Extra-articular manifestations H. Mielants and F. Van den Bosch

Department of , ABSTRACT bowel disease, some forms of psoriatic University Hospital Gent, Gent, Belgium. Rheumatoid and spondyloar- arthritis, and (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 , 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: , 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 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 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 Pulmonary Pleuritis Upper lobe fibrosis Pulmonary nodules Pleural thickening Interstitial pulmonary fibrosis Bronchiolitis obliterans organising pneumonia Cardiac Pericarditis Aoritis, aortic insufficiency Myocarditis (nodules) Conduction abnormalities Endocarditis (nodules) (bundle branch block, AV conduction block) Renal Glomerulonephritis Secondary amyloidosis Secondary amyloidosis IgA nephropathy Neurological Mononeuritis multiplex Cauda Equina syndrome Peripheral entrapment neuropathies Haematological Anaemia, thrombocytosis Lymphadenopathy Felty’s syndrome eye. A typical attack has a sudden onset intestinal bleeding and perforation. in Crohn’s disease (CD), with structural and is unilateral (but in subsequent at- There is no direct relation with arthritis abnormalities in the gut and formation tacks the other eye may be involved): activity, but as with other vasculitides, of granulomas. While in the major- local redness, pain, photophobia and it is mostly observed in RA patients ity of the patients the disease remains reduced vision are the cardinal symp- with high rheumatoid factor and subcu- subclinical, about 6.5% of AS patients toms. In most cases local treatment is taneous nodules. Prognosis is poor and with subclinical gut inflammation will sufficient; relapses however are fre- outcome frequently fatal. later develop overt Crohn’s disease (15). quent, and prolonged, uncontrolled AS: Inflammatory bowel diseases (IBD), Recently polymorphisms in the CARD anterior uveitis can extend into the such as Crohn’s disease and ulcerative 15 gene (16) and studies on the IL23 R posterior part of the eye with formation colitis, are part of the SpA concept. gene, have demonstrated a genetic link- of synechiae and secondary glaucoma. Overt clinical IBD is observed in 5 to age between CD (17) and AS (18), giv- Only in these cases systemic treatment 10% of AS patients. There are many ar- ing further support to this gut-joint axis. with corticosteroids, immunosuppres- guments to consider that the gut could sive agents (such as methotrexate or play an important role in the pathogen- Pulmonary manifestations cyclosporine) or TNF-blocking agents esis of SpA (reviewed in 12). Following RA: Pulmonary involvement in RA is may be necessary. ileocolonoscopy, microscopic intestinal frequent although not always clinically inflammation has been seen in up to recognized. Pleural disease is common Gastrointestinal system 60% of patients with AS (13). The intes- but usually asymptomatic; autopsy RA: Gastrointestinal complications in tinal inflammation seems more frequent studies reported pleural involvement in RA are mostly iatrogenic and caused by in the presence of peripheral arthritis. 50% of cases, with only 10% clinically medications (non-steroidal anti-inflam- Moreover a strong relationship exists detected (19). Pleural effusions are usu- matory drugs, methotrexate, leflunomide between the presence of actual rheuma- ally exudates with mixed cell counts etc.). tological disease activity and the pres- and high protein concentration (20). Primary involvement of the gastroin- ence of gut inflammation; in patients in Multinucleated giant cells are highly testinal tract, caused by mesenteric vas- clinical remission, the gut inflammation specific but seen in fewer than 50% culitis leading to intestinal infarction, usually also disappears (14). Subclinical of the cases. The disease is frequently is very rare (11). This condition causes intestinal inflammation is immunologi- associated with exudative pericarditis, acute abdominal pain, and can lead to cally closely related to the inflammation and with interstitial lung disease.

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Parenchymal pulmonary nodules gener- cardiovascular outcome for both acute with nephrotic syndrome. Glomerulo- ally are asymptomatic and found in RF- coronary syndromes and long-term risk nephritis and interstitial renal disease positive patients with nodules elsewhere. for cardiovascular and cerebrovascular are uncommon in the absence of vas- They can cavitate and cause pleural ef- disease, independent of lipid levels culitis. Renal abnormalities are fre- fusions. Pathological examination of the (25). quently iatrogenic, induced by the use nodules reveals a central necrotic zone Pericarditis is the most common cardiac of DMARDs or NSAIDs (“analgesic surrounded by a cellular area of prolifer- manifestation in RA. Although sympto- abuse nephropathy). ating fibroblasts. As with classical sub- matic pericarditis is relatively uncom- AS: The most common renal manifesta- cutaneous nodules, the underlying proc- mon, autopsy studies revealed evidence tion in AS is secondary amyloidosis (32). ess appears to be a vasculitis. Differen- of pericardial inflammation in 50% of It is reported in 1–3% of patients with tiation with neoplasms and tuberculous the patients (26). It usually occurs in longstanding active disease. Patients or fungal infections can be difficult. RF-positive patients with nodules (27) present with proteinuria progressing to Diffuse interstitial pulmonary fibrosis and analysis of pericardial fluid reveals nephrotic syndrome and renal failure. in RA tends to occur more often in RF- changes similar to those found in rheu- Immunoglobulin (Ig)A nephropathy is positive male patients with longstand- matoid pleural effusions. also uncommon. Patients have increased ing nodular disease (20). The clinical Myocarditis (with presence of rheu- IgA serum levels, microscopic haema- presentation and course of pulmonary matoid nodules) has been observed in turia and proteinuria, and can develop fibrosis in RA is similar to that of idio- autopsy studies, and myocardial fibro- renal insufficiency. In some studies a pathic pulmonary fibrosis, but response sis can lead to conduction abnormalities correlation was shown between high to immunosuppression may be better. (28). Congestive heart failure may be levels of IgA in serum and disease ac- Bronchiolitis obliterans organizing more frequent than is clinically evident tivity in AS patients (33). pneumonia (BOOP) responds to gluco- in RA. corticoid treatment and has a good prog- Endocarditis with formation of rheuma- Neurological manifestations nosis; obliterative or constrictive bron- toid nodules in the aortic or mitral valves RA: Peripheral neuropathy, presenting chiolitis responds poorly and has a poor can lead to valvular dysfunction (28). as diffuse sensorimotor neuropathy or prognosis (20). AS: In daily clinical practice, symptoms mononeuritis multiplex, occurs in a Finally low-dose weekly methotrexate of heart involvement in AS patients small subset of patients with RA. The therapy may rarely lead to life-threat- are rarely seen, and clinical signifi- underlying mechanism is small vessel ening pneumonitis (21). cant cardiac disease occurs in 2 -10% vasculitis of the vasa vasorum of the AS: Pulmonary involvement in AS is of patients, mostly after longstanding nerves with ischemic neuropathy and uncommon and estimated to occur in disease (29), with no association with demyelinisation. These manifestations less than 1%, mostly in long-standing articular disease activity. Nearly all pa- are part of the rheumatoid vasculitis and severe disease (22). Involvement tients with cardiac manifestations are syndrome. of the costovertebral joints and anky- HLA B27 positive. Peripheral entrapment neuropathies, losis of the thoracic spine will lead to Valvular pathology secondary to aor- like carpal tunnel syndrome, are fre- a limited chest expansion which might titis with aortic insufficiency (aortic quent and are related to the degree and affect the patients’ breathing capacity, regurgitation), or bundle-branch block severity of local synovitis or tenosyno- but only rarely leads to restrictive res- occur in approximately 5% of patients vitis, but not related to other extra-ar- piratory impairment, because diaphrag- with AS, usually after longstanding dis- ticular manifestations of RA. They may matic function is not impaired. ease (30). This can lead to heart failure, be the initial symptoms in early RA. The most frequently recognized mani- usually over several years. Cervical myelopathy, caused by atlan- festations are upper lobe fibrosis and Multiple forms of atrioventricular con- toaxial subluxation or pannus forma- pleural thickening (23). Fibrosis is typ- duction blocks have been reported; only tion, occurs frequently in RA patients ically asymptomatic. These manifesta- in a few cases do complete blocks occur, with severe and longstanding disease tions have no direct relationship with necessitating pacemaker implantation. (35). Basilar invagination, with upward the disease evolution, and no treatment Myocardial involvement with abnor- impingement of the odontoid process seems to be efficacious. mal left ventricular diastolic function into the foramen magnum, can also may be the result of the sclerosing in- result in cord compression. This com- Cardiac disease flammatory process, involving aortic plication may require surgical interven- RA: The risk for myocardial infarction root and valves. tion. Surgeons and anaesthetists should in female RA patients is twice that of be aware of this possible atlantoaxial women without RA, and in long-stand- Renal disease subluxation, because intubation could ing disease of at least 10 years, the risk RA: Renal involvement in RA is rare; lead to sudden death secondary to pres- is 3 times higher (24). Although the mesangial glomerulonephritis was the sure and bleeding in the upper part of exact mechanism is not completely most common histopathological find- the spinal cord. understood, there are associations be- ing (31), whereas amyloidosis was the AS: Neurological involvement in AS is tween C-reactive protein levels and most common finding among patients most often related to spinal fracture, at-

S-59 Extra-articular manifestations / H. Mielants & F. Van den Bosch lantoaxial subluxation or cauda equina Conclusion thema nodosum and pyoderma gangrenosum syndrome. This last manifestation, is The occurrence of signs and symptoms in chronic ulcerative colitis: a study of 42 pa- tients. Am J Gastroenterol 2003; 98: 1821-6. slowly progressive and insidious, and outside the locomotor apparatus is a 9. BRAUN J, BARALIOKOS X, LISTING J, SIEPER mostly a late manifestation of AS, of- frequent finding in patients with chron- J: Decreased incidence of anterior uveitis in ten when the disease is no longer active ic inflammatory rheumatic conditions, patients with Ankylosing spondylitis treated (36). It leads to sensory, motor and re- such as AS or RA. Whereas in RA, with anti-tumor necrosis factor agents inflixi- mab and etanercept. Arthritis Rheum 2005; flex loss progressing to sphincter dys- almost all manifestations are a conse- 52: 2447-51. function. quence of longstanding active disease 10. MONNET D, MOACHON L, DOUGADOS M, (vasculitis), the extra-articular manifes- BREZIN AP: Severe uveitis in a HLA-B 27- positive patients with Ankylosing spondylitis. Haematologic manifestations tations in AS can be divided into rather Nat Clin Pract Rheumatol 2006; 2: 393-7. RA: The cause of anaemia in RA is mul- frequent concept-related manifesta- 11. MOSLEY JG, DESAI A, GUPTA I: Mesenteric tifactorial. Iron utilization is impaired tions, sometimes leading to overt dis- arteritis Gut 1990; 31: 956-7. as reflected by decreased serum iron eases such as psoriasis or inflammatory 12. DE KEYSER F, ELEWAUT D, DE VOS M et al.: Bowel inflammation and the spondylo- and transferrin concentrations. There bowel disease, and non-concept-related . Rheum Dis Clin North Am is an increased synthesis of ferritin manifestations. Awareness of these ex- 1998; 24: 785-813. and haemosiderin, and abnormal reten- tra-articular manifestations is important 13. MIELANTS H, VEYS EM, CUVELIER C, DE tion of iron from senescent red blood for the clinician both from a diagnostic VOS M: Ileocolonoscopic findings in seron- egative . Br J Rheuma- cells by the reticuloendothelial system. (concept-related manifestations) and tol 1988; 27: 595-605. Anemia of chronic disease is observed a prognostic viewpoint. As such, it is 14) MIELANTS H, VEYS EM, CUVELIER C et al.: in RA, where it usually correlates with not surprising that occurrence of e.g. The evolution of spondyloarthropathies in the disease activity, particular the de- diarrhoea, uveitis or psoriasis are con- relation to gut histology. Part III: relation be- tween gut and joint. J Rheumatol 1995; 22: gree of articular inflammation. It is sidered valuable clues for classification 2273-8. normochromic and normocytic. of patients presenting with early signs 15. MIELANTS H, VEYS EM, CUVELIER C et al.: Thrombocytosis is a frequent finding of articular disease suggestive of SpA The evolution of spondyloarthropathies in relation to gut histology. Part I: clinical as- in active RA and is correlated with the (38). An initial check-up and regular pects. J Rheumatol 1995; 22: 2266-72. number of active inflamed joints. control of these manifestations should 16. LAUKENS D, PEETERS H, MARICHAL D et al.: Lymphadenopathy is sometimes ob- be a necessary part of the follow-up of CARD 15 gene polymorphisms in patients served in active RA, usually presenting patients with these inflammatory rheu- with spondyloarthropathies identify a specific phenotype previously related to Crohn’s dis- on biopsy as benign follicular hyperpla- matic diseases. ease. Ann Rheum Dis 2005; 64: 930-5. sia. RA is however associated with an 17. 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