Psoriatic disease: concepts and implications

The term Psoriatic disease was recently introduced in an attempt to provide a new perspective on psoriasis and related disorders.1 This concept emerged from a better understanding of the pathogenesis of psoriasis and of its extra-cutaneous manifestations. Beginning with a historical perspective, this manuscript reviews the evolution which led, over the last 30 years, to the development of this new concept. The recognition of psoriatic arthritis (PsA) as a distinct entity unfolded slowly over a long period of time. In fact, apart from some anecdotal case reports, the possible association between psoriasis and arthritis was first mentioned only in 1818.2 The term psoriasis arthritique was introduced in 18603 while in 1888 the arthritis confined to distal interphalangeal (DIP) joints was considered a clinical feature, characteristic of the condition.4 In 1959, Verna Wright proposed the term psoriatic arthritis5 and in 1964 the American College of Rheumatology (formerly the American Rheumatism Association) on the basis of Wright’s suggestions classified for the first time PsA as a distinct clinical entity and separated it from rheumatoid arthritis.6 Later on, family studies conducted in the Leeds area showed that PsA was probably genetically determined, in a multifactorial manner, as uncomplicated psoriasis.7,8 In 1973, Wright, in collaboration with Moll,9 introduced the concept of ‘seronegative spondyloarthropathies’ as a group of articular disorders without serum IgM rheumatoid factor where articular involvement was related to some non-articular conditions named co-diseases (Table 1). Probably, this term could represent the historical origin of the future concept of psoriatic disease because it anticipated the idea of a possible pathogenetic link between joint manifestations and other non-articular features confined to skin, bowel, eye and urogenital tract. The most important similarities between psoriasis and PsA which can support the concept of a unique entity are summarized in Table 2. Although arthritis is more frequent in psoriatic patients with severe involvement of the skin9 it is widely recognized that the variability of psoriasis severity does not impact clinical expression of arthritis which is present in about 30% of the total patients.10,11 PsA patients may develop classic widespread distinctive cutaneous lesions or isolated patches in the scalp, groin, axilla or recall a previous history of psoriasis. More recently, we described patients with a family history of psoriasis in first-or second-degree relatives who developed a psoriatic arthritis clinical phenotype in the absence of psoriasis, which has been defined as ‘psoriatic arthritis sine psoriasis’.12 In these cases, the significant association with HLA-CW6 highlights the strong contribution of genetic factors which undoubtedly play a pathogenic role in the clinical manifestations of the disease. The origins of the concept of psoriatic disease are related to the new data available regarding the molecular basis of psoriasis and its related manifestations. In psoriatic patients immunohistologic studies, data from animal models and results from clinical trials indicate that an altered immune response is essential for the inflammation present in both the skin and the joints. Despite uncertainty about the factor(s) that either initiates and/or perpetuates this immune reaction, considerable progress has been made in characterizing the steps of the inflammatory cascade. According to the model recently proposed by Ritchlin,13 and modified here (Fig. 1), major events start in the skin and subsequently expand to the joints (either synovial membrane and/or enthesis). In the cutaneous phase (step 1) dendritic cells (DCs) triggered by environmental factors activate Th17 and Th1 T lymphocytes which trigger activation and migration of monocytes-macrophages (Mm) into the dermis. These cells release tumour necrosis factor (TNF) while DCs release IL-23.14–16 IL-23 drives hyperplasia of keratinocytes (Ke) and infiltration of neutrophils (Ne) and its release may be upregulated by TNF.16 In addition, the crucial role played by T cells as mediators of the skin damage in psoriasis is emphasized by the recent demonstration of the major pathogenetic role played by IL 21, a T-cell-derived cytokine which controls the switching between inflammatory and suppressive T-cell types.17 In the skin of psoriatic patients, IL 21, produced by activated CD4+ T cells, stimulates human keratinocytes to proliferate, contributing to cause epidermal hyperplasia.18 From the pathogenesis model proposed by C. Ritchlin (partially modified).13 In the articular phase (step 2), which could represent also step 1 in the case of primary localization of environmental stimuli at the joint level, activated monocytes and T cells migrate from the skin and enter the joint, after binding to primed endothelial cells (ECs). Vascular remodelling is controlled by vascular endothelial growth factor (VEGF), metalloproteinase (MMP)-9, and angiopoietin 2 (ang-2). Vascular remodelling seems an early and fundamental process for the evolution of the inflammatory response in synovial joints affected by arthritis.19 The hyperplasia of synovial cells is driven by TNF and other cytokines which have been released by Mm and T cells. The lining cells foster osteoclastogenesis and bone resorption through the expression of receptor activator of NF-κB ligand (RANKL), Dickkopf-1(DKK-1) and cartilage degradation through the release of MMPs. Moreover, inflammatory events in the subchondral bone stimulate enthesitis and osteitis. The activation of bone morphogenetic protein (BMP), either as a response to extensive bone resorption or as a primary event, induces new bone formation (enthesophytes, sacroiliac sclerosis).20–22 On the other hand, it is well known that psoriatic patients, particularly those with arthritis, may show microscopic inflammatory changes of colonic mucosa even in the absence of bowel symptoms.23 Only in a few cases did these changes consist of idiopathic inflammatory bowel disease. Indeed, based on the guidelines suggested by the British Society of Gastroenterology,24 an unclassified form of colitis, completely different from classic ulcerative colitis (psoriatic colitis?) has been found in the majority of the patients studied. Therefore, bowel could be another site where the inflammatory process begins (Fig. 1). Recent evidence in Crohn’s disease confirm the prominent role played by bowel inflammation in the induction of spondyloarthritic involvement,25 reinforcing the concept of a psoriatic disease. Finally, patients with psoriasis have a significantly higher rate of obesity, insulin resistance, type 2 diabetes and metabolic syndrome.26 These patients also show an increased occurrence of hypertension, hyperlipidaemia and cardiovascular disease.27–30 In addition, recent results from a large prospective study (Nurses’Health Study II) indicate also the role of risk factor for incident psoriasis played in women by adiposity and/or weight gain.31 All these clinical aspects complete the emerging concept of psoriatic disease. Psoriatic disease is a systemic disorder which involves several different anatomical sites in the same patient. This concept implies two kinds of problems: (1) the level of clinical expression of cutaneous and articular components of the syndrome may broadly vary in different cases. (2) the treatment approach should favour the early use of drugs simultaneously effective on skin and joint complaints. While the first point has been resolved by the introduction of CASPAR criteria,32 which consider the possibility that skin psoriasis can be currently evident or present in medical or in familial history of the patient, the second point still needs further study. Although we can not exclude in psoriatic disease the effectiveness of conventional drugs, biological agents seem the sole therapeutical approach which could be simultaneously effective on skin and joint complaints.33–36 Therefore, we believe in a clinical co-operation of dermatologist and rheumatologist aimed at recognizing patients who have to be rapidly treated with an effective therapy. Following this idea, we would introduce the concept of a clinical cut-off score which includes: (i) the evaluation of skin and/or nail involvement (using PASI and NAPSI); (ii) the evaluation of articular involvement (including dactylitis) based on the count of tender and the count of swollen joints and/or entheses; (iii) the measure and the evaluation of spinal disease activity (using BASDAI); (iv) the evaluation of disability (using HAQ); (v) the evaluation of quality of life (using DLQI). In the case of patients in whom the global score obtained is superior to a determined value, we should consider the early introduction of biological therapy for the complete control of the disease. Moreover, recent pharmacoeconomic evidence supports the idea that in psoriatic patients biological therapy is cost effective even in the short term.37 The introduction of the new concept of psoriatic disease represents a novel opportunity to better understand the complex associations, at both the pathogenetic and clinical level, of this fascinating disorder. The discovery of basic biological evidences that explain skin and joint involvement has opened a unique window through which dermatologists and rheumatologists today can see a common landscape. This work has been funded by an unrestricted grant provided by Schering-Plough, Italy.