Clinical features Symptoms seldom occur simultaneously and years may elapse before one can be con \201 dent of the diagnosis. The commonest manifestations in early disease include: \200 \200 \200 Other medications utilized include: NSAIDS. Proton pump inhibitors. Low dose glucocorticoid s. DMARDS (e.g. hydroxychloroquine and MTX). \200 \200 \200 Raynaud \200\231s phenomenon (75 \200\223100%). Arthralgia/arthritis. Hand oedema/sclerodac tyly (extension proximally is not a feature). Other early symptoms include Fatigue; Myalgia s/mild myositis; Serositis; Low-grade fever. Less common manifestations include: Prognosis In the early phase of disease the features of a single condition (usually systemi c sclerosis or SLE) predominate over the \200\230overlap \200\231 features. Invariably, al l patients will ful \201 l criteria for another AICTD at some stage. Pulmonary hypertensio n is the major cause of death in MCTD. \200 \200 \200 OVERLAP SYNDROMES 308 Overlap syndromes De \201 nition An overlap autoimmune connective tissue disease occurs when 2 or more autoi mmune rheumatological or connective tissue diseases are present simultaneously in the same indi- vidual. The following are considered established overlap syndromes: \200 \200 \200 \200 Autoantibodies of both disorders are present, such as IgM-RF; ANA, Anti-DNA, Anti-Ro. Sclerodermatomyositis or scleromyositis \200 \200 Features of SSc with myositis skin manifestations. Dermatological change occurs over yea rs and is not severe (absence of digital ulceration, trunk or face involvement, only mild t elangiectasia). High titre ANA. PM-Scl antibodies. Anti-U1 RNA absent. \200\230Rhupus \200\231: SLE/RA. Sclerodermatomyositis. Scleromyositis. MCTD (considered s eparately). Other \200\230overlaps \200\231 may be classi \201 ed as subsets of de \201 ned \200 \200 Treatment of overlap syndromes \200 CTDs including: \200 SLE/myositis. \200 RA/myositis. \200 SLE/APS. \200 RA/vasculit is. \200 SLE/vasculitis. Treatment follows the symptoms and severity of disease. Therapeutic modalities are those us ed in the individual AICTDs (see Rheumatoid arthritis, Systemic lupus erythematosus, System ic sclerosis). Prognosis Prognosis is variable and depends upon the extent of organ involvement, the respo nsiveness to treatment and any intervening complications. Clinical features Disease presentation is varied and comprises features of individual AICTD s in an overlapping fashion (see appropri- ate sections of the book for full descriptions o f the speci \201 c AICTDs). The following gives a brief overview of the recognized overlap AICTDs. Rhupus \200 \200 Criteria met for a diagnosis of both RA and SLE. Rheumatoid factor sero-positive, erosive, symmetrical polyarthritis usually pre-dates the onset of the clinical features of SLE. CHAPTER 8 Autoimmune connective tissue diseases 309 Resources (for UCTD, MCTD, and Overlap syndromes) Speci \201 c assessment tools and guidel ines do not exist for UCTD, MCTD, and Overlap syndromes. The quality and breadth of informa tion on a crude search engine screen is of variable quality. Readers are referred to indivi dual scien- ti \201 c and clinical reports where greater detail is required. Bodolay E, Csiki Z, Szekanecz Z, Ben T, Kiss E, Zeher M, et al. Five-year follow-up of 665 Hungarian patients with undifferenti- ated connective tissue disease (UCTD). Clin Exp Rheum atol 2003; 21: 313 \200\22320. Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a revie w of the literature and a proposal for preliminary classi \201 cation criteria. Clin Exp R heumatol 1999; 17: 615 \200\22320. Mosca M, Tani C, Neri C, Baldini C, Bombardieri S. Undifferentiated connective tissue disea ses (UCTD) Autoimmun Rev 2006; 6: 1 \200\2234 ICD-10 codes M35.1 Other overlap syndromes M35.8 See also SSc (p. 264) SLE (p. 240) RA (p. 197) PM (p. 282) Other speci \201 ed systemic involvement of connec- tive tissue Systemic involvement of co nnective tissue, unspeci \201 ed M35.9 References Alarcon-Segovia, D, Cardiel, MH. Comparison between 3 diagnostic criteria for mi xed connective tissue disease. Study of 593 patients. J Rheumatol 1989; 16: 328. EOSINOPHILIC FASCIITIS 310 Eosinophilic fasciitis De \201 nition Eosinophilic fasciitis (Schulman syndrome) was first described in 1974 as a disorder characterized by peripheral eosinophilia and fasciitis (manifest clinically as sy mmetrical swelling, induration, and thickening of the skin and subcuta- neous tissue of the extremities). It differed from the related condition systemic sclerosis (SSc) in that fasc ia was involved, rather than dermis, the digits were spared and Raynaud \200\231s phenomeno n was absent. More recently, the syndrome has been broadened to include elevation of the er ythrocyte sedimentation rate (ESR) and hypergammaglobulinaemia. Co-morbidities Eosinophilic fasciitis is frequently associated with haemato- logical abnorm alities, including malignant lymphoprolifera- tive diseases and, rarely, as a paraneoplasti c phenomenon (e.g. colorectal adenocarcinoma). It has also rarely been associated with auto immune thyroiditis. Investigations It is worth noting that laboratory changes and the clinical manifestations d o not necessarily correlate well. Peripheral blood eosinophilia is not necessary for the di agnosis. Laboratory \200 Diagnostic criteria The diagnosis rests on the clinical, laboratory, and biopsy \201 ndin gs. Speci \201 c criteria have not been developed. Peripheral blood eosinophilia in 64% (variable over time even in the absence of speci \201 c therapy). Hypergammaglobulinaemia in 75% cases (polyclonal increase in IgG). FBC may rev eal thrombocytopaenia, haemolytic anemia, pernicious anemia, leukemia, and aplastic anemia. In doubtful cases, given the association with haemato- logical malignancy, bone marrow asp iration (and trephine if necessary) should be considered. The majority have a raised ESR. A NA positive in one-third. Creatinine kinase (CK) and aldolase normal. Epidemiology \200 Very rare. \200 Caucasian > Afro Caribbean. \200 Females > males (a lthough data vary). \200 Mean age of onset 40 \200\22350 years. \200 Can occur in child ren who are more likely to suffer from persistent disease. \200 \200 Etiology and pathophysiology The etiology of eosinophilic fasciitis is unknown. It has been shown that \201 broblasts from affected patients pro- duce excess collagen in vitro and up-regulation of TGF-B and type 1 collagen mRNA has been seen. A cytotoxic immune response to an environmental or infectious agent is possible as CD8 positive (CD8+) T lymphocytes an d macrophages have been found in the fascial in \202 ammatory in \201 ltrate. Borrelia bu rgdorferi has been implicated as an inciting agent. Imaging Gadolinium-enhanced MR may reveal fascial enhancement consistent with acute in \202 ammation and/or deep fascial thickening. Histology Deep fascial biopsy, which includes skin, fat, fascia, and super \201 cial muscl e is required for the de \201 nitive diagnosis. Biopsy features include thickening of coll agen bundles of the super \201 cial muscle fascia with in \201 ltration of lympho- cytes, eosinophils and plasma cells. Clinical features \200 A history of signi \201 cant physical activity precedes the onset in 50% of patients. Skin changes occur sub-acutely and progress through several phases in the following order: \200 \200 Other investigations \200 \200 EMG can show evidence of underlying myositis. Pulmonary function tests show restrictive pat tern in those with severe truncal tissue involvement. blotchy skin erythema initially; non-pitting oedema (most commonly of the lower extremities ); peau d \200\231orange with hyperpigmentation; skin tightness with woody induration. Differential diagnosis The average time taken from the \201 rst symptoms to diagnosis has been found to be 9 months due to the rarity and lim- ited awareness of the condition. The differential diagnosis includes: \200 \200 \200 \200 \200 \200 \200 In \202 ammatory arthritis mainly affects hands and wrists (up to 40% cases). Joint contractures are common especially in the upper limb. Carpal and tarsal tunnel syndrome sy mptoms. Restrictive lung disease (extra-thoracic) and pleural effusions. Venous guttering ( linear depressions; \200\230groove \200\231 sign). Not common in the initial stages, but w ith progression of the skin lesion, veins become tethered within the connective tissue. Ele vation of a limb then drains the veins causes guttering at the site of vein. Crucially, the re is an absence of gastrointestinal, pulmo- nary parenchymal, and cardiac involvement, and no Raynaud \200\231s phenomenon. Hypereosinophilia syndrome. Systemic sclerosis. Polymyositis. Churg \200\223Strauss vasculi tis. Eosinophilia-myalgia syndrome. Toxic oil syndrome. \200 Treatment Physical therapies Occupational and physiotherapy are helpful, especially for min imizing the development and impact of joint contractures. Immunosuppression Glucocorticoids are the mainstay of treatment. The initial dose of predni solone is 20 \200\22360 mg/day, which is then tapered over months. CHAPTER 8 Autoimmune connective tissue diseases 311 Resources Assessment tools None available Prolonged courses of GCs may be required to reduce the oedema, skin thickening, and joint c ontracture. Eosinophilia usually resolves rapidly following GC treat- ment. Disease onset i n childhood is less likely to respond to GCs. Although most patients respond to GCs alone, second line agents are often required including ciclosporin, methotrexate, azathioprine, hy droxychloroquine, and cyclophosphamide. Recently, anti-TNFA has been used in recalcitrant d isease. Photochemotherapy has also been utilized for severe skin involvement. Patient resources Articles http://www.emedicine.com/derm/topic119.htm; http://www.medicinenet.com/eosinophili c_ fasciitis/article.htm; Guidelines None available ICD-10 Codes M35.4 Diffuse (eosinophilic) fasciitis Prognosis Early institution of treatment has been found to improve the outcome, yet the dis ease may remit spontaneously. Oedema usually resolves within 1 month of GC treatment. Howev er, 6 months may elapse before maximal skin soft- ening and improvement in contractures occ urs. Residual sclerodermatous-type skin changes may persist inde \201 nitely despite treat ment. Raised ESR and immunoglobulin levels may remain abnormal for 12 months or more. Aplas tic anemia is a rare, but often fatal complication. Factors predicting persistent disease i nclude: Young age at onset (<12 years of age). Morphea-like skin changes. Truncal involveme nt. References Bischoff L, Derk CT. Eosinophilic fasciitis: demographics, disease pattern and r esponse to treatment: report of 12 cases and review of the literature. Int J Dermatol. 2008 ; 47: 29 \200\22335. Endo Y, Tamura A, Matsushima Y, Iwasaki T, Hasegawa M, Nagai Y, Ishikawa O. Eosinophilic fa sciitis: report of two cases and a systematic review of the literature dealing with clinica l variables that predict outcome. Clin Rheumatol. 2007; 26: 1445 \200\22351. Shulman LE. Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome? J Rheumatol 1974; 1: 46. \200 \200 This page intentionally left blank 313 Chapter 9 Vasculitis Introduction 314 Giant cell arteritis 318 Polymyalgia rheumatica 320 Takayasu arteritis 322 Wegener \200\231s granulomatosis 324 Churg \200\223Strauss Syndrome 326 Microscopic polyan giitis 328 Treatment of ANCA-associated vasculitis 330 Polyarteritis nodosa 332 Cryoglobuli naemia 334 Primary central nervous system vasculitis 336 Cogan \200\231s syndrome 338 Beh et \200\231s disease 340 Henoch \200\223Sch nlein purpura 342 Kawasaki disease 344 Relapsi ng polychondritis 346 Thromboangiitis obliterans 348 INTRODUCTION 314 Introduction The vasculitides are group of generally rare conditions characterized by inflammation of bl ood vessels. The conditions have some common features which will be described here, but for greater detail refer to the individual diseases. diagnosis. Age is an important discriminating feature. Takayasu arteritis (TA) is rare aged over 40 years, whilst GCA is most common aged >65 years. Symptoms suggestive of vasculitis include: Systemic Fever, weight loss, myalgia, arthralgia. De \201 nition and classi \201 cation The vasculitides can be classi \201 ed on the basi s of size of vessel involved (Table 9.1), and whether they are primary (or idiopathic) or s econdary to a known cause such as infection or connective tissue disease. The ACR in 1990 d eveloped classi \201 cation criteria for seven types of vasculitis; these are given with t he individual diseases (Fries et al., 1990). The major criticism of the ACR criteria is tha t they did not include MPA or ANCA. They were derived using patients with known vasculitis and not tested against patients with other conditions. ENT Epistaxis, nasal crusting, deafness, sinusitis (all especially suggestive of WG). Pulmonary \200 Cough, haemoptysis (especially WG or MPA), dyspnoea, and wheeze. Late onset asthma is sugge stive of CSS. Cutaneous Purpuric rash, ulcers. The Chapel Hill Consensus Conference (CHCC) in 1994 produced definitions for the major type s of systemic vasculitis. The CHCC included MPA, but not ANCA. They were not designed for u se as classi \201 cation criteria. Neurological \200 \200 Peripheral neuropathy (especially CSS or PAN). Headache \200\223 especially located in the temple, new onset or of a different character to previous headache. Suggestive of GCA. There has until recently been a lack of consensus as to how to reconcile these two systems. A European group has recently produced an algorithm for using both these sys- tems for the classi \201 cation of the AAV (Table 9.2) (Watts et al., 2007). Epidemiology \200 Vascular \200 \200 \200 Jaw claudication is suggestive of GCA. Limb claudication is suggestive of TA or GCA. Caroti dynia (tender carotid arteries) suggests carotid involvement. Dif \201 culty in obtaining blood pressure readings. Overall, the vasculitides are diseases of the extremes of age. Kawasaki disease and Henoch \200\223Sch nlein purpura occur in childhood, whilst GCA occurs in those aged >65 years. T he other types of vasculitis are all much rarer, but also tend to occur in older people. Key features on examination Cutaneous Purpuric rash, ulcers, digital gangrene. Musculoskeletal Synovitis. Clinical features Key features on history In the early stages, the symptoms can be non-spec i \201 c and a high index of suspicion is required to achieve an early Neurological \200 \200 Motor or sensory neuropathy. Mononeuritis multiplex. Table 9.1 Classi \201 cation of the vasculitic syndromes according to vessel size and ANCA Dominant vessel Primary Secondary Large arteries Giant cell arteritis Takayasu arteritis Aortitis associated with RA, infection (e.g. syphilis, TB) Medium arteries Classical PAN Kawasaki disease Hepatitis B associated PAN Small vessels and medium arteries Wegener \200\231s granulomatosis* Churg-Strauss syndrome* Microscopic polyangiitis* Vasculitis secondary to rheumatoid arthritis, systemic lupus erythematosus, Sj gren \200 \231s syndrome, drugs, infection (e.g. HIV) Drugs Hepatitis C associated Infection Small vessels Henoch-Sch nlein purpura Cryoglobulinaemia Cutaneous leucocytoclastic angiitis Diseases most commonly associated with ANCA and a signi \201 cant risk of renal involvemen t, and most responsive to immunosuppression with cyclophosphamide. Adapted from Scott & Wat ts (1994). CHAPTER 9 Vasculitis 315 Table 9.2 Names and de \201 nitions of vasculitides adopted by the Chapel Hill Consensus C onference on the Nomenclature of Systemic vasculitis Large vessel vasculitis Giant cell (temporal) arteritis Granulomatous arteritis of the aorta and its major branches, with a predilection for the ex tra cranial branches of the carotid artery. Often involves the temporal artery. Usually occ urs in patients older than 50 and often is associated with polymyalgia rheumatica. Takayasu arteritis Granulomatous in \202 ammation of the aorta and its major branches. Usually occurs in pati ents younger than 50 Medium-sized vessel vasculitis Polyarteritis nodosa \200 (classic polyarteritis nodosa) Necrotizing in \202 ammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules Kawasaki disease Arteritis involving large, medium-sized, small arteries, and associated with mucocutaneous lymph node syndrome. Coronary arteries are often involved. Aorta and veins may be involved. Usually occurs in children Small vessel vasculitis Wegener \200\231s granulomatosis \200 Granulomatous in \202 ammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels (e.g. capillaries, venules, arterioles, and arteri es). Necrotizing glomerulonephritis is common Churg \200\223Strauss syndrome \200 Eosinophil-rich and granulomatous in \202 ammation involving the respiratory tract, necrot izing vasculitis affecting small to medium-sized vessels, and associated with asthma and eo sinophilia Microscopic polyangiitis \200 (microscopic polyarteritis) \200 Necrotizing vasculitis, with few or no immune deposits, affecting small vessels (i.e. capil laries, venules, or arterioles). Necrotizing arteritis involving small and medium sized art eries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Henoch \200\223Sch nlein purpura Vasculitis, with IgA-dominant immune deposits, affecting small vessels, i.e. capillaries, v enules, or arterioles). Typically involves skin, gut, and glomeruli, and is associated arth ralgia or arthritis Essential cryoglobulinaemic vasculitis Vasculitis, with cryoglobulin immune deposits, affecting small vessels (i.e. capillaries, v enules, or arterioles), and associated with cryoglobulins in serum. Skin and glomeruli are often involved Cutaneous leucocytoclastic angiitis Isolated cutaneous leucocytoclastic angiitis without systemic vasculitis glomerulonephritis Large vessel refers to the aorta and the largest branches directed towards the major body r egions (e.g. to the extremities and the head and neck); medium- sized vessel refers to the main visceral arteries (e.g. renal, hepatic, coronary, and mesenteric arteries); small vess el refers to venules, capillaries, arterioles, and the intraparenchymal distal arterial rad icals that connect with arterioles. Some small and large vessel vasculitides may involve me dium-sized arteries, but large and medium sized vessel vasculitides do not involve smaller than arteries. Essential components are represented by normal type; italicized type represe nts usual, but not essential, components. \200 Preferred term. \200 Strongly associated w ith antineutrophil cytoplasmic antibodies. From Jennette et al. (1994). Vascular \200 Assessment of organ involvement In all patients \200 Tender non-pulsatile temporal arteries. Suggestive of GCA. Absent peripheral pulses, bruits . Dif \201 culty in obtaining blood pressure measurement Urinalysis (proteinuria, haematuria, red cell casts), should be performed urgently in all p atients in whom systemic vasculitis is suspected. Renal function (creatinine clearance, qua nti \201 cation of protein leak if present using either 24-h protein excre- tion or urine protein/creatinine ratio). CXR may show infiltrates, hemorrhage, granuloma (especially WG, CSS, MPA). Liver function. \200 ENT Nasal bridge collapse. Suggestive of WG or RP. General investigations Investigation is directed at establishing the diagnosis and assessing the extent and severity of organ invol vement. \200 FBC anemia, leucocytosis, eosinophils (eosinophilia sug- gestive of CSS). Acute phase respo nse (ESR and CRP). Liver function. Where appropriate \200 Nervous system (nerve conduction studies in all four limbs, biopsy). \200 INTRODUCTION 316 Table 9.3 Relationship between vessel size and response to induction treatment Dominant vessel Corticosteroids alone Cyclophosphamide and corticosteroids Other treatments Large arteries +++ \200\223 + Medium arteries + ++ ++* Small vessels and medium arteries + +++ + Small vessels + +/ \200\223 ++* Includes plasmapheresis, anti-viral therapy for hepatitis B-associated PAN and HCV associat ed cryoglobulinaemia, and IVIg for Kawasaki disease. Adapted from Scott & Watts (1994). \200 Male and female infertility is a recognized complication of cyclophosphamide therapy. These patients should be counseled about the possibility of infertility following cyclophosphami de. Cardiac function (ECG, echocardiography). Gut (celiac axis angiography). Biopsy of an affected organ should be obtained where possible to con \201 rm diagnosis pri or to treatment. Treatment Intensity of initial immunosuppression depends on extent and severity of organ in volvement. Treatment can be divided into stages: induction, consolidation, and mainte- nanc e of remission. Where there is evidence of threatened vital organ involvement treatment sho uld be started urgently. Serological investigations \200 ANCA. A cANCA pattern on indirect immuno \202 uores- cence and PR3 by ELISA are together s trongly associated with WG (>90%). pANCA and MPO is suggestive of MPA or CSS. Preferably bo th indirect immuno \202 uores- cence and ELISA for PR3/MPO should be performed in all pati ents. ANA. RF (may be positive in cryoglobulinaemic vasculitis or systemic rheumatoid vascu litis). Anticardiolipin antibodies (usually negative, but if positive consider anti-phospho lipid syndrome). Complement (low in cryoglobulinaemic vasculitis). Cryoglobulins (suggestiv e of cryoglobulinaemic vasculitis). For speci \201 c details see each individual disease. \200 Resources Guidelines BSR guidelines on treatment systemic vasculitis. EULAR recommendations for the management of large vessel vasculitis. EULAR recommendations for management of med ium and small vessel vasculitis. \200 Differential diagnosis This is from vasculitis mimics (e.g. malignancy, cholesterol embolis m, atrial myxoma, calciphylaxis) or infection (espe- cially subacute bacterial endocarditis ). \200 \200 \200 Patient organizations Vasculitis Foundation. Available at: www. vasculitisfoundation.org St uart Strange Trust. Available at: www.vasculitis-uk. org Blood cultures. Viral serology (HBV, HCV, HIV, CMV). Echocardiogr aphy transoesophageal). D isease assessment \200 (two-dimensional and/or References Bacon PA, Luqmani RA. Assessment of vasculitis. In: Ball GV, Bridges L (eds) Vasculitis. Oxford: Oxford University Press, 246 \200\22354. Severity of involvement of target organs should be carefully assessed. Where appropriate sc oring systems should be used. A number of scoring systems are available. The Birmingham Vas culitis Activity Score is widely used in clinical trials. Active uncontrolled disease is as sociated with cumula- tive organ damage, which should be assessed using the Birmingham Vasc ulitis Damage Index (VDI). General health function can be assessed using the SF-36 or HAQ. British Society for Rheumatology. Vaccinations in the immunocom- promised person. Guideline s for the patient taking immunosup- pressant, steroids and the new biologic therapies. Lond on: BSR, 2002. Available at: www.rheumatology.org.uk De Groot K, Rasmussen N, Bacon P, et al. Randomized trial of cyclo- phpsphamide versus meth otrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody a ssociated vasculitis. Arthritis Rheum 2005; 52: 2462 \200\2238. Fries JF, Hunder GG, Bloch DA. et al. The American College of Rheumatology 1990 criteria fo r the classi \201 cation of vasculitis. Summary. Arthritis Rheum 1990; 33: 1136 \200\2236. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasc ulitis associated with antineutrophil cytoplasmic auto antibodies. N Engl J Med 2003; 349: 36 \200\22344. Patient advice This applies to patients with any type of vasculitis. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37: 187 \200\22392. General \200 Potentially serious multisystem condition, requiring immunosuppressive therapy and lifelong follow-up. Attention to cardiovascular risk. Stop smoking. Healthy balance diet. Regular e xercise. Vaccination (in \202 uenza and pneumococcal). Lapraik C, Watts RA, Scott DG. BSR & BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology 2007; 46: 1615 \200\22316. \200 \200 \200 \200 Mukhtyar C, Guillevin L, Cid M, et al. EULAR recommendations for the management of large ve ssel vasculitis. Ann Rheum Dis 2008 (in press). CHAPTER 9 Vasculitis 317 ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheu m Dis 2007; 66: 222 \200\2237. Mukhtyar C, Guillevin L, Cid M, et al. EULAR recommendations for the management of primary small and medium vasculitis. Ann Rheum Dis 2008 (in press). Watts RA, Scott DGI, Overview of the in \202 ammatory vascular disease. In: Hochberg MC, S ilman AJ, Smolen JE, Weinblatt ME, Weisman MH (eds) Rheumatology. New York: Mosby, 1583 \200\22391. Scott DGI, Watts RA. Classi \201 cation and epidemiology of systemic vasculitis. Br J Rheum 1994; 33: 897 \200\2239. Watts RA, Lane SE, Hanslik T, Hauser T, Hellmich B, Koldingsnes W, Mahr A, Segelmark M, Sco tt DG. Development and validation of a consensus methodology for the classification of the GIANT CELL ARTERITIS 318 Giant cell arteritis Giant cell arteritis (temporal arteritis) (GCA) is the most common of the systemic vasculit ides and is characterized by involvement of large vessels particularly the extra- cranial b ranches of the aorta. There is a close relationship with polymyalgia rheumatica (PMR). Key features on history Systemic \200 \200 Fever, weight loss. Myalgia, arthralgia. Morning stiffness across the shoulder and hip gird les is suggestive of co-existent PMR. De \201 nition The Chapel Hill Consensus Conference de \201 ned GCA as: Granulomatous art eritis of the aorta and its major branches, with a predilection for the extra cranial branc hes of the carotid artery. Often involves the tem- poral artery. Usually occurs in patients older than 50 and often is associated with polymyalgia rheumatica. Headache The characteristic feature is new onset or change in char- acter from previous hea dache. The headache is located typically in the temples. Visual disturbance \200 This may occur suddenly without warning and may be bilateral. Transient visual loss may be a warning, of impeding acute visual loss, which may be profound. Ophthalmoplegia is a rare occurrence. Classi \201 cation criteria The ACR in 1990 developed classi \201 cation criteria, which are widely used in clinical trials. They have a speci \201 city of 91.2% and sensitivity o f 93.5%. There are no validated diag- nostic criteria. Jaw claudication Pain on eating is characteristic, but uncommon symptom. ACR criteria for classi \201 cation of GCA 1. Age at onset > 50 years: development of symp - toms or \201 ndings beginning aged 50 years or older. 2. New headache: new onset or new type of localized Arm or leg claudication This is uncommon. Leg claudication is more likely to be due to athe rosclerosis in the elderly. Arm claudication is an uncommon feature of atherosclerosis pains in the head. Key features on examination Vascular \200 3. Temporal artery abnormality: temporal artery tenderness to palpation or decreased pulsat ion, unrelated to atherosclerosis of cervical arteries. 4. Increase in ESR: ESR > 50 mm/h b y Westergren The temporal arteries may be tender, thickened, and non-pulsatile. Bruits may be audible ov er affected arteries, especially in the carotid and supraclavicular regions. method. 5. Abnormal artery biopsy: Biopsy specimen with artery showing vasculitis characterized by a predominance of mononuclear infiltration or granulomatous in \202 ammation. Eye Signs anterior ischaemic optic neuropathy. Formal slit lamp examination by an ophthalmo logist may be required. The optic disc may be pale with profound loss of acuity to counting \201 ngers or less. Note: for purposes of classi \201 cation a patient shall be said to have giant cell arteri tis if at least 3 of these 5 criteria are present (Hunder et al., 1990). Investigations \200 \200 Epidemiology \200 \200 \200 \200 FBC microcytic anemia, thrombocytosis. Acute phase response (ESR and CRP). These are both u sually raised in active GCA. Rarely patients may present with a normal ESR or CRP Incidence in people aged > 50 years 10 \200\22333/100 000/year. There is a female preponder ance. Peak age onset >75 years, very rare < 50 years More common in populations of Scandina vian descent. Occurs much less frequently in other ethnic groups such as Japanese or Afro-C aribbeans. Serological investigations ANCA, ANA, RF, Anticardiolipin are usually negative Etiology The etiology is unknown. There is an association with HLA DRB*0401. Although infec tious triggers have long been suspected, no clear associations have yet been con \201 rmed . Temporal artery biopsy A biopsy of the temporal artery should be obtained where possible. \200 A negative biopsy does not exclude the diagnosis because the lesions are focal in nature an d may be missed due to sampling error. Bilateral biopsies should not routinely be performed . A biopsy should be obtained as speedily as possible, but if delayed more than 2 weeks may not show changes of active vasculitis, but changes consistent with previous vasculitis. A proposed hypothesis suggests that the arterial wall dendritic cells become activated and then recruit CD4+ lymphocytes, which become clonally expanded producing IL-2 and IFN-g. Mac rophages produce PDGF, which stimu- lates intimal arterial thickening. Monocyte- macrophage s become multinucleate giant cells. Clinical features In the early stages, the symptoms can be non-speci \201 c and a high ind ex of suspicion is required to achieve an early diagnosis. Imaging Ultrasound Ultrasonography of the temporal arteries shows a charac- teristic halo s ign in active disease. Ultrasonography should CHAPTER 9 Vasculitis 319 Steroids should be started as soon as the diagnosis is suspected, as there is a risk of bli ndness, which is signi \201 - cantly reduced by the use of early corticosteroids. The head ache should resolve rapidly (<48 h) with the intro- duction of steroids. A recent randomize d study suggested that use of IV methylprednisolone (15 mg/kg) for 3 days in addition to or al prednisolone 40 mg/day permitted more rapid steroid taper. In patients with ocular sympt oms IV methylprednisolone 1 g daily for 3 days should be used in addition to oral corticost eroids. Oral corticosteroids should be tapered quickly aiming for 10 mg/day at 6 months. Lo w dose aspirin reduces the risk of thrombosis. only be performed by experienced operators and its role in the routine assessment of patien ts with suspected GCA is uncertain. 18FDG-PET scintigraphy 18FDG-PET scintigraphy is a usef ul method of demonstrating disease active in large vessels, such as the aorta and its major branches. The technique is too insensitive to dem- onstrate the temporal arteries. PET sca nning has a role in the assessment of disease activity, but its role in the assess- ment of relapse or remission remains to be determined (see Plate 32). Angiography Angiography is not usually required to make the diagnosis. The role of MRA of t he temporal arteries remains to be established. Where extra-cranial large vessel involvemen t is suspected MRA or contrast angiography should be considered. Relapsing disease Minor relapse can be treated with an increase in predniso- lone dose to t he last effective dose. Differential diagnosis Takayasu arteritis (TA) in the younger patient. Other forms of syste mic necrotizing vasculitis may rarely present with vasculitis affecting the temporal arteri es. Refractory disease \200 Use of azathioprine or methotrexate should be consid- ered in patients with relapsing disea se or who are resist- ant to corticosteroids. However, a randomized trial of methotrexate s howed no bene \201 t in either reduction of relapse rate or reduction of steroid dosage. T he role of biologic agents such as in \202 iximab remains to be determined. Disease assessment ESR and CRP are a guide to disease activity, but may be normal in relaps e particularly in patients on corticosteroids. Prognosis Untreated GCA is associated with a signi \201 cant risk of per- manent blindness risk. This is greatly reduced by the early introduction of corticosteroids. The risk of th e second eye being involved in a patient with profound visual loss is 70% within 1 week unl ess treated. The risk of blindness occurring in patients on corticosteroids is very low. Resources Guidelines EULAR recommendations for the management of large vessel vasculitis (M ukhtyar et al., 2008). Patient organizations Vasculitis Foundation. www.vasculitisfoundation.org Pathology Granulomatous necrotizing vasculitis affecting large vessels especially the extra cranial branches of the aorta. There is destruction of the internal elastic lamina with gia nt cells and granuloma formation. The lesions are focal and careful examination of adequate biopsy is required. ICD-10 coding M31.5 Giant cell arteritis with polymyalgia rheumatica M31.6 Other giant cell arteritis References Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classi \201 cation of Giant Cell Arteritis. Arthritis Rheum 1990; 33: 11 22 \200\22318. Patient advice General Potentially serious condition, requiring glucocorticoid therapy with a risk of blindness Mazlumzadeh M, et al. Treatment of giant cell arteritis using i nduction therapy with high- dose glucocorticoids: a double-blind, placebo controlled, randomized prospective clinical t rial. Arthritis Rheum 2006; 54: 3310 \200\22318. Treatment Observational studies support the use of high dose gluco- corticoids in GCA. \200 Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large v essel vasculitis. Ann Rheum Dis 2008 (in press). In patients without ocular symptoms oral corticoster- oids starting at 0.7 \200\2231 mg/kg (maximum dose 60 \200\22380 mg). POLYMYALGIA RHEUMATICA 320 Polymyalgia rheumatica Polymyalgia rheumatica (PMR) is an in \202 ammatory condi- tion of the elderly characteriz ed by proximal shoulder and hip girdle pain and morning stiffness. It commonly co-exists wi th giant cell arteritis. Diagnostic criteria Several sets of diagnostic criteria have been proposed, the most useful are given in the Table 9.4. New criteria are being developed by c onsensus, but are still being validated. Key features on history Systemic Fever, weight loss. Musculoskeletal Typically, there is a proximal myalgia affecting the shoulder and hip girdl es. There may be local tenderness, but there should not be muscle tenderness. This may be o f acute onset, and is associated with signi \201 cant morning stiffness. Headache New onset or change in character of headache suggests co-existent giant cell arter itis. Table 9.4 Diagnostic criteria for PMR Bird et al. (1979) Jones & Hazleman (1981) Arthritis A peripheral arthritis may occur, but this is suggestive of elderly onset rheumat oid arthritis. Age (years) >65 Onset <2 weeks Duration >2 months Key features on examination Musculoskeletal \200 Pain location Bilateral shoulder pain and stiffness Shoulder and pelvic girdle There may be muscle tenderness proximally, but this should not be major feature. Weakness i s not a feature of PMR; if present suggests an in \202 ammatory myopathy. The presence of a small joint synovitis suggests elderly onset rheumatoid arthritis. Temporal artery tender ness suggests co-existent GCA. Morning stiffness >1 h Present Tenderness Systemic symptoms Upper arms Depression, weight loss ESR >40 mm/h >30 mm/h, or CRP >6 mg/l General investigations Investigation is directed at establishing the diagnosis and excludin g malignancy. \200 Response to glucocorticoids Prompt and dramatic All criteria Requirements to ful \201 l criteria If any 3 criteria are present, sensitivity is 92% and speci \201 city 80% Acute phase response (ESR and CRP): these are both usually raised active PMR. Rarely patien ts may present with a normal ESR or CRP. CK: this should normal. A raised CK suggests an in \202 ammatory myopathy. Renal, liver, bone, and thyroid function: FBC, PSA, Igs, electrop horetic strip, chest X-ray may be needed to exclude malignancy. Epidemiology \200 \200 PMR is more common than GCA. GCA occurs in 4-31% of PMR patients and PMR is present in 1 \200\22366% of GCA patients. The incidence like GCA is highest in Scandinavia 68 \200\22311 2/100 000 persons aged >50 years. Prevalence rates of up to 1:30 in person aged >65 years h ave been reported. There is a female preponderance. The peak age of onset >75 years, very r are < 50 years. Serological investigations \200 RF: a positive RF is suggestive of elderly onset RA, especially if anti-CCP antibodies are also present. ANCA, ANA: anticardiolipin antibodies are all negative. \200 Detection co-existent GCA The optimum method of detecting co-existent GCA is uncertain. Rou tine temporal artery biopsy has a very low detection rate. Biopsy of symptomatic patients i mproves the detection rate. Etiology The etiology is unknown. No clear HLA associations for pure PMR have emerged and i t is likely because of the overlap with GCA that similar HLA associations will be observed. Imaging 18FDG-PET scan 18FDG PET scanning is a useful method of demonstrating associated GC A with large vessel arteritis. The technique is too insensitive to demonstrate the temporal arteries. A PET scan may detect a previously unsuspected malignancy. Polymorphisms in a number of other genes (e.g. ICAM-1, IFN-y, VEGF, IL-1 and endothelial ni tric oxide synthase have been described, suggesting a polygenic etiology. The striking association with age and disease onset suggests that immunosenescence may be i mportant, with possible breakdown in immune tolerance or increased susceptibility to infect ious triggers. Ultrasonography \200 Numerous infections have been implicated in small stud- ies but none so far has emerged fol lowing rigorous case control studies. Ultrasonography of the temporal arteries may demon- strate co-existent GCA. The halo sign i s characteristic. Ultrasonography of the shoulders and hips may reveal evidence of bursitis or synovitis, but similar appearance may occur in elderly onset RA. Clinical features In the early stages, the symptoms can be non-speci \201 c and a high ind ex of suspicion is required to achieve an early diagnosis. CHAPTER 9 Vasculitis 321 MR MR of the shoulders and hips may reveal evidence of bursitis or synovitis, but similar a ppearance may occur in elderly onset RA. Refractory disease \200 