Hot topic debate: preventing psoriatic arthritis in patients with psoriasis

Can effective treatment of Psoriasis prevent the development of Psoriatic Arthritis? by Dr. Soriano

To answer this question, Dr. Soriano began his presentation by spotlighting two recent studies about this matter. One study by Acosta Felquer et al, a single centre retrospective cohort study with 461 patients years with psoriasis taking biologics, showed a lower risk of developing Psoriatic Arthritis (incidence rate ratio (IRR)=0.26; 95% CI 0.03-0.94; P=0.0111) compared with topics.² On the other hand, another study by Meer et al, a multi-centre retrospective cohort study that included data on 32,460 patients-years, reported an increased incidence of PsA among PsO patients using biologics (Hazard Ratio (HR)= 4.8; 95% CI 4.23 to 4.75) compared with oral or phototherapy users.³ For an association found in these studies to be considered likely causal, the following Bradford Hill criteria must be met: consistency of findings, temporal sequence of association, and biological plausibility.³

With respect to the consistency of findings, to date 7 retrospective studies have explored this association.^2,3,5-9 Six of them found a lower incidence of PsA in psoriatic patients treated with biologics compared with those treated with topicals or phototherapy.^2,59 The remaining manuscript concluded the opposite: patients with PsO treated with biologics have an increased incidence of PsA.³ Two additional studies investigated the incidence of PsA in patients with severe psoriasis, using biologic therapy usage as a surrogate marker for severity and assessed the association with PsA risk.^10,11.

These results may differ because observational studies are susceptible to bias. Here, several types are particularly relevant: selection bias, confounding by indication, protopathic bias, survival bias, and assessment bias.¹² It should be emphasised that the possible direction of bias must always be considered. Most biases present in these observational studies tend to overestimate the incidence of PsA in patients treated with biologics, which might explain the results of Meer et al, Merola et al, and Lindberg et al. but not those of other studies. Moreover, these three studies showing increased risk were in large databases whereas the others are in clinical populations which could lead to some of these differences.

The reliance on electronic health records (EHR) and coded diagnoses for patient identification in Meer et al, a large retrospective study, raises concerns about potential confounding by indication and protopathic bias They found that there was a considerable number of diagnoses of PsA within the first year of biologic treatment. Although sensitivity analysis demonstrated a persisting increased risk of PsA development during the first 5 years, protopathic bias might be playing a role.³

In terms of biological plausibility, studies have shown that subclinical (asymptomatic) enthesitis is present in patients with PsO.¹³ This enthesitis is pathogenic and a risk factor for PsA. Additionally, it can be effectively treated with biologics.¹⁴ Similarly, biologic treatment can effectively abort subclinical synovitis.¹⁵ Since skin inflammation triggers and activates inflammatory cells in joints and entheses, it's reasonable to believe that a significant reduction in skin inflammation with effective treatment can decrease the incidence of PsA.¹⁶ Therefore, Dr. Soriano contended that resolving subclinical enthesitis, subclinical synovitis and skin inflammation might prevent PsA development. As a final point, Dr. Soriano cited Meer et al study: “We do not suggest that these results should be interpreted causally; in other words, biologics likely do not cause PsA. On the contrary, there are several biases that may play a role in this finding, suggesting that caution should be used in interpreting observational studies that study the impact of biologic therapy on the development of PsA.”³

Summing up, Dr Soriano alleged that, despite the lack of consistent findings across studies, the available data suggest a potential benefit of PsO treatment in PsA prevention. To conclude, Dr. Soriano declared that while actual evidence suggests the potential benefits of biologics in preventing PsA development for PsO patients, definitive proof requires randomised trials. When finished, the PAMPA (Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort) trial by Haberman et al. may be able to shed light on this issue.¹⁷ Until then, although biologics aren't currently indicated for PsA prevention, they might offer an additional benefit for PsO patients already prescribed them.

Argument: Treatment of Psoriasis does not prevent PsA by Dr. Ogdie

Dr. Ogdie described the complex story of progression to PsA among patients with psoriasis. She explained that multiple environmental factors (such as obesity, biomechanical stress, and infections) and genetic factors (such as having a first-degree relative with PsA or carrying the HLA-B27 allele) are known to contribute to inflammation or disease activity in psoriatic patients. This may be called preclinical PsA. Then, an unknown factor, such as trauma, comorbidities, biomechanical stress, or a microbiome-related event, may trigger a “second hit” response, leading to the development of evident PsA.¹⁸ When subclinical enthesitis, synovitis, or nonspecific symptoms are detected, this may be known as subclinical PsA.

Dr. Ogdie then focused on the question "What is the effect of biologic therapies on the development of PsA in psoriasis?" Based on current evidence (observational studies), it is uncertain whether treating psoriasis with biologics reduces the risk of developing PsA. Data from retrospective observational studies have inherent design biases that make it difficult to draw firm conclusions.¹⁹

Dr. Ogdie presented data from the Meer et al. study³ suggesting a higher incidence of PsA in PsO patients treated with biologics (77/1000 person/years [PY]) compared with patients who had not received therapy (6/1000 PY), those who received oral therapy (62/1000 PY), or those who received phototherapy (26/1000 PY). These differences persisted despite adjustment for confounders, use of a time-varying analysis, use of propensity score matching, and after several sensitivity analyses. However, she raised concerns about several biases that may contribute to the results.

First of all, in the best-case scenario, treatment decisions for psoriasis involve a collaborative approach between dermatologists and patients, taking into account several factors:

1. Severity of PsO
2. Affected locations (e.g., face or genital regions)
3. Emotional impact of skin lesions on the patient
4. Severity of fatigue or other symptoms attributable to PsO
5. Success and tolerance of previous treatments
6. Comorbidities
7. Risk tolerance of both the doctor and the patient
8. Accessibility to treatments
9. Presence of joint pain (e.g., if the dermatologist suspects the patient has or is about to develop PsA)
10. Accessibility to a rheumatologist (surrogate for PsA diagnosis)

This approach is known as confounding by indication. None of these factors are directly measured and potential unmeasured confounders may alter the results.

Second, dermatologists might prescribe biologics due to suspected PsA and not necessarily PsO severity alone. In this study, using EHR data, the highest incidence of PsA was within 6 to 12 months after prescription of the biologic therapy or oral therapy (protopathic bias).³ Therefore, questions about whether the observed association reflects a direct effect of biologics on PsA risk or not, remain unanswered.

Then, Dr. Ogdie mentioned potential biases of these retrospective studies which are important to consider when interpreting data to infer causality: confounding by indication, confounding by prognosis, unmeasured confounding, survival bias, protopathic bias, and collider stratification bias. She highlighted confounding by indication bias: patients are prescribed medication for “reasons” beyond a simple set of rules and often these reasons are not measured, and protopathic bias: a therapy is prescribed because of a symptom or an undiagnosed disease that is also the outcome of interest.

Singla et al. investigated the effects of different biologics prescribed to psoriatic patients on the incidence of PsA. They found that patients prescribed anti-TNF as their first biologic had the highest probability of developing PsA vs other biologics, and that the risk was significantly lower with IL 12/23 (adjusted HR 0.58; 95% CI 0.43-0.76) and IL23 (adjusted HR 0.41;95% CI 0.17-0.95) than with TNF inhibitors.²⁰ This highlights changeling bias but generates hypotheses.

A retrospective study based on electronic data presented at EULAR 2024 by Joven-Ibañez analysed the effect of different biologic therapies on the development of PsA in 1.101.000 psoriatic patients. They found a risk reduction in psoriatic patients receiving IL 12/23 and IL23 in both first- and second-line treatment versus TNF inhibitors. These differences persist after propensity score matching and adjusted for different known risk factors for PsA.²¹ However, the possibility of confounding by indication bias should be considered when interpreting these results.

Dr. Ogdie remarked on the numerous limitations of retrospective analyses, such as reliance on codes, associations, not causations, observation bias, missed diagnoses, and missing data. For example, she noted that dermatologists in the US rarely code for symptoms like arthralgia/itis the six years prior PsA diagnosis.²² Then Dr. Ogdie presented a lighthearted interpretation of what an epidemiologist does, explaining they spend time doing precise “guesswork” based on “unreliable” data provided by those of “questionable data entry skills”.

Finally, Dr. Ogdie went to discuss the ongoing PAMPA study, a randomised, double-blind, placebo-controlled trial in the US investigating whether Guselkumab can prevent PsA in psoriatic patients with power doppler ultrasound evidence of inflammation.¹⁷

In conclusion, the available evidence is insufficient to answer whether biologic therapy can prevent the onset of PsA. Prospective studies and randomised controlled trials are needed to answer this question.

Can we prevent psoriatic arthritis?

Prof Laura Coates gave an inspiring keynote talk on the topical area of ‘Can we prevent psoriatic arthritis (PsA)?’²³ She began by explaining that we do not know if PsA can be prevented but that she will focus on how we should answer the question through the ‘PICO’ (Population, Intervention, Comparison, Outcome) framework.

In terms of identifying the population that we need to recruit and study; this will need to include patients with psoriasis who are at high risk of developing PsA. From the current evidence, we know that the following features increase your risk of developing PsA: positive family history, higher psoriasis severity (PASI), longer psoriasis duration, arthralgia, stiffness, fatigue, being overweight (BMI >35), uveitis history, thyroid disease history, site of psoriasis (nail, scalp, gluteal), hyperlipidaemia, depression, smoking and trauma. In contrast, protective features include very long psoriasis duration and smoking (which can also be a risk of developing PsA).²⁴ Lindbergh et al’s study showed that the more severe the psoriasis is (using treatment as a proxy), the higher the risk of developing PsA is.²⁵ However, this may be due to confounding; Merola et al found that patients’ risk of developing PsA is much higher after being started on a conventional synthetic or biologic DMARD.²⁶ This may be due to the Dermatologists choosing a systemic treatment as the patient may have reported having joint symptoms.

Eder et al. have recently published a study on a clinical risk prediction model for PsA, called ‘PRESTO’ (prediction of PsA tool), which aims to predict your risk of developing PsA in 1- and 5-years’ time. The predictors in the 1-year model included age, male sex, positive family history of psoriasis, back stiffness, nail pitting, stiffness level (VAS 0-100), use of bDMARD for psoriasis, PtGA (very good/ good versus fair/ poor), patient pain severity (any level versus none). The predictors in the 5-year model included morning stiffness, PASI score, psoriatic nail lesion, FACIT-fatigue score, use of non-bDMARD systemic therapy or phototherapy and patient pain severity (any level versus none).²⁷

Another important consideration when identifying the population to study is when to intervene. There is an evolution of psoriasis to PsA with people developing sub-clinical symptoms/ imaging changes/ basic immunological changes before they are diagnosed with PsA. Currently, we only treat once someone has developed a diagnosis of PsA, but Prof Coates questioned whether if we treat people in the phases (pre-clinical, sub-clinical, prodromal) before they develop PsA, we can change the outcome of them then developing PsA.

Prof Coates then went on to highlight the important work of Perez-Chada et al in defining classification terminology for patients who are in this ‘middle’ phase where they have not yet got a diagnosis of PsA but have some features to show they are progressing towards that diagnosis.²⁸

Moving onto the ‘intervention’ part of the PICO question- this can be done either via pharmacological or non-pharmacological (i.e., lifestyle) modifications. The key questions around this are how long we treat people and how long we keep monitoring them for off-treatment/ intervention afterwards. The iPROLEPSIS consortium running across Europe in PsA is looking at digital non-pharmacological interventions through a series of games which aim to manage stress, for example, to improve people’s outcomes.²⁹

In terms of the ‘comparator’ part of the PICO question, the control could be no treatment and we ideally should be randomising patients but the ethical implications of this need to be considered. It would not be ethical to withhold treatment from people with moderate to severe psoriasis. If we do not randomise, we need to consider if we can control for confounders, and this may be easier for lifestyle interventions as opposed to medications. For the ‘outcome’ part of the PICO question, Prof Coates reiterated the importance of having agreed definitions of the pre-PsA phases to ensure we recruit suitable patients for our studies.

Prof Coates then went on to discuss several ongoing studies in this area. The PAMPA study in the US is looking at giving psoriasis patients who have had the disease >2 years, with a BSA <3% and USS inflammation but no symptoms, guselkumab versus placebo over 24 weeks and following them up over 2 years to see if this impacts on their outcomes.³⁰ The HIPPOCRATES consortium, which is also running across Europe in PsA, is running a study called the HIPPOCRATES Prospective Observational Study (HPOS). This study is currently recruiting patients for a web-based study to follow people with psoriasis to see who gets PsA and embed interventional studies into this. Over 3000 participants have been recruited to date. The Psorcast study developed an app which helps patients monitor themselves for the development of PsA.³¹ Moreover, the iPROLEPSIS study is also developing an app to identify and monitor changes in psoriasis patients before they develop PsA or a flare of their PsA.

In conclusion, Prof Coates concluded that there is a huge potential to answer this question with an easily identifiable psoriasis population that we can study. She explained that we need to evaluate the risk of developing PsA more accurately and we need to know what treatment is best; it might not be the same treatment that treats disease that also prevents disease. She reiterated that all the way through it is important to consider patient acceptability and whether they would be happy to take part in such studies.

Take Home Messages

The debate at the 7^th World Psoriasis & Psoriatic Arthritis Conference covered the complex relationship between psoriasis treatment and the prevention of psoriatic arthritis. While Dr. Soriano highlighted studies suggesting that biologics may lower the risk of developing PsA, Dr. Ogdie countered with the limitations of current observational studies, which are prone to biases such as confounding by indication and protopathic bias. Both experts acknowledged the need for prospective randomised trials, such as the ongoing PAMPA study, to determine whether biologic therapies can effectively prevent PsA. Moreover, Prof. Laura Coates stressed the importance of identifying at-risk patients early and exploring both pharmacological and non-pharmacological interventions. Ultimately, more robust data is required before definitive conclusions can be drawn about whether biologic treatment of psoriasis can prevent PsA.

Funding

AV is funded by an NIHR Doctoral Research Fellowship.

Conflict of interest

AV has been funded to attend research conferences from Novartis.
LCC has received grants/research support from AbbVie, Amgen, Celgene, Eli Lilly, Novartis and Pfizer; worked as a paid consultant for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer and UCB; and has been paid as a speaker for AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Medac, Novartis, Pfizer and UCB.
AO has received consulting fees from Abbvie, Amgen, BMS, Celgene, CorEvitas, Gilead, GSK, Janssen, Lilly, Novartis, Takeda, TREG, Pfizer, UCB and grants/research support from Abbvie (to Penn), Amgen (to Forward), BMS (to Forward), Janssen (to Penn), Novartis (to Penn), Pfizer (to Penn), Forward/National Databank for Rheumatic Diseases, NIH/NIAMS, Rheum Research Foundation.
ERS is on the speaker’s bureau of AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB; is a consultant of AbbVie, Janssen, Novartis, and Roche; and has received grant/research support from AbbVie, Janssen, Novartis, Pfizer, Roche, and UCB.
MA declares no conflict of interest.

References

1. Hot Topic Debate, 7th World Psoriasis & Psoriatic Arthritis Conference, 27-29 June 2024 in Stockholm, Sweden.
2. Acosta Felquer ML, LoGiudice L, Galimberti ML, Rosa J, Mazzuoccolo L, Soriano ER. Treating the skin with biologics in patients with psoriasis decreases the incidence of psoriatic arthritis. Ann Rheum Dis. 2022;81(1):74–9. 10.1136/annrheumdis-2021-220865
3. Meer E, Merola JF, Fitzsimmons R, Love TJ, Wang S, Shin D, et al. Does biologic therapy impact the development of PsA among patients with psoriasis? Ann Rheum Dis. 2022;81(1):80–6. 10.1136/annrheumdis-2021-220761
4. Hill AB. THE ENVIRONMENT AND DISEASE: ASSOCIATION OR CAUSATION? Proc R Soc Med. 1965;58(5):295–300. doi:https://doi.org/10.1177/003591576505800503
5. Gisondi P, Bellinato F, Targher G, Idolazzi L, Girolomoni G. Biological disease-modifying antirheumatic drugs may mitigate the risk of psoriatic arthritis in patients with chronic plaque psoriasis. Ann Rheum Dis. 2022;81(1):68–73. 10.1136/annrheumdis-2021-219961
6. Solmaz D, Ehlebracht A, Karsh J, Bakirci S, McGonagle D, Aydin SZ. Evidence that systemic therapies for psoriasis may reduce psoriatic arthritis occurrence. Clin Exp Rheumatol. 2020;38(2):257–61. 10.55563/clinexprheumatol/8thj0l
7. Watad A, Zabotti A, Patt YS, Gendelman O, Dotan A, Ben-Shabat N, et al. From Psoriasis to Psoriatic Arthritis: Decoding the Impact of Treatment Modalities on the Prevention of Psoriatic Arthritis. Rheumatology and Therapy. 2024;11(4):963-976. 10.1007/s40744-024-00680-3
8. Rosenthal YS, Schwartz N, Sagy I, Pavlovsky L. Incidence of Psoriatic Arthritis Among Patients Receiving Biologic Treatments for Psoriasis: A Nested Case-Control Study. Arthritis Rheumatol. 2022;74(2):237–43. 10.1002/art.41946
9. Floris A, Mugheddu C, Sichi L, Anedda J, Frau A, Sorgia J, et al. Treatment of psoriasis with different classes of biologics reduces the likelihood of peripheral and axial psoriatic arthritis development. Rheumatology. 2024;keae257. 10.1093/rheumatology/keae257
10. Merola JF, Tian H, Patil D, Richardson C, Scott A, Chen YH, et al. Incidence and prevalence of psoriatic arthritis in patients with psoriasis stratified by psoriasis disease severity: Retrospective analysis of an electronic health records database in the United States. J Am Acad Dermatol. 2022;86(4):748–57. 10.1016/j.jaad.2021.09.019
11. Lindberg I, Lilja M, Geale K, Tian H, Richardson C, Scott A, et al. Incidence of Psoriatic Arthritis in Patients with Skin Psoriasis and Associated Risk Factors: A Retrospective Population-based Cohort Study in Swedish Routine Clinical Care. Acta Derm Venereol. 2020;100(18):adv00324. 10.2340/00015555-3682
12. Merola JF, Ogdie A. Does psoriasis treatment affect PsA development? Nat Rev Rheumatol. 2021;17(12):708-709. 10.1038/s41584-021-00706-y
13. Naredo E, Möller I, de Miguel E, Batlle-Gualda E, Acebes C, Brito E, et al. High prevalence of ultrasonographic synovitis and enthesopathy in patients with psoriasis without psoriatic arthritis: a prospective case-control study. Rheumatology. 2011;50(10):1838–48. 10.1093/rheumatology/ker078
14. Savage L, Goodfield M, Horton L, Watad A, Hensor E, Emery P, et al. Regression of Peripheral Subclinical Enthesopathy in Therapy-Naive Patients Treated With Ustekinumab for Moderate-to-Severe Chronic Plaque Psoriasis: A Fifty-Two-Week, Prospective, Open-Label Feasibility Study. Arthritis Rheumatol. 2019;71(4):626–31. 10.1002/art.40778
15. Kampylafka E, Simon D, d’Oliveira I, Linz C, Lerchen V, Englbrecht M, et al. Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation-data from the prospective IVEPSA study. Arthritis Res Ther. 2019;21(1):178. 10.1186/s13075-019-1957-0
16. Carvalho AL, Hedrich CM. The Molecular Pathophysiology of Psoriatic Arthritis-The Complex Interplay Between Genetic Predisposition, Epigenetics Factors, and the Microbiome. Front Mol Biosci. 2021;8:662047. 10.3389/fmolb.2021.662047
17. Haberman RH, MacFarlane KA, Catron S, Samuels J, Blank RB, Toprover M, et al. Efficacy of guselkumab, a selective IL-23 inhibitor, in Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA): protocol of a randomised, double-blind, placebo controlled multicentre trial. BMJ Open. 2022;12(12):e063650. 10.1136/bmjopen-2022-063650
18. Scher JU, Ogdie A, Merola JF, Ritchlin C. Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition. Nat Rev Rheumatol. 2019;15(3):153–66. 10.1038/s41584-019-0175-0
19. Merola JF, Ogdie A. Does psoriasis treatment affect PsA development? Nat Rev Rheumatol. 2021;17(12):708–9. 10.1038/s41584-021-00706-y
20. Singla S, Putman M, Liew J, Gordon K. Association between biological immunotherapy for psoriasis and time to incident inflammatory arthritis: a retrospective cohort study. Lancet Rheumatol. 2023;5(4):e200–7. 10.1016/S2665-9913(23)00034-6
21. Joven-Ibáñez B, Rivera R, Hernandez G, García-Donoso C, Pablos Álvarez JL. Evaluation of the risk of psoriatic arthritis in patients with psoriasis undergoing biological treatment. Global population study (trinetx). Ann Rheum Dis. 2024;83:168-169 (abstract Op0010).
22. Ogdie A, Rozycki M, Arndt T, Shi C, Kim N, Hur P. Longitudinal analysis of the patient pathways to diagnosis of psoriatic arthritis. Arthritis Res Ther. 2021;23(1):252. 10.1186/s13075-021-02628-2
23. Keynote lecture, 7th World Psoriasis & Psoriatic Arthritis Conference, 27-29 June 2024 in Stockholm, Sweden.
24. Scher JU, Ogdie A, Merola JF, Ritchlin C. Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition. Nat Rev Rheumatol. 2019;15(3):153-166. 10.1038/s41584-019-0175-0
25. Lindberg I, Lilja M, Geale K, Tian H, Richardson C, Scott A, Osmancevic A. Incidence of Psoriatic Arthritis in Patients with Skin Psoriasis and Associated Risk Factors: A Retrospective Population-based Cohort Study in Swedish Routine Clinical Care. Acta Derm Venereol. 2020;100(18):adv00324. 10.2340/00015555-3682
26. Merola JF, Tian H, Patil D, Richardson C, Scott A, Chen YH, Kim N, Hur P, Armstrong AW. Incidence and prevalence of psoriatic arthritis in patients with psoriasis stratified by psoriasis disease severity: Retrospective analysis of an electronic health records database in the United States. J Am Acad Dermatol. 2022;86(4):748-757. 10.1016/j.jaad.2021.09.019
27. Eder L, Lee KA, Chandran V, Widdifield J, Drucker AM, Ritchlin C, Rosen CF, Cook RJ, Gladman DD. Derivation of a Multivariable Psoriatic Arthritis Risk Estimation Tool (PRESTO): A Step Towards Prevention. Arthritis Rheumatol. 2023. 10.1002/art.42661
28. Perez-Chada LM, Haberman RH, Chandran V, Rosen CF, Ritchlin C, Eder L, Mease P, Reddy S, Ogdie A, Merola JF, Scher JU. Consensus terminology for preclinical phases of psoriatic arthritis for use in research studies: results from a Delphi consensus study. Nat Rev Rheumatol. 2021;17(4):238-243. 10.1038/s41584-021-00578-2
29. Dias et al. Determinants of patient’s intention to use serious games in psoriatic arthritis: A partial least squares structural equation modelling approach. Ann Rheum Dis 2024 (submitted).
30. Haberman RH, MacFarlane KA, Catron S, et al. Efficacy of guselkumab, a selective IL-23 inhibitor, in Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA): protocol of a randomised, double-blind, placebo-controlled multicentre trial. BMJ Open 2022;12:e063650. 10.1136/bmjopen-2022-063650
31. Webster D, Haberman R, Perez-Chada L, Simon S, MacDuffie W, DePhillips M, Reddy S, Ogdie A, Mangravite L, Merola J, Scher J. Development and Preliminary Validation of Smartphone Sensor-based Measurement Tools for Psoriatic Arthritis [abstract]. Arthritis Rheumatol. 2020;72(suppl 10):abstract 0322.

 

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Posted on 11 November 202422 November 2024