. . . REPORTS . . .

Clinical Features of Psoriatic Arthritis

Gerald G. Krueger, MD

Abstract differentiate RA from PsA is an important The past 5 years have seen major advances in component in the management of patients understanding the immunology and molecular who present with clinical features consis- biology of psoriatic arthritis (PsA), especially the tent with an arthropathy. impact of cytokines such as tumor necrosis factor The social devastation associated with (TNF), which has produced striking, long-term PsA is enormous and has been well docu- benefits in patients with rheumatoid arthritis (RA). mented. In a sample of 180 patients with Because PsA is not the same disease as RA, the 6 ability to distinguish between them is important to PsA, Torre Alonso et al found that 57% had physicians in managing patients who have clinical erosive arthritis and 19% had marked phys- 7 features consistent with an arthropathy. The devel- ical limitations. Jones et al reported that opment of TNF inhibitors directed specifically at 64% of their patients presenting with the mechanisms of skin and joint inflammation oligoarticular disease progressed to poly- offers hope to patients who suffer from the debili- articular disease over time. Gladman et al8 tating effects of PsA. showed that a significant percentage of (Am J Manag Care 2002;8:S160-S170) patients developed joint damage and defor- mities that progressed over time and con- tributed to functional limitation. Husted et al9 demonstrated that patients with PsA experience reduced health-related quality of life compared with persons from the gen- eral population. Specifically, patients reported significantly lower scores on the physical functioning, pain, role limitations, soriatic arthritis (PsA) is a debilitat- and general health perceptions scales of ing inflammatory disease that the Medical Outcomes Study 36-item P affects the skin and joints. PsA may short-form health survey. affect a significant number of patients PsA can be a debilitating disease when with psoriasis. The clinical and societal associated with significant skin disease impact of PsA—resulting from both skin and significant radiographic progression, and joint manifestations of the disease— even when patients receive ongoing ther- has only recently begun to be appreciated. apy with conventional disease-modifying Over the past 5 years, there have been antirheumatic drugs (DMARDs).10,11 In significant advances in our understanding one meta-analysis of published random- of the immunology and molecular biology ized trials evaluating the efficacy of of PsA, particularly the pathogenic role of DMARDs such as methotrexate and cytokines such as tumor necrosis factor cyclosporine in the treatment of PsA,11 (TNF). Furthermore, we have observed the placebo groups in all of the trials dramatic and long-term clinical benefits included showed a clinically significant in patients with rheumatoid arthritis (RA) improvement, thereby bringing into ques- treated with TNF inhibitors.1-5 PsA is not tion the efficacy of treatment with con- the same disease as RA, and being able to ventional DMARDs.

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Patients with PsA are typically affected ed group of disorders that also includes with psoriasis before showing signs of ankylosing , Reiter’s syndrome, joint disease; approximately 15% of enteropathic arthropathy, Whipple’s dis- patients develop signs and symptoms of ease, and Behçet’s syndrome—so called PsA before a diagnosis of psoriasis has because of the absence of rheumatoid fac- been established.12 Both rheumatologists tor (RF).13 The cause of PsA is unknown. and dermatologists manage PsA; each spe- Clearly, genetic susceptibility and exoge- cialist approaches the management of PsA nous influences have roles in the etiology from his or her unique professional per- of the disease. The primary clinical fea- spective. Dermatologists focus primarily ture that characterizes the seronegative on the skin manifestations of PsA and is enthesopathy rheumatologists concentrate on the artic- (inflammation of sites of ligamentous ular manifestations of the disease. Few insertion into bone). This destructive controlled trials have examined the effica- process affects tendons and ligaments at cy of DMARDs for both PsA and psoriasis. their insertions, resulting in tendonitis, Hence, if PsA does not respond to the pso- dactylitis, and fasciitis. Full-blown PsA is riasis treatment offered by the dermatolo- characterized by a pattern of clinical fea- gist, referral to a rheumatologist typically tures, including the combination of psori- follows. The corollary is also true—psoria- asis with asymmetrical peripheral joint sis not responding to PsA therapy offered disease, variable involvement of the axial by the rheumatologist typically results in skeleton, nail disease, tenosynovitis, and referral to the dermatologist. Currently enthesopathy.14 Baseline relationships in available DMARDs are relatively slow act- terms of disease manifestations between ing, can inflict serious adverse reactions, psoriasis and PsA have been demonstrat- and no long-term dose can universally be ed, particularly with regard to nail considered “safe and effective.” involvement and joint activity.14 Given these limitations, excitement has A relationship between psoriasis and developed in response to research that has joint manifestations was initially recog- focused on novel, targeted treatments for nized in the early 1800s. Numerous clini- PsA—treatments that work against both cians substantiated this relationship, and the skin and articular manifestations of in 1959 Wright introduced the term “pso- the disease. Fueling the hope for better riatic arthritis.”15 As our understanding of treatments are rapid advances in the the disease increased, a variety of thera- understanding of the disease processes peutic approaches evolved, including the that underlie both psoriasis and PsA. Such use of nonsteroidal anti-inflammatory understanding has led to the discovery of a drugs and DMARDs to treat the articular new class of products broadly named bio- manifestations and antipsoriatic agents to logic response modifiers. These agents are treat the skin manifestations. Yet, targeted to alter the cascade of cytokines, although the condition is common, PsA chemokines, and other cellular modula- has not been routinely part of trials for tors that regulate the inflammatory state new drugs that have been brought to the of both the skin and the joints in PsA. market for arthritis; the converse is also Some of these cytokines, particularly TNF, true—drugs developed for psoriasis typi- are currently among the most studied in cally have not included joint manifesta- a list of possible treatment targets for tions as an outcome measure in pivotal both psoriasis and PsA. These therapeutic trials. Studies that have been undertaken approaches hold enormous promise for typically have been phase 4 trials with patients with psoriasis and PsA. small sample sizes; hence, definitive con- clusions are lacking. As a result, drugs Relationship Among Rheumatoid developed for psoriasis do not have indi- Arthritis, Psoriatic Arthritis, and Psoriasis cations for both the skin and joint mani- PsA is classified as a seronegative festations of the disease. Consequently, —a loosely connect- PsA remains a debilitating disease, with

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few agents currently available to effective- than previously believed.26 The recently ly treat both the articular and skin mani- reported National Psoriasis Foundation festations of the disease. Furthermore, Benchmark Survey for Psoriatic therapy for PsA has largely been derived Arthritis27 is the first research to establish from clinical experience in RA, without the prevalence of psoriatic arthritis corroborating evidence from studies of among US adults. In surveys conducted in patients with PsA.11,16 The few controlled December 2001 of more than 27,000 trials assessing the efficacy of various adults, 0.5% said they had been diagnosed DMARDs in patients with PsA have not as having PsA. That number translates to shown clinically significant effects.17-22 about 1 million of the total US adult pop- Recent advances in the molecular biol- ulation—roughly double the number that ogy and immunology of PsA have led to an the medical community previously sus- increased understanding of the role of pected had the disease.27 The surveys cytokines such as TNF in the pathogenesis showed a strong link between PsA and of the events that foster inflammation in psoriasis. About 85% of those with PsA the skin and joints of patients with the dis- reported that they had psoriasis. At the ease. This understanding, in turn, has led same time, about one third of those with to the development of TNF inhibitors, psoriasis said they had joint stiffness, but such as etanercept, as therapeutic agents had not been diagnosed as having PsA. specifically targeted to the mechanisms of This finding suggests that many of these cutaneous and articular inflammation in people may have had PsA and not have PsA.23-25 known it. Follow-up interviews were con- ducted with 448 people who had been Prevalence diagnosed as having PsA. Of those, 84% Epidemiologic studies since 1980 have said PsA had a moderate-to-large impact demonstrated that PsA is more common on their everyday lives. Seventy-five per- cent said they lost sleep or slept badly because of the disease, and nearly two thirds said the condition has forced them Figure 1. Typical Skin Lesion Found in to alter their daily activities. Psoriasis and Psoriatic Arthritis A recent reassessment of this question in more than 5000 patients in Northern Europe was presented at the 2001 European Academy of Dermatology and Venerology Conference,28 in which it was reported that the incidence of PsA did not consistently correspond to the severity of psoriasis. The medical records of more than 700 patients in the study sample were evaluated, and 30% to 40% of patients with psoriasis had PsA. The percentage of men and women affected with PsA is roughly equal, and the disease can appear at any age. The peak age of onset is between 45 and 54 years,29 and the average time of onset is approximately 10 years after the first signs of psoriasis.

Clinical Aspects of Psoriatic Arthritis and Psoriasis Skin Manifestations. The typical lesions of psoriasis are characterized by a sharp,

S162 THE AMERICAN JOURNAL OF MANAGED CARE APRIL 2002 Clinical Features of Psoriatic Arthritis definable border, a bright red color, and a or generalized; either form may cause silvery white scale (Figure 1). The sharp severe disability. Generalized pustular border, which can usually be felt and seen, psoriasis is sometimes referred to as the abruptly demarcates the epidermal hyper- von Zumbusch variety, and is associated plasia and epidermal changes of psoriasis. with fever, malaise, and leukocytosis. The bright red color, which on dependent Localized pustular psoriasis is usually lim- areas may have a violet hue, is indicative ited to the palms and soles. When the pus- of the dilated superficial vasculature of tules rupture, thick scaling and fissuring psoriasis. In fact, the capillaries of psoriat- occur, causing severe pain. Many patients ic skin so closely approach the skin sur- with pustular psoriasis have psoriatic nail face at the apex of the elongated dermal changes. papillae that the removal of psoriatic The clinical hallmark of guttate psoria- scales frequently produces fine bleeding sis is a generalized, rapidly developing, points (Auspitz sign).30 small, tear-shaped psoriatic plaque. The scaly plaques of psoriasis (Figure Guttate psoriasis is commonly seen in 2) are an almost constant feature, except children and young adults, and may be possibly after effective topical or systemic triggered by streptococcal infections of the therapy. Although the plaques are usually respiratory tract as well as, many derma- silvery white, they may assume a duller, tologists believe, other upper respiratory less reflective white appearance as the tract infections.30,31 Flare-ups of guttate scales become thicker. The scales are nor- psoriasis may also be precipitated by mally loosely adherent, and are the result withdrawal of systemic corticosteroid of the greatly accelerated and incomplete therapy, drug sensitivity, and miliaria.31 keratinization process. They may be very Inverse psoriasis affects the axillary and thin, usually curling up slightly as they gluteal folds, the submammary area, and detach, or they may be piled up and thick- the navel. In these intertriginous sites, the ened to produce a keratin plate or mound lesions are erythematous and moist, with- over the erythematous skin lesions. Much of the pain, itching, and inflammatory change is a result of the dryness and Figure 2. Psoriatic Plaque cracking of this layer. Psoriatic plaques may regress spontaneously without scar- ring after several weeks, months, or years. Relapses are common, and their frequen- cy and severity in affected patients can be reduced by avoiding exacerbating factors such as stress, mechanical injury to the skin, and sunburn. The distribution is usu- ally symmetrical, affecting the elbows, knees, buttocks, and scalp. The plaques may persist for months to years, with little change in shape or distribution of individ- ual lesions. Several variants of psoriasis have been identified based on clinical features. These include plaque (discussed above), pustu- lar, guttate, inverse (flexural), and ery- throdermic (exfoliative) psoriasis. Pustular psoriasis may appear on top of existing psoriatic plaques and may spread to uninvolved skin.30 In severe cases, the pustules become confluent and form lakes of pus. Pustular psoriasis may be localized

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out the scaling that is characteristic of Although it is accepted that all types of plaque psoriasis. Because of constant fric- psoriasis may occur in patients with PsA,7 tion and maceration, the lesions of inverse the relationships between skin and joint psoriasis may become extensive and spread lesions are not clear. to previously normal skin. Pruritus and dis- comfort are more common in inverse pso- Joint Manifestations. A classification riasis than in plaque, pustular, or guttate scheme for PsA based on joint manifesta- psoriasis because the lesions are more like- tions proposed by Moll and Wright32 ly to become inflamed and fissured. (Table 1) describes 5 patterns of disease: Erythrodermic psoriasis is character- ized by diffuse erythema and scaling, and Predominantly Distal Interphalangeal is often associated with fever, chills, and Arthritis. Distal interphalangeal arthritis malaise.30 In severe cases, there may be is considered the classic form of PsA, hypothermia and hypoalbuminemia sec- although this pattern accounts for only ondary to skin exfoliation. Erythrodermic about 5% of cases.32 This condition can psoriasis may involve the entire skin, occur as the sole presentation or in combi- including the trunk, extremities, nails, nation with other patterns. It may be sym- hands, feet, face, and scalp. It is sometimes metric or asymmetric and can involve seen as a rebound phenomenon following many joints or only a few. In many cases, withdrawal of systemic corticosteroids or adjacent nail(s) may have psoriatic changes. secondary to irritation from topical anti- Progressive bony erosions are common. psoriatic preparations. Pustules are not a regular feature of . Although this pat- most clinical types of psoriasis, although tern occurs in only 1% to 5% of PsA on close inspection they may be seen, cases, it is important because it is char- especially during acute episodes. acterized by severe disease with osteoly- Nail involvement—usually nail pitting— sis of the phalanges, metatarsals, and helps confirm the diagnosis of PsA metacarpals.30,32 because it occurs in most cases. Other nail abnormalities seen in PsA are onycholysis, Symmetric Polyarthritis. The clinical subungual hyperkeratosis, furrows or picture of symmetric polyarthritis resem- transverse depressions (Beau’s lines), leuk- bles that of RA, in that inflammation of the onychia (white spots or patches under the metacarpals and the proximal interpha- nails), oil spotting (reddish-brown spots langeal joints is prominent. However, sever- under the nail), and crumbling nail plates.32 al features help distinguish it from RA. It Nail lesions occur more commonly among usually runs a milder course; subcutaneous patients with PsA than those with psoriasis nodules and other extra-articular manifesta- uncomplicated by arthritis; therefore, these tions of RA are not usually seen; and, as lesions may help to identify patients with with all forms of PsA, patients are usually psoriasis who are destined to develop PsA.33 RF negative.

Oligoarthritis. This is the most com- mon pattern of PsA, accounting for more Table 1. Psoriatic Arthritis: Moll and than half of cases.32 It is characterized by Wright Classification of Joint Involvement asymmetric involvement of fewer than 4 joints. Any joint can be involved. Arthritis ■ Predominantly distal interphalangeal arthritis in a single knee may be the first sign of ■ Arthritis mutilans oligoarthritis. ■ Symmetric polyarthritis ■ Oligoarthritis Spondylitis and/or . This ■ Spondylitis and/or sacroiliitis pattern resembles but is considered a separate entity. Source: Reference 32. Human leukocyte antigen (HLA)-B27 is

S164 THE AMERICAN JOURNAL OF MANAGED CARE APRIL 2002 Clinical Features of Psoriatic Arthritis less likely to be present and disease is langes and expansion of the base of the generally less disabling than in patients distal phalanx. with ankylosing spondylitis. The axial Bulky, asymmetric, unilateral syn- skeleton tends to be involved in an atypi- desmophytes (bony outgrowths) may form cal fashion; the lumbar spine is the most in the axial skeleton. These can be pres- common site of involvement. Sacroiliitis ent in the lumbar, thoracic, or cervical is present in about one third of cases, spine in a “skip” pattern, often sparing often with bilateral changes. Spondylitis some segments. Asymmetric sacroiliac and may occur alone or in association with paravertebral ossification may be present. peripheral arthritis. Osteolysis may also be seen.36 Some clinical overlap has been noted The presence of spurs and the periosteal within the various patterns of PsA reaction are characteristic of the enthe- (Table 2),6,34 with evolution from one sopathy of PsA.36 In the spine, both typical clinical entity to another. As the disease marginal syndesmophytes and paramar- progresses and more joints become ginal syndesmophytes are seen. involved, patients may move from an oligoarticular presentation to a polyarticu- Differentiating Psoriatic Arthritis lar pattern; if radiographs are performed, From Rheumatoid Arthritis. Patients the presence of a spondyloarthropathy with PsA can be presumptively differenti- may be recognized in a patient who previ- ated from those with RA based on several ously had not complained of any back clinical features. First, in general, PsA pain. Conversely, as patients who present affects fewer joints than does RA, and with polyarthritis improve, the number often has asymmetric distribution of of joints involved may be reduced and affected joints (versus the symmetric dis- the pattern of joint involvement may become oligoarticular. These patterns of joint involvement are not different arthropathies, but different presentations Table 2. Clinical Features in Patients Who Present of the same arthropathy—namely, PsA. With Psoriatic Arthritis A characteristic finding in several types of PsA is dactylitis (“sausage Common Features digit”), in which the entire digit appears ■ Polyarthritis swollen because of inflammation involv- ■ ing the tendons and periosteum as well Spinal inflammation as the joints. Factors that may con- ■ Peripheral enthesitis tribute to disease progression include a ■ Distal interphalangeal joint arthritis high number of swollen joints, the pres- ■ Monarthritis/oligoarthritis ence of actively inflamed joints, and an ■ Dactylitis (“sausage digits”) elevated erythrocyte sedimentation 35 rate. Because of the poor prognosis for Uncommon Features people with active disease, it is necessary ■ Palmar plantar pustulosis to treat early, prevent erosions, and ■ Synovitis, acne, pustulosis, hyperostosis, and osteolysis maintain function. Radiographic Features. Radiographic (SAPHO) syndrome features seen in patients with PsA are ■ Spondylodiscitis those of inflammatory arthritis. They may ■ Arthritis mutilans include the distinctive asymmetric pat- ■ Onycho-pachydermo-periostitis tern of joint involvement; sacroiliitis and spondylitis; bone erosions with new bone formation; bony ankylosis; and distal There may be some clinical overlap within the various patterns 36 over time, with evolution from one clinical entity to another. interphalangeal joint involvement. Source: McGonagle D, Conaghan PG, Emery P. Psoriatic “Pencil-cup” deformities may occur as a arthritis. A unified concept twenty years on. Arthritis Rheum result of “whittling” of the proximal pha- 1999;42:1080-1086. Reprinted with permission.

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tribution seen in RA). PsA, as mentioned and abnormal bone remodeling. Prior to previously, also involves the distal joints the 1990s, the role of the keratinocyte and is typically associated with nail pit- and abnormal keratocyte proliferation ting. Patients with PsA are typically RF were emphasized in the development of negative, and they tend to present with psoriatic plaque. Recent experiments, milder symptoms than patients with RA. however, reveal an important role for For example, patients with PsA typically the T cell in driving this unusual skin experience morning stiffness for shorter phenotype.41-45 periods of time than do patients with RA. A number of parallels can be made Patients with PsA generally display fewer between what happens pathologically in swollen and tender joints than do those the skin and what can be seen in the with RA. Although the number of actively rheumatoid and psoriatic joint. In the inflamed joints is typically lower in PsA skin, mononuclear cells (predominantly T than in RA, the number of damaged joints cells) infiltrate the dermis. This infiltration and the degree of joint involvement may is accompanied by increased cytokine pro- be similar.37 Finally, patients with PsA duction by these T cells, which results in demonstrate less tenderness than do those the hyperproliferation of keratinocytes with RA.38 and the phenotypic plaque. This sequence Socially, patients with PsA may be even of events is analogous to what is seen in more isolated than those with RA because the rheumatoid joint in the sense that in of the open and more disfiguring appear- the deep layers of subsynovial tissue there ance of skin plaques. Unlike RA, which is is infiltration with mononuclear cells, 3 times more prevalent in women than in release of cytokines, and a significant men,39 PsA occurs with similar frequency synovial proliferation of lining cells.45 in men and women.40 In addition, patients In the skin, infiltration by activated T with PsA are, on average, slightly younger cells (CD4 and CD8) precedes the devel- than those with RA. opment of the psoriatic plaque.46 The cytokine profile in psoriatic plaques is dis- Pathophysiology tinctive, with increased levels of inter- Four key elements are part of the leukin-2 (IL-2) and interferon-gamma pathogenesis of psoriasis and PsA. They expressed.47 An associated increase in the include the psoriatic plaque, psoriatic levels of IL-6, IL-8, and TNF has been synovial inflammation, enthesopathy, noted.48 In addition, the role of infection as a potential driver of the T-cell response has been touted in the psoriasis and PsA liter- Table 3. Genetic and Environmental Factors in ature. For example, as already noted, gut- Psoriatic Arthritis (PsA) tate psoriasis may be triggered to expression by streptococcal and viral Genetic susceptibility predisposing to PsA trait infections of the respiratory tract.30 ■ HLA-Cw6 Elevated antistreptococcal antibody titers ■ Other class I HLA specificities (B13, B17, B27, B38, B39) and positive streptococcal throat cultures ■ Non-MHC genes? appear to be associated with acute dis- ease.49 Psoriatic plaques are often colo- Environmental factors influencing expression of PsA trait nized by bacteria. This observation has ■ Trauma caused significant conjecture regarding an ■ Repetitive motion etiologic role for these bacteria in trigger- ■ Human immunodeficiency virus infection ing either the onset or exacerbation of ■ Bacterial infection? existing disease. However, at this time, this association remains only conjecture, HLA = human leukocyte antigen; MHC = major histocompatibil- as no data have been reported to support ity complex. a direct link between bacteria in the Source: Reference 13. plaque with disease activity.

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Several genetic and environmental fac- form this attachment site. In enthesopath- tors are believed to contribute to the predis- ic diseases, a prominent inflammatory position to develop PsA (Table 3). These infiltrate can be found in this area with factors include the expression of certain associated bony erosion. This abnormality major histocompatibility complex antigens can present clinically as dactylitis. (particularly HLA-B27), trauma, and joint McGonagle et al52 looked at the pres- injury as a result of repetitive motions.13 ence of high-intensity signals in the knees The presence of specific genetic factors in of patients with PsA and other spondy- determining the trait of PsA is shown by the loarthropathies, and compared the results familial aggregation of PsA, although the to those of similar studies in patients with disease does not follow a simple mono- RA. They used fat-suppressed, T2-weight- genic pattern of inheritance.13 The proba- ed magnetic resonance imaging (MRI) to bility of a first-degree relative of a person demonstrate signal intensity at the patel- with PsA having the disease is about 40 lar attachment site, the periarticular tis- times greater than that in their unaffected sues, and the bony attachments in the spouses.50 Yet PsA is pleomorphic in its patella itself. Prominent entheseal abnor- expression, affecting different parts of the malities on MRI were a constant feature of musculoskeletal system, skin, and other new-onset synovitis in spondyloarthropa- organs, and varies in its clinical manifesta- thy-related arthritides, but were a minor tion from individual to individual. feature of RA.52 There were 2 significant findings on MRI in patients with spondy- Synovitis and Enthesopathy—The loarthropathy-related arthritides in this Pathogenic Hallmarks of Psoriatic study. First, focal soft-tissue edema out- Arthritis. Early PsA is thought to start in side the joint capsule adjacent to enthe- areas adjacent to the synovium.10 With seal insertions (perientheseal edema) was progression, synovitis develops, which common, and this edema was believed to resembles the same chronic inflammatory be secondary to enthesitis. The soft-tissue process found in many other arthritides, including RA. PsA is further characterized by metaplastic proliferation of the synovial lining-cell layer, converting the lining Figure 3. Inflammatory Enthesopathy of a Tendon from a single- into a multicelled layer; Attachment extensive infiltration of lymphocytes and monocytes; and new vessel formation sim- Normal attachment of Inflammation and erosion in ulating a granulomatous reaction.10 Early tendon fiber to bone inflammatory enthesopathy synovial damage is caused by inflammato- ry edema with fibrin deposition and pro- gressive hyperplasia of the lining-cell layer, along with lymphocytic infiltration in the subsynovial layer.10 Cartilage destruction and bone erosions ensue. Besides synovitis, the other pathogenic hallmark of PsA is enthesopathy. Entheso- pathy is characterized by an accumulation of lymphocytes and monocytes at the site of tendon or ligament insertion, resulting in inflammation and erosions (Figure 3) that eventually cause spurs and periostitis. The enthesis is a potentially important structure, representing the site of attach- ment of ligaments, tendons, capsules, and fascia to bone.51 Enthesopathic fibers pen- etrate deep into the bony trabeculae and

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abnormalities outside the joint that were techniques. They demonstrated entheso- seen in a subset of RA patients may have pathic changes in 5 of 12 specimens; in 2 been secondary to severe synovitis with patients significant pannus was found to nonspecific extension of the inflammatory be invading the sacroiliac area with sub- process beyond the joint capsule. Second, stantial subchondral bone absorption. In bone marrow edema that was maximal one biopsy with significant loss of sub- adjacent to entheseal insertions was seen chondral bone, osteoclasts were present only in spondyloarthropathy-related arthri- and multinuclear cells were eroding the tides, and was accompanied by perienthe- bone. The investigators concluded that seal edema. The pattern of bone edema inflammation of the enthesis is part of seen in this study has previously been PsA; however, controversy remains as to reported in relation to peripheral enthesitis whether or not the enthesis is critically and spondylitis,53 which suggests a com- important to the development of ongo- mon pathogenic link between spinal dis- ing inflammation and later bony damage ease, peripheral enthesitis, and knee in PsA.55 synovitis in spondyloarthropathy-related arthritides. Summary In a later article, McGonagle et al54 sug- PsA is a debilitating, chronic spondy- gested that enthesitis may be the link loarthropathy that for years has been between infection and subsequent patho- underrecognized and undertreated. The logic and clinical manifestations. In this social devastation associated with the skin model, a microorganism may emerge from and joint manifestations of the disease is the gastrointestinal or genitourinary tract, enormous and has been well documented. lung, or skin, and result in enthesitis with Patients with PsA may have severe skin the clinical findings of tendonitis, disease, debilitating and progressive joint spondylitis, synovitis, dactylitis, or local- disease, and profound decreases in func- ized bone damage, and the pathologic tional status, even while undergoing ther- equivalents of tendon-insertion enthesitis, apy with conventional DMARDs. Many ligamentous-insertion enthesitis, second- patients who have PsA or psoriasis are dis- ary regional enthesitis, and localized syn- satisfied, predominantly because of the ovitis (Figure 4).54 shortcomings of current therapeutic A somewhat contrary view was pub- approaches. lished by François et al,55 who examined With advances in our understanding of the sacroiliac joints of patients with anky- the pathogenesis of PsA—particularly the losing spondylitis using standard histologic role of cytokines such as TNF in the gene-

Figure 4. Etiopathogenesis of Enthesitis-Related Clinical Syndromes

Microorganism Clinical Finding Pathology

Gastrointestinal Tendonitis Tendon insertion enthesitis

Genitourinary Spondylitis Ligamentous insertion enthesitis

RespiratoryENTHESITIS Synovitis Secondary to regional enthesitis

Skin Dactylitis Synovitis, tenosynovitis, enthesitis Other; eg, vaccine Entheseal bone damage Lytic bone lesions; eg, SAPHO and arthritis mutilans

SAPHO = synovitis-acne-pustulosis-hyperostosis osteolysis. Source: McGonagle D, Gibbon W, Emery P. Classification of inflammatory arthritis by enthesitis. Lancet 1998;352:1137-1140. Reprinted with permission.

S168 THE AMERICAN JOURNAL OF MANAGED CARE APRIL 2002 Clinical Features of Psoriatic Arthritis sis of skin and joint disease—has come a 11. Jones G, Crotty M, Brooks P. Psoriatic arthritis: A potential milestone in the therapy of both quantitative overview of therapeutic options. Br J Rheumatol 1997;36:95-99. PsA and psoriasis. The development of 12. American College of Rheumatology. Psoriatic TNF inhibitors targeted specifically to the arthritis fact sheet. Available at: http://www.rheuma- mechanisms of skin and joint inflamma- tology.org/patients/factsheet/psoriati.html. Accessed tion in PsA and psoriasis represents a November 12, 2001. 13. Winchester R. Psoriatic arthritis. In: Winchester major advance in what physicians will be R, Fitzpatrick TB, Eisen AZ, Wolff K, Freeberg able to offer patients. For the first time in FM, Austin KF, eds. Dermatology in General more than a decade, a new and innovative Medicine, 4th ed. 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