of 14 721 py (median follow-up 7.3 years; IQR: 2–15) were included in the primary analysis. Patient’s characteristics are shown in table 1 (primary analysis; for the secondary analysis: online supplemental table 1). One thousand three hundred eighty-seven (81%) patients were treated with topics phototherapy or no treatment, 229 (13%) with cDMARDs (77%, MTX; 13%, CycA; and 10%, both sequentially) and 103 (6%) with biologics (TNFi, n=92; etanercept, n=53; adalimumab, n=31; infliximab, n=8; IL-17i, n=47; ixekizumab, n=15; secukinumab, n=32; IL-12-23i: ustekinumab, n=19; some patients received more than one biologics). Patients treated with biologics were significantly younger and men (table 1).

Table 1

Patients’ disease characteristic according to treatment group (primary analysis)

During follow-up, 239 patients (14%) developed PsA (231 under topics, six under cDMARDs and two under bDMARDs (table 2) in the primary analysis) with a median time between PsO onset and PsA development of 9.8 years (IQR: 3–20). Patients that developed PsA started their PsO at a significantly earlier age, were more frequently men, had significantly more frequent nail involvement and had higher BMI (table 2).

Table 2

Patient’s disease characteristics in those that did and did not develop psoriatic arthritis (PsA)

In most cases (222 patients: 93%), the diagnosis was recorded in the EMR (and confirmed by manual check of fulfilment of CASPAR criteria). In 17 cases (7%), the diagnosis was not recorded, but patients fulfilled CASPAR criteria after review of EMR 15/231 (6.5%) patients in topics, 1/6 (17%) in cDMARDs and 1/2 (50%) in bDMARDs.

PsA diagnosis was recorded by rheumatologists in 87% of the cases, by dermatologists in 3% and by others or not recorded in 10% of the cases.

Among patients who developed PsA while on cDMARDs, five were under treatment with MTX, and this was the only cDMARD they received, and one patient developed PsA while under treatment with CycA on which had been for 3 months. This patient received MTX for 4 months 13 months before starting CycA. Two patients developed PsA while under biological therapy (one secukinumab and one ustekinumab). Global IR of PsA development was 1.6 per 100 py (table 3). In the primary analysis, the risk of PsA in patients with PsO treated with bDMARDs was significantly lower than that of patients treated with topics (IRR=0.26; 95% CI 0.03 to 0.94; p=0.0111), but not that of patients treated with cDMARDs (IRR=0.35; 95% CI 0.035 to 1.96; p=0.1007) (table 3). Results of the secondary analysis are shown in table 3; again, the risk of PsA was lower in patients with bDMARDs compared with patients with topical treatment (IRR: 0.34; 95% CI 0.07 to 0.99; p=0.0158).

Table 3

Incidence of psoriatic arhtritis (PsA) according to treatment group, primary and secondary analysis

Adjusted Cox proportional hazards regression analysis (table 4) showed that male sex, nail involvement and higher BMI were associated with increased risk of developing PsA, while biologics use was protective relative to topical/no treatment (test of proportional hazards assumption: p=0.5438). The adjusted model for the secondary analysis showed similar results (online supplemental table 2).

Table 4

Results of Cox proportional hazards model of time to onset of psoriatic arthritis in patients with skin psoriasis (PsO) with primary analysis

The ATE and ATET by PSM were −0.19, 95% CI −0.25 to −0.15 ; p<0.0001 and −0.31, 95% CI −0.43 to −0.18 ; p<0.0001, respectively. This implies that had the entire population been treated with biologics, the incidence of PsA would be 20% less than the average that would occur if none of the patients with PsO had received biologics. Distribution of variables before and after PSM is shown in online supplemental table 3.

Discussion

Early detection and treatment of PsA might represent an opportunity to prevent the development of PsA. We found that patients with PsO treated with bDMARDs had a lower risk of developing PsA compared with patients treated with topicals or without treatment. There are few studies that had explored the role of treatment of PsO as prevention of PsA. Ogdie et al at EULAR (EUropean Alliance of Associations for Rheumatology) meeting presented a study performed in the USA with Optum de-identified Electronic Health Record dataset.20 Using a traditional multivariable adjustment approach, they found in the fully adjusted model that treatment with biologics was protective of PsA development in patients with PsO; however, when the analysis was done after PSM, patients treated with biologics had higher risk compared with patients treated with no biologics.20 Authors concluded that given the directional discrepancy in their results, further work is needed to understand the nature of this relationship.20

Recently, Lindberg et al in a population-based study using secondary administrative registries reported the incidence of PsA in patients with PsO according to disease severity in Sweden between 2007 and 2017.21 To classify patients into severity subgroups, they used treatment received as proxy of severity: patients receiving skin PsO-indicated biological treatments or apremilast were classified as biological-treated patients (severe disease proxy), those receiving skin PsO-indicated conventional systemics including phototherapy were classified as conventional systemic-treated patients (moderate proxy) and the remaining patients were classified as others (mild proxy). Lindberg et al, in contrast with our study, found an increased incidence in those patients treated with biologics (IR: 5.49 (95% CI 4.94 to 6.04) per 100 py). There are some differences between their cohort and ours. They used administrative data, while we review the electronical medical records. The percentage of patients treated with cDMARDs and bDMARDs was lower in the Lindberg study compared with ours (9.8% and 1.3% vs 13% and 6%, respectively), perhaps indicating differences in patients’ characteristics.

More recently, Gisondi et al in a retrospective non-randomised study involving patients with moderate-to-severe plaque PsO, who were prescribed at least 5 years of bDMARDs, compared with patients treated with narrowband ultraviolet light B phototherapy, also found that bDMARDs treatment reduced the risk of incident PsA.22 This study included a larger number of patients treated with bDMARDs, followed for a similar amount of time than our study.22

Interestingly, Lindenberg’s IR of PsA of 1.69 per 100 py and Gisondi’s IR of 1.20 per 100 py are remarkably similar to that found in our study (1.6 per 100 py). The incidence of PsA in patients with PsO in different population studies has varied between 0.27 per 100 py23 and 2.7 per 100 py.6 Our figures are well within this range.

Among the risk factors associated with the incidence of PsA in our study, some have already been described, such as nail involvement6 22 24 and obesity.23 25 A significantly increased incidence of PsA in men has been found by Green et al 23 and a non-significant increase in Wilson’s24 and Gisondi’s22 studies, while the incidence was higher in women in the Swedish study.21 In our study cohort, men had slightly shorter PsO disease duration before PsA development, perhaps explaining higher incidence because of earlier onset.

Our study has several limitations. It is a retrospective study based on the review of electronical medical records. We could not completely discard that some prevalent cases were included; however, there is no reason to think that this would have been different in the different treatment groups. On the other side, we have already proved in several studies that EMR review in our setting provides reliable incidence and prevalence data.1 26–30 We did not have full data for adjustment for some confounders, such as severity of skin involvement. As mentioned in the Lindberg study, treatment with biologics could be considered a proxy of severe skin involvement and lead to confounding by indication. However, on the other side, patients with more severe PsO have increased risk of developing PsA,31 so confounding by indication would have been towards higher incidence of PsA in patients treated with biologics. When we performed the analysis using matching by propensity score, biologics still protected against development of PsA. As all patients were not routinely evaluated to assess the presence of PsA, we could not rule out some PsA underdiagnosis. However, usually, patients on biological therapy are more closely followed, so it is unlikely that PsA was missed in that group and not in the others. Also, as mentioned before, our IR is similar to that of previous studies, which makes major underdiagnosis unlikely. Another potential limitation is the presence of protopathic bias that would occur if biologics were prescribed because of the presence of early manifestations of PsA that were not noticed or registered. To avoid this bias, the patients’ charts were carefully reviewed around the dates of cDMARDs and bDMARDs prescription searching for potential signs or symptoms of PsA. Also, the event was attributed to that treatment only if at least 1 month after the initiation of therapy elapsed. Another limitation is the relatively low number of patients treated with cDMARDs and bDMARDs; however, low numbers are usually associated with type II error that would have prevented us from finding differences. Finally, the study was performed at a single centre; however, there is no reason to believe that results are not generalisable, as patient’s characteristics are similar to those of other cohorts.

Our study has also some strengths, we used a proved methodology for incidence assessment and we have a long period of follow-up and a considerably large number of controls. On the other side, as mentioned in the introduction, there is biological plausibility for biologics administered in PsO impairing the development of PsA by subclinical enthesitis improvement and/or reducing systemic inflammation.4

In conclusion, in our study, we found that treating patients with PsO with biologics might reduce the risk of developing PsA. However controversial results with other studies leave this association still unresolved.

Data availability statement

Data are available upon reasonable request. Our data are not in a repository; data are available upon request to ERS.

Ethics statements

Patient consent for publication

Ethics approval

The study was conducted according to the Declaration of Helsinki and local regulations. Ethical approval for the study was obtained from the Hospital Institutional Board: approval number 3635 (2018).

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Handling editor Josef S Smolen

  • Presented at Preliminary data from this study were previously presented at 2019 ACR Meeting: Lo Giudice L, Acosta Felquer M, Mazzuoccolo L, Galimberti M, Soriano E. Can Biologics “Prevent” the Development of Psoriatic Arthritis in Psoriasis Patients? Data from a Large University Hospital Cohort in Argentina [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/can-biologics-prevent-the-development-of-psoriatic-arthritis-in-psoriasis-patients-data-from-a-large-university-hospital-cohort-in-argentina/. Accessed May 25, 2021. And at the 2020 EULAR Meeting: Lo Giudice L, Acosta Felquer ML, Galimberti ML, et al. Sat0426 can biologics “prevent” the development of psoriatic arthritis in psoriasis patients? Data from a large university hospital cohort in Argentina. Annals of the Rheumatic Diseases 2020;79:1167-8.

  • Contributors MLAF and ERS: designed the study and performed data analysis and interpretation. LLG and MLG: contributed to data collection, data quality control and interpretation of the data. JR and LM: contributed to data quality control and interpretation of the data. All authors contributed intellectual content during the drafting and revision of the work and approved the final version to be published.

  • Funding This study was supported by a grant from PANLAR (Pan-American League of Associations for Rheumatology).

  • Competing interests ERS received grants from AbbVie, Janssen, Novartis, Pfizer and Roche, outside the submitted work, and consulting/speaker’s fee from AbbVie, Amgen, BMS, Janssen, Novartis, Lilly, Pfizer, Roche, Sandoz and UCB outside the submitted work. MLAF received consulting/speaker’s fee from AbbVie, Janssen, Novartis, Lilly and Pfizer outside the submitted work. JR received consulting/speaker’s fee from AbbVie, Amgen, Janssen, Novartis, Lilly and Pfizer outside the submitted work. LM received consulting/speaker’s fee from AbbVie, Janssen, Novartis and Lilly outside the submitted work.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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