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Extra-Articular Manifestations H Extra-articular manifestations H. Mielants and F. Van den Bosch Department of Rheumatology, ABSTRACT bowel disease, some forms of psoriatic University Hospital Gent, Gent, Belgium. Rheumatoid arthritis and spondyloar- arthritis, and reactive arthritis (Fig. 1). Herman Mielants, MD, PhD, thritis, a concept which includes diseas- In early disease a large group of patients Professor of Rheumatology es like ankylosing spondylitis, psoriatic will initially be classified as undifferen- Filip Van den Bosch, MD, PhD arthritis, and arthritis/spondylitis asso- tiated (axial) SpA; over time this may Please address correspondence to: ciated with inflammatory bowel disease, evolve into a more specific diagnosis. Prof. Herman Mielants are both chronic inflammatory rheumato- In AS, extra-articular manifestations Department of Rheumatology, logic conditions. This article focuses on University Hospital, can be subdivided in 2 groups: those De Pintelaan 185, extra-articular manifestations, defined related to the SpA concept , such as in- B-9000 Gent, Belgium. as diseases and symptoms not directly volvement of skin, eye, gut or urogeni- E-mail: [email protected] related to the locomotor system. The dif- tal system, and those more reflecting Received and accepted on July 29, 2009. ferent manifestations are addressed per chronic, longstanding inflammation, Clin Exp Rheumatol 2009; 27 (Suppl. 55): body system. Diagnostic and prognostic which are involvement of lung, heart, S56-S61. implications of these manifestations in kidney and nerves. The concept-related © Copyright CLINICAL AND daily practice are discussed. manifestations are relatively frequent EXPERIMENTAL RHEUMATOLOGY 2009. (20–60%) (2), can occur at any moment of the disease evolution (sometimes as Introduction Key words: Rheumatoid arthritis, first manifestation), and can sometimes Ankylosing spondylitis (AS) and rheu- spondyloarthritis, ankylosing be related to axial or peripheral joint matoid arthritis (RA) can be considered spondylitis, extra-articular inflammation. The non-concept related as prototypes of inflammatory rheu- manifestations. manifestations are very rare (1 to 5%), matic diseases. In both diseases, the are frequently subclinical, occur only locomotor problem is prominent: it in- in longstanding disease, and are not re- cludes arthritis (RA, AS), but also other lated to the locomotor manifestations. specific problems such as tenosynovitis We will discuss the different manifes- (RA), enthesitis (AS), dactylitis, sacro- tations per body system. iliitis and axial disease (AS). Besides the articular/axial component, other Skin manifestations body systems are frequently involved. RA: Rheumatoid nodules are the most We consider extra-articular manifesta- frequent skin manifestation in RA. tions, all the conditions and symptoms They have a firm, rubbery consistency, which are not directly related to the are painless and subcutaneously, and locomotor system. occur most commonly on pressure ar- Systemic features in RA are frequent, eas, including elbows, finger joints, mostly related to vasculitis, and often sacral prominences and Achilles ten- a reflection of longstanding inflam- don. They occur mainly in rheumatoid mation. Most organs can be involved. factor positive RA patients and in early These manifestations occur as frequent RA give risk to severe extra-articular in men as in women, and may appear at manifestations. A recent study found any age (1). Prevalence of these mani- that positivity for rheumatoid factor, festations is about 40% of patients at smoking and human leucocyte anti- any time during the course of the dis- gen (HLA)DRB1*0401 were the only ease. The occurrence of these systemic factors independently associated with manifestations is a major predictor of nodules (3). Histologically focal central mortality in patients with RA. fibrinoid necrosis with surrounding fi- Whereas RA is a relatively homogene- broblasts is observed: it is believed to ous disease, AS belongs to a broader dis- occur as a result of small vessel vascu- ease concept, namely spondyloarthritis litis. Regression of nodules may occur (SpA). Major diseases belonging to this during treatment with disease modify- concept (beside AS) are arthritis/spon- ing drugs (DMARD); paradoxically Competing interests: none declared. dylitis associated with inflammatory methotrexate may increase nodules, S-56 Extra-articular manifestations / H. Mielants & F. Van den Bosch despite improvement in overall disease activity (4). Other manifestations of rheumatoid small vessel vasculitis affecting the skin are splinter haemorrhages, periungual infarcts, leg ulcers, digital gangrene and sharply demarcated painful ulcera- tions. They appear mostly at the lower extremities or where skin is exposed to pressure. Vasculitis can be present without active joint disease, mostly in RA patients with high rheumatoid factor, and the skin manifestations are frequently associated with other ex- tra-articular features like episcleritis, pleural and pericardial effusions (5). Capillaries, small venules, veins, arte- rioles, and medium-sized arteries are most frequently involved (6), but large vessels can also be affected. Early le- sions show fibrinoid necrosis of the vessel wall, with an inflammatory cell infiltrate. Later on, artery wall fibrosis Fig. 1. The Spondyloarthritis (SpA) concept. with occlusion can appear. AS: Psoriatic or psoriatic-like lesions occur more frequently in AS, compared systemic disease, most commonly IBD Episcleritis, inflammation of the layer to the general population, and can pre- (8). The lesions present as erythema- superficial to the sclera, occurs in few- cede the disease in 15% of the cases. tous papules or pustules, with subse- er than 1% of patients with RA and is The skin and nail lesions are identical quent necrosis of the dermis, leading to generally a self-limiting condition. It to isolated skin disease, mostly com- deep ulcerations. presents with focal dusky redness and patible with plaque psoriasis (vulgaris), Keratoderma blennorrhagica (mostly irritation of the eye, but without disturb- but the lesions are sometimes localised related to genitourinary involvement) ing visual acuity. The phenomenon usu- on more atypical localisations, such as is an unusual, but more severe skin ally correlates with the activity of RA. palms of hands and feet (palmoplantar manifestation, which begins with clear Scleritis is a more aggressive process, pustulosis). The clinical picture of pso- vesicles, progressing to pustular kera- characterized by an intensely painful riatic AS is identical to that of non-com- totic lesions that are painful on pres- inflammation of the sclera itself. This plicated AS; radiologically, however, sure. There is no relationship with the process may be either nodular or dif- sacroiliitis is more frequently asym- activity of the AS inflammation. In fuse. It is seen in patients with vasculitis metrical, while the syndesmophytes most cases, from a histological point of and long-standing arthritis. Untreated occur also more asymmetrical and can view, this condition cannot be differen- scleritis may progress to scleromalacia be more plump; zygoapophyseal fu- tiated from palmoplantar pustulosis. with a risk for perforation. sion is more seldom. There are no data Peripheral ulcerative keratitis develops supporting a parallelism between the Ocular manifestations as an extension of scleral inflammation activity of psoriasis and the locomotor RA: Different eye manifestations can with involvement of the peripheral cor- inflammation. occur in RA. The most frequent is kera- nea and can lead to corneal melt; it is Erythema nodosum, which are painful toconjunctivitis sicca, which affects at frequently bilateral and can cause poor red nodules mostly localised on the dis- least 10% of patients. It is frequently outcome for vision. tal extremities, are observed in associ- observed together with xerostomia in a AS: Acute anterior uveitis (AAU) oc- ated inflammatory bowel disease (IBD), secondary Sjögren’s syndrome. Ocular curs in 30 to 40% of AS patients (9), occurring in up to 15% of patients (7). symptoms range from dry eyes, over a and is strongly associated with HLA- It is seen in association with peripheral burning sensation of a foreign body, to B27. In large series of patients, the arthritis and often parallels the activity mucoid discharge. The diagnosis is sup- mean frequency of active episodes of of the inflammatory bowel disease. Bi- ported by a positive Schirmer test and a uveitis was 0.8 attacks per year (10). opsy shows focal panniculitis. reduced tears break-up time. In patients About 50% of patients with AAU as an Pyoderma gangrenosum is an ulcera- with dry mouth syndrome, a reduced initial presentation, have or will devel- tive disease of the skin of unknown salivary flow rate, and minor salivary op a form of SpA. The disease primarily origin, associated with an underlying gland biopsy, can support the diagnosis. affects only the anterior chamber of the S-57 Extra-articular manifestations / H. Mielants & F. Van den Bosch Table I. Rheumatoid arthritis and spondyloarthritis: summary of extra-articular manifestations per body system. Rheumatoid arthritis Spondyloarthritis (SpA) SpA concept-related Non-SpA concept-related Skin Rheumatoid nodules Psoriasis Erythema nodosum Rheumatoid vasculitis Pyroderma gangrenosum Keratoderma blenorrhagica Eye Keratoconjuctivitis sicca Acute anterior uveitis Episcleritis Scleritis Gastrointestinal Vasculitis Inflammatory bowel disease * Crohn’s disease * Ulcerative colitis
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