Initial treatment The immediate aim is to reverse the renal failure or stop it progressing. This treatment is therefore urgent. 1. Counter the precipitants and aggravants. \200 \200 \200 2. Redu ce the load of light chains. \200 Rehydration. Treat hypercalcemia. Stop NSAIDs. Prescribe dexamethasone to suppress the malignant plasma cell clone. Consider plasma exchan ge. One clinical trial has shown no bene \201 t but another is in progress. Light chain concentrations can be reduced more effectively with a high \202 ux dialysis t echnique. This treatment is being tested in a randomized trial. Subsequent treatment Once attempts at renal rescue have been made a medium and long-term ma nagement plan is needed. 1. Chemotherapy: The treatment choice will be made by hematooncolo gists and will depend on whether the aim is palliation or remis- sion induction. (Cure is r arely possible unless a bone mar- row allograft is feasible.) Melphalan doses should be red uced but cyclophosphamide and dexamethasone are used in conventional doses. Thalidomide and its analogs can be used without dose reduction. High dose chemotherapy with stem cell resc ue is offered to selected, usually younger patients without major comor- bidity but higher treatment-related mortality has to be expected. 2. Renal support: Patients whose renal fail ure is complete and irreversible will require dialysis. Because the presentation is usually acute, most patients will be treated by hemodialysis but there is no contraindi- cation to peritoneal dialysis. Both modalities carry an infection risk and myeloma patients are espe cially vulnerable because of hypogamma- globulinemia and leukopenia. Treatment This is generally aimed at neutralizing the abnormal plasma cell clone in the hop e of reducing the amount of precursor LC available to produce further amyloid deposits. Des pite the insolubility of amyloid, tissue damage can be stabilized by halting the production of the offending LC. Hematological remission is associated with an improved prognosis. C. WINEARLS 160 In practice the choice of treatment will be tailored to the individual patient depending on age, the number and extent of organ involvement and the presence or absence of mye- loma. Indeed in some patients it is appropriate to do no more than provide support for organ fail ure. In patients without extensive organ involvement the treat- ment choice is between high dose melphalan and PBSCT (peripheral blood stem cell support), or high dose combi- nation chemotherapy, e.g. VAD (vincristine, adriamycin and dexamethasone). Whether the higher trea tment-related mortality of high dose melphalan is justi \201 ed remains to be established. Those patients who develop end-stage renal failure have a two-fold greater annual risk of death than the general dial- ysis population. Renal transplantation is seldom a realistic o ption but there are cases of successful outcomes in individuals fortunate enough to receive both a marrow and a renal allograft. A quick screening test is the \201 nding of a high titer rheuma- toid factor and a low C4 level (evidence of activation of the classic complement pathway by the immune complexes). A bone marrow examination may reveal clusters of mono- clonal IgM (usually )-positive pla sma cells. Treatment is directed against the clone and the in \202 amma- tion but because the condition is chronic and often indo- lent, corticosteroids, alkylating agents and plasm a exchange/cryo \201 ltration are only deployed during nephritic \202 ares. Patients wit h hepatitis C virus-associated disease are treated with interferon-A and those with underly ing lym- phomas with conventional chemotherapy. Monoclonal Ig deposition disease and immunotactoid glomerulopathy The deposition of monoclo nal light or heavy chains on basement membranes is dependent on their particular physicoche mical properties. Cryoglubulinemia Cryoglobulins are so-called because of their tendency to precipitate at lo wer than body temperature: a dramatic in vitro phenomenon and a partial explanation of the micro- circulatory problems that occur in the periphery. They are classi \201 ed according to their constituents (Table 4.3.3). Types 1 and 2 are associated with plasma cell dyscras ias but the abnormal clone is recognized more from its prod- uct than its expansion. It is type 2 that causes renal injury by the deposition of IgM/IgG complexes manifesting usually as a mesangiocapil- lary glomerulonephritis causing the nephritic and/or neph- rotic syndro mes. The extrarenal manifestations are: lower limb purpura and ulceration, arthritis and a multifocal ischemic neuropathy (mononeuritis multiplex) caused by occlusion of the vasa ner vorum. The diagnosis will be suspected from the clinical presenta- tion and con \201 rmed by identi \201 cation of the cryoglobulin in serum extracted from a blood sample allowed t o clot at 37 C. The constituents are identi \201 ed by immunochemistry. Monoclonal Ig deposition disease LC deposition disease (LCDD), which is more common, is usu ally caused by an abnormal chain, and heavy chain deposition disease (HCDD) by either or chains. The disease presents with the classic signs and symptoms of glomerular injur y: proteinuria, hematuria, nephritic syndrome and renal impairment which often progresses r apidly. The diagnosis is usually made with a renal biopsy. The histological appearances are of a nodular glomerulo- sclerosis with both glomerular and tubular basement membrane thick ening (Fig. 4.3.3). The electron microscopic and immunohistochemical \201 nd- ings of rib bon-like deposits with chain-restricted reactivity are diagnostic (Fig. 4.3.3). A plasma ce ll dyscrasia is obvious in 50% of cases but the majority will have an identi \201 able pa raprotein in the urine or blood. The heart, liver and nerves can also be affected by the de position of the abnormal light or heavy chains. Treatment is directed against the plasma ce ll dyscrasia using the same regimens and criteria applied to myeloma. Some patients will re spond but the majority are refrac- tory. Response to treatment is monitored by measurement of the serum concentration of the free LC in LCDD. To avoid recurrent disease, transplantat ion should not be performed unless there is complete remission of the plasma cell dyscrasia . Table 4.3.3 Classi \201 cation of cryoglobulins Type Constituent Cause 1 Monoclonal IgG, IgM or IgA Lymphoma Myeloma Waldenstr m \200\231s Immunotactoid glomerulopathy This is a rare condition caused by deposition of whole monoclo nal IgG ( or ). Deposition is confined to glomeruli. Patients present with proteinuria or renal impairment and may have an underlying lymphoma or chronic leukemia. The light micr oscopic appearances are of an atypical mem- branous glomerulopathy but electron microscopy reveals microtubular deposits (Fig. 4.3.3). These are Congo Red negative. The condition is refractory to treatment and patients progress rapidly to renal failure. \200\230Essential \200\231 Lymphoma Hepatitis C Sj gren \200\231s syndrome 2 Monoclonal IgM rheumatoid factor and polyclonal IgG 3 Polyclonal IgM RhF and polyclonal IgG SLE Rh arthritis Chronic infections Hepatitis B virus Hepatitis C virus Idiopathic CHAPTER 4.3 Plasma cell dyscrasias 161 (a) (b) (c) (d) Fig. 4.3.2 AL amyloid. (a) Glomerular amyloid deposits (arrows) (periodic acid \200\223Schi ff). (b) Congo Red-stained medium-sized renal artery. Birefringence (Apple Green) can be se en under polarized light (arrow). (c) Anti- staining of glomerulus (immunoperoxidase). (d ) Electron micrograph of amyloid deposit showing randomly orientated, nonbranching \201 b rils 8 \200\22315 nm in diameter. (a) (b) (c) (d) Fig. 4.3.3 (a) Nodular glomerulosclerosis in light chain deposition disease (LCDD) (H&E). A rrows indicate nodules. (b) Immunoperoxidase for light chain demonstrating staining of t ubular basement membrane in LCDD (arrows). (c) Electron micrograph demonstrating ribbon-lik e deposits in the GBM in LCDD. (d) Elecron micrograph of a GBM deposit in immunotactoid glo merulopathy demonstrating microtubular substructure (arrowheads). Arrows indicate podocyte foot processes. C. WINEARLS 162 Further reading Clark WF, et al. Plasma exchange when myeloma presents as acute renal failu re. A randomized, controlled trial. Ann Intern Med 2005; 143: 777 \200\223784. Internet resources General information about myeloma: http://myeloma.org Multiple Myeloma Research Foundation. General informa- tion: Korbert SM, Schwartz MM. Disease of the month: multiple mye- loma. J Am Soc Nephrol 2006; 17: 2533 \200\2232342. Rajkumar SV, Gertz MA. Advances in the treatment of amyloidosis. http://www.multiplemyeloma.org/about_myeloma/ New Engl J Med 2007; 356: 2413 \200\2232415. See also Amyloid or immunotactoid glomerulopathy, p. 150 Mixed cryoglobulinemia and hepatit is C infection, p. 176 Ronco P, Plaiseier E, Mougenot B, Aucouturier P. Immunoglobulin light (heavy)-chain deposit ion disease: from molecular medicine to pathophysiology-driven therapy. Clin J Am Soc Nephr ol 2006; 1; 1342 \200\2231350. This page intentionally left blank R.WESTACOTT 164 Sarcoidosis Sarcoidosis is a chronic multisystem granulomatous disorder that most commonly affects the lungs. Clinically significant renal involvement, although uncommon in sarcoidosis, may pres ent in a number of different ways (Table 4.4.1). Disordered calcium homeostasis Problems related to disordered calcium homeostasis are far m ore common than interstitial nephritis. It is caused by increased calcitriol production res ulting from 1A-hydroxylase expression by granulomatous macro- phages. Epidemiology The prevalence of sarcoidosis is 10 \200\22320 per 100 000 popu- lation. The e xact prevalence of renal sarcoid is unknown. Renal insufficiency only occurs in 1% of sarc oidosis patients. 10 \200\22390% of cases present between 10 and 40 years of age. There is worldwide distribution but the prevalence is higher in certain races and geographical locat ions (African- Americans, Scandinavians). The incidence is increased among \201 rst- and second-degree relatives of affected patients. Hypercalciuria: \200 \200 This is de \201 ned as >300 mg/day. It occurs in up to 50% of sarcoidosis patients. Hypercalcemia This occurs in 10 \200\22320% of sarcoidosis patients. It is more common in: \200 \200 \200 male patients; Caucasians; patients aged >40 years (cf. pulmonary sarcoidosis). Tubular dysfunction This occurs frequently with hypercalcemia and/or GIN. Polyuria is the m ost common abnormality and is caused by a urinary concentrating defect (which may result in frank nephrogenic diabetes insipidus). Other possible defects include the development of: \200 \200 \200 \200 Etiology The etiology is unknown. There is thought to be a genetic in \202 uence and vario us infectious agents have also been implicated. Genetic: \200 renal tubular acidosis; glycosuria; salt wasting; Fanconi syndrome. A genetic predisposition is supported by familial cluster- ing and variations in incidence amongst different races. Several studies have also shown associations (both posi- tive and negative) with class II MHC alleles. Nephrolithiasis Hypercalciuria increases the incidence of calcium oxalate stone formation. 10 \200\22314% of sarcoidosis patients develop at least one symp- tomatic stone. Infective: Mycobacteria and Propionibacteria have both been sug- gested to be involved in t he pathogenesis but there is cur- rently no \201 rm evidence to support or refute either. Renal involvement in sarcoidosis Renal involvement can be broadly divided into conditions r esulting from disordered calcium homeostasis, the classi- cal granulomatous interstitial ne phritis (GIN) and a few rare disorders (Table 4.4.1). Nephrocalcinosis This can result from persistent hypercalcemia. It is the commonest cause of progressive ren al impairment in sarcoidosis. It is generally not visible on plain radiography but can be s een on histological examination. Table 4.4.1 Renal involvement in sarcoidosis Granulomatous interstitial nephritis (GIN) This is more common in male patients. 50% of pat ients with GIN have a normal CXR and 50% have an elevated serum angiotensin-converting enzy me level (even in the absence of CXR changes). Hypercalcemia is frequently observed with GI N and may contribute to the renal insuf \201 ciency. Frequency Common Functional (Disordered Ca2+ metabolism) Hypercalcemia \200 Hypercalciuria \200 Tubular dysfunction Structural Clinical features Patients with renal sarcoidosis may present with polyuria or loin pain, o r may present with symptoms relating to sar- coid involvement in another organ (malaise and dyspnea are the commonest symptoms). There may be no speci \201 c \201 ndings on examin ation but a thorough physical examination should be carried out pay- ing particular attenti on to the skin, lungs and eyes. Ophthalmic examination may reveal evidence of uveitis, reti nal vasculitis, or keratoconjunctivitis. (Due to disordered Ca2+ metabolism) Nephrolithiasis \200 Nephrocalcinosis Structural (Due to granulomatous in \201 ltration or other mechanism) Granulomatous interstitial nephritis \200 Glomerular disease \200 Retroperitoneal disea se Rare CHAPTER 4.4 Sarcoidosis 165 Diagnosis There is no de \201 nitive diagnostic test and other conditions can present in a similar way. Diagnosis is therefore one of exclusion and depends on: \200 \200 \200 noncaseating granulomas on histological examination; compatible clinical and radiological s igns; exclusion of other conditions. Differential diagnosis Consideration should be given to whether any of the fol- lowing may explain the clinical \201 ndings: \200 \200 \200 berylliosis: hilar lymphadenopathy and granulomata; tuberculosis: hilar lymphadenopathy and granulomata; fungal infection (e.g. histoplasmosis): hilar lymphaden- opathy and granuloma ta; drug-induced interstitial nephritis: GIN; malignancy (lymphoma, breast, lung): GIN; for eign body reaction (e.g. cholesterol emboli): GIN; Wegener \200\231s granulomatosis: GIN. \200 \200 \200 It is therefore essential that a thorough history is taken when assessing any patient suspe cted of having sarcoidosis, paying particular attention to: \200 \200 \200 occupational history (beryllium exposure); exposure to infections (TB); risk factors for im munode \201 ciency (fungal infection). General investigations Full blood count This may be normal or may show an eosinophilia or l euko- penia. Fig. 4.4.1 Chest X-ray showing hilar lymphadenopathy. (Courtesy of Dr Nick Mayer, Universit y Hospitals of Leicester, UK.) Renal biopsy Renal biopsy findings depend on which pathological process(es) is/are present. The commonest \201 ndings in sar- coidosis are GIN and/or nephrocalcinosis. Glomeruli ar e usually normal. GIN is the classical lesion of sarcoidosis. Noncaseating granulomas are f ormed from epithelioid macrophages surrounded by T cells (see Fig. 4.4.2). GIN is seen in 7 \200\22340% of biopsy series of sarcoidosis (includ- ing autopsy studies). Lesions may be scant and are often clinically silent, thus these numbers may underestimate the true incide nce. Serum biochemistry This may be normal or may show hypercalcemia and/or renal impairment. Immunology This may reveal hypergammaglobulinemia. Serum ACE This is raised in 75% cases of sarcoidosis. False positives are rare but can occu r with advanced renal disease. It may be more useful in monitoring the response to treat- m ent rather than for diagnosis. Parathyroid hormone This is normal or low \200\223normal in the presence of hypercal- cemia . Urinalysis This may be bland, or show hematuria and/or proteinuria (usually <1 g/day). Urinary calcium excretion This is elevated in up to 50% of patients. Chest X-ray Hilar lymphadenopathy is the commonest abnormality and is classed as stage I pu lmonary disease (Fig. 4.4.1). Pulmonary function tests A restrictive pattern on spirometry with reduced diffusing capacit y for carbon monoxide (DLCO) is seen with lung involvement. Fig. 4.4.2 Granulomatous interstitial nephritis showing a granuloma with multinucleate gian t cell and calcinosis (H&E) (Courtesy of Dr Nick Mayer, University Hospitals of Leicester, UK.) Consider also: ECG to look for conduction defects. Tuberculin skin test (no response in sar coidosis). R.WESTACOTT 166 Nephrocalcinosis may be seen as calcium deposits within the renal parenchyma (see Fig. 4.4. 2). ATN can occasionally occur with GIN or hypercalcemia. Consideration should be given toward gastric protection and prophylaxis against bone diseas e especially in at-risk groups. Prognosis Functional defects are generally fully reversible with pred- nisolone. Recovery o f renal function may be incomplete if \201 brosis has occurred. Nephrolithiasis and nephr ocalcinosis do not regress fol- lowing steroid treatment. Treatment Hypercalcemia General measures \200 \200 Adequate oral hydration. Dietary calcium, vitamin D and oxalate (spinach, rhu- barb, certai n nuts) restriction. Avoidance of sunlight. Avoidance of thiazide diuretics (which can pred ispose to hypercalcemia in sarcoid patients). \200 Internet resources Renal Involvement in sarcoidosis: Pharmacological treatment Prednisolone 20 \200\22340 mg/day. Calcium levels and renal funct ion usually respond within a few days if sarcoidosis is the cause of the hypercalcemia. Aft er an adequate response is obtained, tapering the dose while monitoring serum and urine cal cium levels and calci- triol levels is advised. http://www.kidneyatlas.org/book4/adk4-08.pdf Sarcoidosis: http://www.emedicine.com/PED/topic2043.htm Further reading Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet 2003; 361: 1111 \200\2231118. Berliner AR, Haas M, Choi MJ. Sarcoidosis: the nephrologist \200\231s pers- Granulomatous interstitial nephritis Pharmacological treatment Prednisolone 1 mg/kg/day ini tially. A prolonged course or steroids is required. Treatment for <6 months frequently resu lts in relapse. One author suggests continuing the full dose for 2 months then tapering the dose gradually, but continuing steroid treatment for \211 1 year. pective. Am J Kidney Dis 2006; 48: 856 \200\223870. Mery JP. The patient with sarcoidosis. In: Davison AM, et al. (eds), Oxford textbook of nep hrology, 3rd edn. Oxford; Oxford University Press; 2005. This page intentionally left blank L. HARPER 168 Systemic vasculitis Classi \201 cation of vasculitis In \202 ammation and necrosis of blood vessels occurs in a number of disorders; classically these conditions have been categorized based on the pre dominant size and types of blood vessels involved. The American College of Rheumatology has also produced classi \201 cation criteria for most forms of vasculitis based on signs and symptoms. These are not meant to be used as diagnostic criteria. granulomatosis. Patients carrying the main de \201 ciency allele, PiZ, have more severe di sease and a poor prognosis. However, A1-antitrypsin de \201 ciency per se is not suf \201 cient to induce vasculitis, suggesting that it acts as a \200\230second-hit \200\231 ampl i \201 er of in \202 ammation. Polymorphisms that predispose to autoimmunity per se are a lso associated with ANCA-associated vasculitis. For example, Wegener \200\231s granulomatos is has been shown to be associated with polymorphisms of the protein tyrosine phosphatase P TPN22 (R620W allele which in \202 uences the signaling threshold of the T-cell receptor), and also poly- morphisms in the CTLA4 gene. Aorta (Large Artery) Environmental Infection: nasal carriage of Staphylococcus aureus is associ- ated with an in creased risk of relapse of Wegener \200\231s granu- lomatosis. No other infectious agents h ave been associated with disease. Exposure to silica has been associated with an increased risk of disease. Drug exposure may precipitate disease, including propylth- iouracil, minoc ycline and penicillamine. Renal Artery (Medium-sized artery) Lobar Artery (Medium-sized artery) Arcuate Artery (Small artery) 1 2 Glomerulus 3 Pathogenesis ANCA are pathogenic: murine models show that when antimyeloperoxidase (MPO) an tibodies are transferred to na ve mice they develop disease. Direct evidence in humans tha t ANCA are pathogenic was provided by a newborn in which the placental transmission of mate rnal anti-MPO antibodies resulted in the develop- ment of a pulmonary \200\223renal syndrom e. ANCA activate cytokine-primed neutrophils and mono- cytes that express myeloperoxidase a nd PR3 on the cell surface. ANCA-activated neutrophils generate a respiratory burst, degran ulate and release proin \202 ammatory cytokines. Cytokine-activated endothelial cells, whi ch express adhesion molecules, are important in localizing damage: ANCA promote neutrophil transmigration across endothelial cells. Neutrophils are important in the induction of earl y dam- age, whereas T-cells and monocytes are important for chronic in \202 ammation. T-ce lls are thought to be important in pathogenesis; the phenotype of T-cells is altered with a n expansion in effector memory T-cells which are a source of Th1 cytokines. ANCA are T-cell -dependent, class-switched IgG antibodies. 1. Large: giant cell arteritis, Takayasu \200\231s. 2. Medium: polyarteritis nodosa, Kawasa ki \200\231s disease. 3. Small: without immune complex: Wegener \200\231s granu- lomatosis, microscopic polyangiitis, Churg \200\223Strauss syndrome. 4. Small: with immune complex: Henoch \200\223Sch nlein pur- pura, SLE, rheumatoid, essential cryoglobulinemia. ANCA-associated vasculitis This group of vasculitides is associated with a circulating anti neutrophil cytoplasmic antibody (ANCA) and includes: \200 \200 \200 Wegener \200\231s granulomatosis; microscopic polyangiitis; Churg \200\223Strauss syndrome. Epidemiology In the UK: \200 \200 incidence 20 pmp per year; prevalence 170 pmp. Churg \200\223Strauss syndrome is less common, with an inci- dence of 2.4/million populatio n. It occurs in all age groups with a peak age of onset of 55 \200\22370 years. Wegener \200\231s granulomatosis is predominant in northern Caucasian populations with microscopic polyangiitis being predominant in southern Caucasian and non-Caucasian populations. Pathology The characteristic lesion is small vessel vasculitis with in \202 ammation and n ecrosis of arterioles, venules and capil- laries (although larger vessels may be affected). Granulomatous lesions occur in Wegener \200\231s granulomato- sis and Churg \200\223Straus s syndrome, but not in microscopic polyangiitis. In the lung, there are often large, ill-de \201 ned collections of in \202 ammatory cells near affected vessels; these may present as cavitating nodules. In the kidney, the process primarily affects glomeruli, lead- ing to focal segmental necrotizing glomerulonephritis with Etiology It is an autoimmune disease of unknown etiology. Both genetic and environmental fa ctors are thought to be important. Genetic HLA associations have not been consistently reported in ANCA-associated vasculitis. An association exists between A1-antitrypsin de \201 ciency (the main inhibitor of protei nase-3 (PR3)) and Wegener \200\231s CHAPTER 4.5 Systemic vasculitis 169 Speci \201 c organ involvement This may occur in Wegener \200\231s granulomatosis or micro - scopic polyangiitis (Table 4.5.1). \200 crescent formation without immunoglobulin deposition; this is termed \200\230pauci-immune glomerulonephritis \200\231. There is often associated interstitial in \202 ammation. With in the kidney there are no absolute differences in pathology between microscopic polyangiit is and Wegener \200\231s granulomatosis, although patients with microscopic poly- angiitis tend to have more chronic lesions. Granulomata are generally not found in the kidney. Pulmonary disease: This is recorded in 45 \200\22370% of patients at presentation. However, 85% of patients with Wegener \200\231s granulomato- sis will have pulmonary involvement at some stage of the disease. Presentation may be with asymptomatic pulmonary in \201 ltrate s or cough, hemoptysis, pleuritis or dyspnea. Life-threatening alveolar hemorrhage may occu r and is associated with a poor prognosis. Pulmonary disease is less common in microscopic polyangiitis but 30% of patients will have pulmonary hemorrhage. Renal disease: This can ra nge from an active urinary sediment to rapidly progressive glomerulonephritis with severe d amage. Renal involvement in microscopic polyangiitis is invaria- ble. Hypertension occurs i n 30% of patients. So-called idiopathic rapidly progressive glomerulonephritis, with- out i mmune deposits and with no systemic features of vasculitis, is now considered part of the s pectrum of microscopic polyangiitis. Renal involvement is not a common presentation in pati ents with Wegener \200\231s granulomatosis (18%), but 77% of patients will develop glomerul onephritis at some stage. Disease of other organs: Ocular involvement is not uncommon and m ay present as conjunctivitis, scleritis or uveitis. In those with granu- lomatous in \202 ammation, proptosis may occur and is com- monly associated with extensive sinus disease. Op tic nerve vasculitis and retinal artery thrombosis are rare but important complications. Lo ss of sight has been reported in 8% of patients. Myalgia and arthralgia are common. Noneros ive arthritis occurs in 28% of patients. Skin disease may manifest as palpable purpura, ulc ers and subcutaneous nodules, and occurs in up to 50% of patients. The heart (pericarditis, coronary arteritis), nervous sys- tem (mononeuritis multiplex, peripheral neuropathy) and gastrointestinal tract (hemorrhagic ulceration, bowel perforation) may also be involved. Clinical features The clinical differentiation between Wegener \200\231s granuloma- tosis a nd microscopic polyangiitis is often dif \201 cult. However, this distinction is not impor tant clinically, because their treatment and prognosis are similar. Systemic nonspeci \201 c symptoms such as malaise, \202 u-like symptoms and weight loss are common and may pre- date the development of other symptoms. Wegener \200\231s granulomatosis \200\223 limited disease Respiratory tract symptoms are c ommon and may be present in 90% of patients at the time of diagnosis; symp- toms include: \200 sinusitis; \200 epistaxis; \200 otitis media; \200 hoarseness. Complications of granulomatous in \202 ammation may cause mucosal ulceration, nasal septal perforation, and develop- ment of a saddle nose. Subglottic stenosis occurs in up to 16% o f adults and 48% of children. It often becomes \201 xed and irreversible and can cause li fe-threatening upper airways obstruction. So-called limited disease may have an indolent co urse for many years before transforming into systemic disease. Wegener \200\231s granulomatosis \200\223 systemic disease This is characterized by: \200 \200 \200 \200 upper respiratory tract involvement; pulmonary disease; renal involvement with glomerulonep hritis; ANCA directed against the neutrophil enzyme PR3. Microscopic polyangiitis This is characterized by: \200 \200 \200 renal disease; pulmonary disease; ANCA directed against myeloperoxidase (MPO). Table 4.5.1 Organ involvement in small vessel vasculitis Organ involvement throughout disease course Wegener \200\231s granulomatosis Microscopic polyangiitis Churg \200\223Strauss syndrome Upper respiratory tract 80% Uncommon 55% Lower respiratory tract 70% 30% 100% Eye 46% 10% 6% Kidney 80% 90% 33% Peripheral nervous system 35% 20% 67% Gastrointestinal system 5% 5% 17% Heart Uncommon Uncommon 28% Skin 50% 25% 44% Constitutional symptoms 95% 90% 94% L.HARPER 170 Churg \200\223Strauss syndrome This is characterized by: Hypereosinophilia with tissue in \201 ltration, formation of granulomata and vasculitis. Allergic rhinitis and/or asthma pre cedes the develop ment of vasculitis, often in association with nonspeci \201 c symptoms. Asthma is often more severe in the weeks preceding the development of vasculitis. ANCA dire cted against MPO are identi \201 ed in 50% of patients, particularly in the vasculitic ph ase. Rash and mononeuritis multiplex commonly occur at pres- entation. Pulmonary involvemen t is characterized by dyspnea, alveo- lar hemorrhage or pleurisy and is associated with non spe- ci \201 c pulmonary in \201 ltrates on chest radiography. Cardiac involvement, manif est by myocarditis with eosi- nophilic in \201 ltration, coronary artery vasculitis and my ocar- dial infarction carries a poor prognosis and is often a late manifestation. Gastroint estinal involvement can present in various ways including abdominal pain, diarrhea and asci tes. Renal involvement is not uncommon but it is usually mild. Churg \200\223Strauss syndrome: 50% ANCA positive, majority MPO-ANCA particularly during va sculitis phase. Chest radiography Pulmonary hemorrhage is the most serious form of lung involvement and is seen as diffuse pulmonary shadowing associated with a reduced hemoglobin concen- tration, l ow arterial pO2 and a raised corrected transfer factor. In Wegener \200\231s granulomatosis , chest radiography commonly shows pulmonary nodules, which often cavitate. Other radiograp hic features include reticulonodular shadowing, pneumonic changes, collapse and pleural inv olvement with effusions. Tissue biopsy A tissue biopsy usually con \201 rms disease. The kidney is usually the best site for diagnosis. In Wegener \200\231s granulomatosis nasopharyngeal or trans- bronchial biopsy often shows nonspeci \201 c in \202 ammation. Lung biopsy generally requires an o pen procedure, and special stains and cultures need to be undertaken to exclude the presenc e of infections that can produce granu- lomata, vasculitis and necrosis. Differential diagnosis The differential diagnosis of the pulmonary \200\223renal syn- drome is wide (Table 4.5.2). A serological assessment for circulating autoantibodies is necessar y and distinguishes primary small vessel vasculitis from other causes. Investigations Routine laboratory investigations These will reveal nonspeci \201 c abnorma lities. Common abnormalities include: \200 \200 \200 \200 leukocytosis; thrombocytosis (>400 000/mm3); normochromic, normocytic anemia; elevation of in \202 ammatory markers including erythrocyte sedimentation rate (ESR) and C-reactive pro tein (CRP). In addition, Churg \200\223Strauss syndrome is usually associated with a blood eosinophilia (>1.5 \227 109/L) and elevated IgE levels. Urinalysis is a sensitive marker o f renal involvement. An active urinary sediment with red blood cells and casts indicates gl omerular disease. Proteinuria is often present although rarely in the neph- rotic range. El evated urea and creatinine levels are common, though active renal disease may be present ev en if biochemical indices are normal. Management Diagnosis and treatment should be made rapidly before permanent organ scarring o ccurs. Treatment should be tailored to the stage and severity of disease: the level of immu nosuppression should re \202 ect the severity of disease (Table 4.5.3). There are no treat ment guidelines provided by NICE although the British Rheumatology Society have recently pu blished guidelines on the management of systemic vas- culitis (BSR & BHPR Guidelines for th e Management of Adults ANCA Associated Vasculitis. Rheumatology 2007; 46: 1615 \200\2236). Induction therapy: Wegener \200\231s granulomatosis and microscopic polyangiitis Initial th erapy in patients with ANCA-associated vasculitis and generalized or threatened vital organ loss should include cyclophosphamide and a reducing course of corti- costeroids (Tables 4. 5.4 and 4.5.5). Cyclophosphamide can be administered using an oral or pulsed regimen. Preli minary results of a randomized con- trolled trial suggest that there is no difference in th e relapse rate or safety using either regimen although with the pulsed regimen the total do se of cyclophosphamide is lower. In those with limited disease, methotrexate in combination with a reducing course of steroids may be appropriate, although this may be at the expense of a higher relapse rate compared to when cyclophosphamide is used as an induction agent. Antineutrophil cytoplasmic antibodies ANCA are a useful marker for diagnosis. Wegener \200 \231s granulomatosis is associated with ANCA directed against PR3 (PR3-ANCA), giving a gran ular cytoplasmic staining pattern on indirect immuno \202 uorescence (IIF). Combining IIF and ELISA is highly sensitive (>95%) and speci \201 c (>99%) in patients with active syste mic disease. Microscopic polyangiitis is associated with ANCA directed against MPO (MPO-ANC A) in 70% of patients, but PR3- ANCA can also occur. MPO-ANCA give a perinuclear staining p attern on IIF. The positive predictive value of a positive test for ANCA is dependent on th e clinical situation. \200 Maintenance therapy: Wegener \200\231s granulomatosis and microscopic polyangiitis Cyclopho sphamide should be discontinued after remission is achieved, usually after 3 \200\2236 mont hs of treatment. Wegener \200\231s granulomatosis: 85 \200\22390% ANCA positive in systemic disease, 73% PR3 -ANCA or cANCA. Microscopic polyangiitis: 85 \200\22390% ANCA positive, 67% MPO-ANCA or pAN CA. CHAPTER 4.5 Systemic vasculitis 171 Table 4.5.2 Differential diagnosis of pulmonary \200\223renal syndrome Disease Vasculitis Granuloma ANCA status Features Present Present PR3-ANCA See text. Wegener \200\231s granulomatosis Primary small vessel vasculitis is the most common cause of pulmonary renal syndrome ( 56% of cases). Present Absent MPO-ANCA Microscopic polyangiitis Present Present MPO-ANCA (50%) See text. Churg \200\223Strauss syndrome Present Absent Seldom positive (10 \200\22338%) Linear IgG deposition on glomerular basement membrane. Goodpasture \200\231s disease Antiglomerular basement membrane antibody positive. In patients with ANCA, treatment should be as for primary small vessel vasculitis; prognosi s may be better than in those with antiglomerular basement membrane antibody alone. Present Absent Seldom positive Antinuclear factor and anti-dsDNA positive. Systemic lupus erythematosus Low C3 and C4. Present Absent Negative Lung involvement uncommon. Henoch \200\223Sch nlein purpura IgA deposition in vessel walls and mesangium. Present Absent Negative Diagnosed on clinical criteria. Beh et \200\231s disease Associated with recurrent oral and genital ulceration, eye lesions (including uveitis) and skin lesions; renal involvement usually mild. Absent Negative Pneumonia may be associated with acute tubular necrosis or interstitial nephritis (rarely). Subacute bacterial endocarditis may be associated with ANCA-negative pauci-immune glomerul onephritis. Rarely present (e.g. subacute bacterial endocarditis) Infection Post-streptococcal glomerulonephritis. Blood cultures, atypical serology and antistreptolysin-O titre should be undertaken. Rescue therapy for relapsing and refractory disease Standard induction therapy fails to ind uce remission in 10% of patients; patients who frequently relapse necessitating recurrent u se of cyclophosphamide are also a dif \201 cult group to treat. Newer therapies that may p rove bene \201 cial include B-cell depletion with rituximab, polyclonal antithymocyte glob u- lin, deoxyspergualin and other newer immunosuppressant drugs that have shown promise in organ transplantation or other autoimmune diseases. Patients should be maintained on immunosuppres- sion therapy following remission to reduce the risk of relapse, e.g. azathioprine. The optimum duration of maintenance therapy is unkn own, but it should continue for \211 24 months following the induc- tion of remission. Cot rimoxazole may reduce upper respiratory tract relapses in Wegener \200\231s granulomatosis but it is not a substi- tute for conventional immunosuppression. Methotrexate may be used a s maintenance therapy in those with limited disease. It is contraindicated in those with cr eatinine >170 mol/L. Mycophenolate may be used as maintenance therapy in those who have c ontraindications to azathioprine or who have a disease relapse while on azathioprine. Churg \200\223Strauss syndrome Steroids are the mainstay of treatment; however, in those wi th more severe disease an induction maintenance regi- men as for Wegener \200\231s granulom atosis or microscopic poly- angiitis should be used. Disease severity can be assessed using the \201 ve factor score, 1 point for each: \200 \200 \200 \200 \200 creatinine >140 mol/l; proteinuria >1 g/day; severe GI involvement; cardiomyopathy; CNS s igns. Table 4.5.3 Disease strati \201 cation Typical Constitu- Clinical ANCA tional subgroup sta tus symptoms Serum creatinine ( mol/L) <150 Threatened vital organ function Yes Positive or negative No Localized/ early systemic Cyclophosphamide improves survival in those with a \201 ve- factor score of >2. Side-effects of therapy \200 Corticosteroids: Diabetes, hypertension, gastritis, osteopor osis, mood disturbance, and infection. Generalized Yes Positive Yes <500 Yes Positive Yes >500 Severe L.HARPER 172 Table 4.5.4 Management of primary small vessel vasculitis Continued for 3 months following remission. Prednisolone 1 mg/kg, maximum dose 80 mg; rapid reduction in corticosteroid dose: 50% over 2 weeks and to a dose of 0.25 mg/kg at week 8. Cyclophosphamide, 2 mg/kg/day PO, maximum dose 200 mg; age >60 years reduce by 25%, age >70 years reduce by 50%. Pulsed cyclophosphamide can also be given: 10 pulses over 25 weeks, 1 5 mg/kg IV; dose reductions must be made for age and creatinine. (See http://www.vasculitis .org/protocols/CYCLOPS.pdf for suggested dose reduction.) Induction therapy Methotrexate 20 \200\22325 mg/week. Limited disease Reducing dose of corticosteroid (Table 4.5.5). May be at expense of increased relapse rate compared with cyclophosphamide. Life-threatenin g disease includes creatinine >500 mol/L and/or pulmonary hemorrhage. Plasma exchange sho uld be considered. Adjuvant therapy for life- threatening disease Prednisolone 5 \200\22310 mg/day. Maintenance therapy Azathioprine 1.5 mg/kg/day, maximum dose 200 mg. Methotrexate 20 \200\22325 mg/week (contraindicated in patients with creatinine >170 mol/ L). Alternatives to azathioprine include mycophenolate mofetil, 1 g bd. Consider addition of cotrimoxazole. Major relapse: return to initial induction therapy. Relapse therapy Minor relapse: increase corticosteroid dose. Check the FBC between days 10 and 14 after a pulse. If the leukocyte nadir is <3 \227 109/ L, even if the WCC just before to the next pulse is >4 \227 109/L, reduce the dose of the next pulse according to: leukocyte nadir 1 \200\2232 \227 109/L reduce cyclophosphamide pu lse by 40% of previous dose. leukocyte nadir 2 \200\2233 \227 109/L reduce cyclophosphamid e pulse by 20% of previous dose. Counsel for the risks of infertility and consider gamete s torage.