Moleculaire reclassificatie van chronisch inflammatoire aandoeningen voor personalized medicine. Feit of fictie?

Artikel in PDF

The Psoriatic spectrum

Psoriatic arthritis (PsA) is a disease most typically characterized by inflammation in the joints, spine, and enthesial-sites in a patient with a known history of psoriasis. The prevalence of PsA in the general population is presumed to be approximately 2 cases per 1000 individuals.1,2 Whereas nearly all patients with PsA have psoriasis, it remains unclear why only ~20% of patient with psoriasis eventually develop PsA.3 Although PsA was once considered relatively mild in comparison to the more prevalent articular inflammatory disease rheumatoid arthritis (RA), studies have shown that the burden of PsA on quality of life is equal to the burden of RA on quality of life.4 In addition, patients with psoriasis and patients with PsA have an increased risk of cardiovascular morbidity and mortality, which is independent of traditional risk factors and presumably do to the disease itself.5,6 The presence of systemic inflammation and other disease-specific factors in PsA is thought to underlie the accelerated development of atherosclerosis in these individuals.7

Unfortunately, PsA can be difficult to diagnose by non-specialists. This was well illustrated in a recent study8 which examined patients with known psoriasis, none of whom were deemed to have PsA by their treating dermatologist. However, upon subsequent evaluation by a rheumatologist, ~30% of
these patients in fact had a diagnosis of PsA. The delay in diagnosing PsA presumably contributes to the fact that over one-quarter of patients will already have irreversible joint damage upon their first visit to a rheumatologist.9 In the last few decades there has been a remarkable turnaround in the treatment strategy for RA, in which early aggressive therapy is started to prevent irreversible joint damage and its subsequent symptoms. Such an approach is most likely an advisable strategy in PsA as well.10 However, current standard treatment strategies incorporating disease-modifying anti-rheumatic drugs (DMARD’s), originally developed for use in patients with RA, have shown disappointing results for patients with PsA: after two years of treatment only ~20% of patients will have reached remission and irreversible joint damage will still develop in ~50% of patients.9

These results emphasize the necessity to identify early (sub-clinical) PsA and identify which subset of patients is likely to respond to the first line of therapies we currently offer (i.e. DMARDS) and which subset of patients should instead be treated more aggressively using the more expensive second-line “biological-therapies” (e.g. tumor necrosis factor alpha inhibitors).

UMCU: collaborative Dermatology and Rheumatology effort

In the UMC Utrecht a collaborative effort is in place between the Department of Dermatology and the Department of Rheumatology and Clinical Immunology with the goal of improving psoriasis patient care, while at the same time allowing for meaningful, translational scientific research. All psoriasis patients are seen at a special psoriasis clinic in which care is provided by a psoriasis nurse and a dermatologist. In addition, a rheumatologist runs a parallel clinic that allows for the screening of psoriatic arthritis in the psoriasis patients attending the clinic. All patients are offered such screening and recent publications from our group11 have shown that in our academic setting, the use of simple questionnaires can be useful to aid the referral process. Treatment guidelines for treating psoriasis and for treating psoriatic arthritis do not always overlap and the needs of the individual patient are best met when these specialists deliver personalized medicine that goes beyond a skin-perspective-only or joint-perspective-only.12 The specialized psoriasis clinic offers a unique opportunity for both psoriasis and psoriatic arthritis patients to participate in translational scientific research (see below). The strength of our research is greatly enhanced by the fact that participants are clinically well-characterized, for instance enabling an immunological comparison between patients with psoriasis limited to the skin versus psoriasis patients with concomitant arthritis.13

The systems medicine approach

PsA is thought to occur from the interaction of environmental factors with the immune system in individuals with polygenic susceptibility for the disease. In particular, there appears to be a problem in the innate immune response that leads to the development of PsA. On the basis of this disturbance in the first-line of the hosts’ defence mechanism, it has been proposed that the subsequent occurrence of tissue-specific damage through micro-trauma or via the invasion of foreign pathogens in the skin, joint, bone, or enthesial-sites could explain the clinical manifestations of the disease.14

Because biological systems, such as the (innate) immune system, are able to maintain homeostasis under a multitude of circumstances, it can be difficult to pinpoint the exact interaction between the diverse genetic, epigenetic, and environmental factors that will ultimately cause a state of disease. This is specifically the case for PsA, in which all of these factors are known to play a role. The so-called “systems medicine approach”15 aims to tackle this problem by integrating computational research with experimental medical research. This approach exploits the large amount of data collected from high-through-put technologies (called “omics” technologies) in order to analyse the different “layers” of the system of interest. Mathematical modelling is then used on the data in order to decode the sequence of events that define either normal or pathological functioning of that system. This method has proven fruitful in understanding the mechanism of successful vaccination.16 Using this method, our group has recently made important discoveries in the disease systemic sclerosis.17

In our current research, we are examining all the “layers” of the immune response—the epigenetic modifications to deoxyribonucleic acid (DNA) (called epigenome), the set of RNA molecules that reveal gene expression profiles (called transcriptome), and the final product being the set of proteins (called proteome). The gene expression profile of a cell is of particular interest and can be revealed by RNA sequencing and analysing the sites on DNA that have become methylated, the latter modification being an important long-term regulator of gene expression and linked to the development of autoimmune disorders.18 The final layer of the system explored is the cellular compartment of the immune system, in this case the function and phenotype of the white blood cells. The exploration of the interaction between these distinct layers can produce important discoveries, without needing prior knowledge about specific individual interactions between the subsets of the system. In a clinically well-defined cohort of psoriasis and PsA patients followed throughout time, the use of this systems medicine approach is well suited to identify new diagnostic and prognostic biomarkers. By unravelling the underlying pathogenesis, this approach could provide important insights into novel therapeutic targets.

References

1. Gelfand JM, Gladman DD, Mease PJ, Smith N, Margolis DJ, Nijsten T, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol 2005;53:573.
2. Ogdie A, Langan S, Love T, Haynes K, Shin D, Seminara N, et al. Prevalence and treatment patterns of psoriatic arthritis in the UK. Rheumatology (Oxford) 2013;52:568-75.
3. Christophers E, Barker JNWN, Griffiths CEM, Daudén E, Milligan G, Molta C, et al. The risk of psoriatic arthritis remains constant following initial diagnosis of psoriasis among patients seen in European dermatology clinics. J Eur Acad Dermatol Venereol 2010;24:548-54.
4. Sokoll KB, Helliwell PS. Comparison of disability and quality of life in rheumatoid and psoriatic arthritis. J Rheumatol 2001;28:1842-6.
5. Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients with severe psoriasis are at increased risk of cardiovascular mortality : cohort study using the General Practice Research Database. Eur Heart J 2010;31:1000-6.
6. Han C, Robinson DW, Hackett M V, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol 2006;33:2167-72.
7. Angel K, Provan SA, Gulseth HL, Mowinckel P, Kristian T, Atar D, et al. Tumor Necrosis Factor-alpha Antagonists Improve Aortic A Controlled Study. Hypertension 2010;55:333-8.
8. Haroon M, Kirby B, FitzGerald O. High prevalence of psoriatic arthritis in patients with severe psoriasis with suboptimal performance of screening questionnaires. Ann Rheum Dis 2013;72:736-40.
9. Kane D, Stafford L, Bresnihan B, FitzGerald O. A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience. Rheumatology (Oxford) 2003;42:1460-8.
10. Gladman DD, Thavaneswaran A, Chandran V, Cook RJ. Do patients with psoriatic arthritis who present early fare better than those presenting later in the disease? Ann Rheum Dis 2011;70:2152-4.

11. Leijten EFA, Sigurdsson V, Wenink MH, Radstake TRDJ. Screening for psoriatic arthritis using the PEST questionnaire: examining the optimal cutoff. Br J Dermatol [Internet]. 2016;(1). Available from: http://doi.wiley.com/10.1111/bjd.14953
12. Gossec L, Coates LC, Wit M de, Kavanaugh A, Ramiro S, Mease PJ, et al. Management of psoriatic arthritis in 2016: a comparison of EULAR and GRAPPA recommendations. Nat Rev Rheumatol [Internet] 2016;12:743-50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27829672
13. Leijten EFA, Kempen TS van, Boes M, Michels-van Amelsfort JMR, Hijnen D, Hartgring SAY, et al. Brief report: enrichment of activated group 3 innate lymphoid cells in psoriatic arthritis synovial fluid. Arthritis Rheumatol (Hoboken, NJ) [Internet] 2015;67:2673-8. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/26137857

14. McGonagle D, Ash Z, Dickie L, McDermott M, Aydin SZ. The early phase of psoriatic arthritis. Ann Rheum Dis 2011;70 Suppl 1(Suppl 1):i71-6.
15. Kitano H. Computational systems biology. Nature 2002;420:206-10.
16. Pulendran B, Oh JZ, Nakaya HI, Ravindran R, Kazmin D a. Immunity to viruses: learning from successful human vaccines. Immunol Rev 2013;255:243-55.
17. Bon L van, Affandi AJ, Broen J, Christmann RB, Marijnissen RJ, Stawski L, et al. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med [Internet] 2014;370:433-43. Available from: http://www. ncbi.nlm.nih.gov/pubmed/24350901
18. Heyn H, Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nat Rev Genet. Nature Publishing Group 2012;13:679-92.

Conflict of interest
None

Correspondence
T.R.D.J. Radstake
E-mail: T.R.D.J.Radstake@umcutrecht.nl