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. Prevent gastritis with an H2-blocker or proton pump inhibitor. Consider bone prophylaxis (c alcium and vitamin D, or bisphosphonates). Consider TB prophylaxis in those at risk as sugg ested by British Thoracic Guidelines (http://www.brit-thoracic. org.uk/AntiTNFaTreatmentGui dline). Patients should receive pneumococcal and in \202 uenza vac- cines but avoid all li ve vaccines until immunosuppression is discontinued. Cyclophosphamide: Infertility, opportu nistic infection, bone marrow suppres- sion, hemorrhagic cystitis, bladder cancer, lymphoma . Monitor for leukopenia regularly. If continuous oral cyclophosphamide is administered: ch eck the white cell count (WCC) weekly for the \201 rst month, 2- weekly for the second an d third month, and then monthly thereafter. If the WCC falls to <4 \227 109/L cyclophospha mide should be discontinued temporarily. Restart with a dose reduced by \211 25 mg/day whe n WCC has recovered, thereafter monitor weekly for 4 weeks. If neutropenia is severe (<1 \227 109/L) or leukopenia is prolonged (total WCC <4 \227 109/L for >2 weeks) then restart cyclophosphamide at 50 mg/day (when the WCC has recovered), increasing to target dose week ly if the WCC permits. For a falling WCC (<6 \227 109/L and a fall of >2 \227 109/L from the previous count), reduce the dose by 25%. If pulsed cyclophosphamide is administered: ch eck the FBC on the day of the pulse or the day before. If the WCC prior to the pulse is <4 \227 109/L, postpone the pulse until the WCC is >4 \227 109/L (check the FBC weekly). Red uce the dose of the pulse by 25%. With any further episodes of leukopenia make an equiv- al ent dose reduction. Table 4.5.5 Suggested algorithm for reduction of prednisolone Prednisolone dosage (mg/kg/day) Prednisolone dosage (mg/day for 60 kg person) Time from diagnosis (weeks) 0 1 60 1 0.75 45 2 0.5 30 3 0.4 25 4 0.4 25 6 0.33 20 8 0.25 15 Prednisolone dosage (mg/day) 12 15 15 16 12.5 12.5 6 months 10 10 During months 12 \200\22315 7.5 7.5 >15 months 5 5 Based on EUVAS trials: www.vasculitis.org/comptrials.htm CHAPTER 4.5 Systemic vasculitis 173 Polyarteritis nodosa (PAN) PAN typically affects medium-sized arteries but not veins and is characterized by transmural in \202 ammation. The incidence is 4 \200\2239 pmp in Europe, which rises with age, peaking in the 6th decade. The cause in most cases is unknown but 30 % are associ- ated with hepatitis B virus (HBV) infection, typically occur- ring early (wit hin 1 year of infection), and occasionally in association with hairy cell leukemia. Consider prophylaxis for Pneumocystis jiroveci (previ- ously known as Pneumocystis carinii) with cotrimoxazole (Septrin) or dapsone and for Candida with amphotericin lozenges. Consid er co-administration of mesna, which binds the cyclophosphamide metabolite acrolein that is toxic to the uroepithelium, to reduce risk of hemorrhagic cystitis. Patients should be enc ouraged to drink unless \202 uid- restricted. In those receiving continuous therapy, cycl o- phosphamide should not be given last thing at night. Regular urinalysis should be perfor med and unexplained microscopic or macroscopic hematuria should precipi- tate cystoscopy to exclude bladder cancer. Clinical features PAN typically presents with systemic features: Kidney disease: this is th e most commonly affected organ. It is associated with chronic renal failure, an inactive ur inary sediment, mild \200\223moderate proteinuria, and hyper- tension. Neurologic disease: mononeuritis multiplex occurs most commonly, but PAN may cause ischemic or hemorrhagic stro ke in up to 10% of patients. Gastrointestinal disease: weight loss and abdominal pain (whic h may be most prominent after meals) are typical. The disease may lead to frank bowel ische mia and perfora- tion. It affects the small bowel more often than the large bowel. Skin: li vedo reticularis, ulcers, tender erythematous nod- ules. It may cause myocardial ischemia a lthough infarction is rare. Orchitis. Azathioprine: Bone marrow suppression, infection, cutaneous malig- nancy, liver dysfunction. Monitor the WCC weekly for 6 weeks then 2- and 4-weekly after any dose adjustment. There is a risk of m arrow suppression, particularly in those with thiopu- rine methyltransferase enzyme de \201 ciency. Monitor liver function monthly until the dose is stable. Assessment and monitoring of disease activity ANCA-associated vasculitides are relapsing co nditions; 50% of patients will relapse within 5 years of diagnosis. The risk of relapse is increased if patients: \200 \200 \200 \200 remain ANCA positive despite disease remission; are PR3-ANCA positive; have Wegener \200 \231s granulomatosis; have lung or upper respiratory tract involvement. Diagnosis Mesenteric or renal arteriography demonstrates multiple aneurysms and irregular c onstrictions in larger vessels with occlusion of smaller penetrating arteries. PAN is not a ssociated with ANCA. Indicators of relapse: \200 rising ANCA levels or reappearance of ANCA; however, the positive predictive value of a ris ing ANCA titer is not suf \201 cient to alter immunosuppressive therapy; raised in \202 a mmatory markers. Treatment Steroids are the mainstay of treatment in idiopathic PAN; however, as in Churg \200\223Strauss syndrome cyclophosphamide should be added in those with a \201 ve-factor score >2. Those with severe PAN should receive pulses of cyclo- phosphamide (0.6 g/m2 month ly) for 1 year. In those with HBV infection, treatment should include a short course of ste roids initially (2 weeks), plasma exchange and antiviral therapy such as lamivudine. PAN re lapses infrequently. Relapse is usually milder than the initial presentation. Monitoring Patients should be seen regularly to assess disease activity; the intensity of c linic visits will be dependent on disease phase (at least monthly until disease remission i s achieved, 2 \200\2233-monthly for \201 rst 12 months following remission, and 3 \200 \2236-monthly thereafter). Investigations at each clinic visit should include: \200 \200 \200 \200 ANCA. CRP and/or ESR. Urinalysis. Assessment of renal function. Takayasu \200\231s disease This is a chronic inflammatory condition of unknown etiology tha t results in a granulomatous arteritis, with marked intimal proliferation and \201 brosis of the media and adventitia. This causes arterial stenosis, occlusion, and occasionally po st- stenotic dilations and aneurysms when the media is destroyed. The disease typically aff ects the aorta and its main branches and may include the pulmonary vessels in 50 \200\22380 % of patients. It preferentially affects young Asian women, although the incidence in older patients may be rising. In middle- aged patients chronic vasculitis latently progresses wi th atherosclerosis. Clinicians should maintain a high index of suspicion for both disease relapse and the side- effects of therapy. Prognosis Survival is 70 \200\22380% at 5 years and is dependent on renal involvement. Earl y mortality often results from opportunistic infection. Poor prognostic indicators include greater age, pulmonary hemorrhage and severe renal disease. End-stage renal disease occurs in 20 \200\22325% of patients. With improved survival, long-term damage from disease and dr ug toxicity is associated with signi \201 cant morbidity. L.HARPER 174 require revascularization using bypass grafting. However, 20 \200\22330% of grafts re-steno se. Lesions are often not amenable to angioplasty, and re-sten- ose more often following an gioplasty and stenting than grafting. Regrafting of renal arteries may reduce blood pressur e. Sildena \201 l may be useful for ischemic symptoms such as dig- ital ischemia. Treatmen t should also include strict management of the traditional cardiovascular risk factors. The prevalence is reported as 2.6 pmp in Caucasians and 1 per 3000 in Japan. Clinical features There is a classic triphasic pattern of disease expression, with an early prepulseless phase with systemic features, a vascular in \202 ammatory phase, and a quies cent occlusive phase. However, disease is recurrent and different phases may coexist. Syste mic symptoms, weight loss, fever, fatigue are common in the early phase. Vascular symptoms are rare at onset but 98% will develop stenosis or occlusion causing ischemic symptoms, suc h as limb claudication, angina, stroke, vertebrobasilar insuf \201 - ciency, and/or subcla vian steal syndrome. 27% of patients will develop aneurysms. Development of collateral circ ulations may minimize some ischemic symptoms. There is often reduced blood pressure in one or more limbs. Vascular bruits are present, especially in the subclavian and abdominal arte ries. 50% develop renovascular hypertension which may be associated with renal failure and congestive cardiac failure. Aortic regurgitation is common particularly if the ascend- ing aorta is involved. Prognosis Sustained remission is uncommon. At least 75% of patients will relapse following steroid taper despite use of other immunosuppressants. Patients tend to have considerable m orbidity due to the chronic vascular damage. Further reading Chan AT, Flossman O, Mukhtyar C, Jayne DR, Luqmani RA. The role of biologic therapies in the management of systemic vasculitis. Autoimmune Rev 2006; 5: 273 \200\22327 8. Guillevin L, Cohen P, Mahr A, Arene JP, Mouthon L, Puechal X, et al. Treatment of polyarter itis nodosa and microscopic polyangiitis with poor prognosis factors: a prospective trial c omparing gluco- corticoids and six or twelve cyclophosphamide pulses in 65 patients. Arthri tis Rheum 2003; 49: 93 \200\223100. Guillevin L, Mahr A, Callard P, Pagnoux C, Leray E, Cohen P. Hepatitis B. Virus-associated polyarteritis nodosa: clinical char- acteristics, outcome and impact of treatment in 115 pa tients. French Vasculitis Study Group. Medicine (Baltimore) 2005; 84: 313 \200\223322. Diagnosis Acute phase proteins may be elevated in the early phase and fall in response to t herapy but they do not always cor- relate with disease activity. Anemia of chronic disease is typical. Autoantibodies are negative although antiendothelial cell antibodies may be pos itive. Angiography should be performed for diagnosis. MR angi- ography has advantages over conventional angiography as it may provide information on active inflammation. Gadolinium e nhancement of vessel walls is thought to be indicative of edema associated with active in \202 ammation. Late phase \201 ndings include stenosis, typically of the proxi- mal porti on of vessels. Occlusions commonly are abrupt, often with abrupt change to collateral vesse ls and \202 ame- shaped terminations. The disadvantages of MRA are that it may overestima te the degree of stenosis, and it is poor at demonstrating vascular calci \201 cation. Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Limitations of therapy and a guarded prognosi s in an American cohort of Takayasu arteritis patients. Arthritis Rheum 2007; 56: 1000 \200 \2231009. Morgan MD, Harper L, Williams J, Savage C. Anti-neutrophil cyto- plasm associated vasculitis. J Am Soc Nephrol 2006; 17: 1224 \200\2231234. Internet resources European Vasculitis Study Group (EUVAS) website: www.vasculitis.org/comptrials.htm Paper describing steroid taper protocol: http://www.vasculitis.org/protocols/CYCLOPS.pdf National Kidney Federation vasculitis infor mation: http://www.kidney.org.uk/Medical-Info/kidney-disease/ vasc.html Cochrane Collaborat ion review of Treatment for renal vasculitis and Goodpasture \200\231s disease in adults: Treatment Steroids are the mainstay of treatment but 50% of patients will relapse during th e steroid taper requiring additional use of immunosuppressants. There are no randomized con trolled trials to guide therapy. Responses have been seen with methotrexate, azathio- prine and other immunosuppressants. Anti-TNF therapy may be bene \201 cial in cases that are re sist- ant to these therapies. Stenotic lesions are not reversible with immunosuppres- sant therapy. Hemodynamically signi \201 cant stenosis may http://www.cochrane.org/reviews/en/info_ 001400081113510954.html The Stuart Strange Vasculi tis Trust. Patient support group in the UK: http://www.vasculitis-uk.org.uk/ See also Urinalysis and microscopy, p. 8 Immunological investigation of renal disease, p. 3 6 Proteinuria and/or hematuria, p. 76 Crescentic glomerulonephritis, p. 120 Infection-relat ed glomerulonephritis, p. 128 This page intentionally left blank P. TOPHAM 176 Mixed cryoglobulinemia and hepatitis C infection \200 Cryoglobulins (CG) are immunoglobulins that precipitate from both serum and plasma at tempe ratures <37 C and dissolve on rewarming. Cryoglobulinemia refers to the presence of a CG i n the blood, although often the term is used to describe the clinical syndrome that results from the presence of CG. Cryoglobulinemia is commonly asymptomatic but may lead to feature s of hyperviscosity or systemic vasculitis. formation of immune complexes; defective immune complex clearance, leading to accu- mulatio n and disease induction. Mechanism of cryoprecipitation The mechanism of cryoprecipitation is not well under- stood. A number of factors that appear to be important for aggregation have been identi \201 ed: Antibody \200\223antigen interaction-dependent mechanisms. \200 \200 Rheumatoid factor activity appears to be important. The individual components of CGs do not interact or aggregate. Intrinsic properties of the target antibody/antigen are critical si nce cryoprecipitation is optimal when the iso- lated RhF component is mixed with IgG isolat ed from the same patient, but not when mixed with IgG from normal serum. IgG3 is enriched i n precipitates and anti-IgG3 RhF activ- ity is prevalent in CGs. IgG3 is more able to self- aggre- gate via Fc \200\223Fc interactions than other IgG subclasses. Fibronectin is invari ably found in cryoprecipitates and IgM RhF found in CGs has strong af \201 nity for immobi lized \201 bronectin. Cryoglobulin classi \201 cation Type I These are comprised of monoclonal immunoglobulin (u su- ally IgG or IgM) and account for 5 \200\22325% of cases. It usually results from plasma cell dyscrasias (usually Waldenstr m \200\231s macroglobulinemia and multiple myeloma) bu t can also rarely be associated with connective tissue diseases. Type II These are comprised of polyclonal IgG and a monoclonal IgM directed against the IgG (i.e. IgM rheumatoid factor (RhF)), and account for 40 \200\22360% of cases. This is also known as essential mixed cryoglobulinemia although it is now recognized that most cases are due to persistent viral infection (typically with hepatitis C virus (HCV), although can al so be seen with HIV, hepatitis B virus (HBV) and Epstein \200\223Barr virus (EBV)). It can also be associated with chronic lymphocytic leukemia, and B-cell lymphoma. Immunoglobulin-dependent mechanisms. \200 Some CGs do not have RhF activity (usually type I CGs). In these cases the intrinsic physic ochemical properties of the immunoglobulin molecule determine its cryopre- cipitability. Th e absence of sialic acid moieties has been described. Overall changes in physicochemical pr operties that render the immunoglobulin more hydrophobic increase cryoprecipitability. \200 Type III These are comprised of polyclonal IgG and a polyclonal IgM rheumatoid factor, and account for 40 \200\22350% of cases. Up to half of cases are due to HCV infection but it ca n also result from other infections (HBV, EBV, endocarditis, schis- tosomiasis etc.), chron ic in \202 ammatory conditions (e.g. sys- temic lupus erythematosus, rheumatoid arthritis) , and lymphoproliferative disorders. Occasionally CGs are identi \201 ed that do not \201 t into either the type II or type III classi \201 cation. It is thought that these re present a transition from type III to type II (i.e. polyclonal to monoclonal transformation ). 60 \200\22375% of cryoglobulinemic patients have an identi \201 able underlying cause ( connective tissue disease, lymphoprolif- erative disease, infection, hepatobiliary disease) and are known as secondary cryoglobulinemia. When an underly- ing cause is not identi \201 able, the term essential mixed cry- oglobulinemia is used. Type I cryoglobulinemia This results from an underlying lymphoproliferative disor- der that produces high levels of monoclonal immunoglob- ulin that, due to its physicochemical prope rties, has CG activity. Clinically these cold-induced precipitates can induce vasculitis bu t more usually result in problems related to hyperviscosity. Type II and III cryoglobulinemia Mixed CGs result from the chronic activation and prolif- e ration of CG-producing B-cell clones by chronic in \202 am- matory disease and chronic vir al infection, particularly HCV infection. The mechanism of CG production has been best desc ribed in HCV infection. Epidemiology Clinically signi \201 cant cryoglobulinemia is found in 1 per 100 000 of the general population. In speci \201 c groups CGs can be detected in a signi \201 cant pro- portion (2 \200\22315% in patients with HIV infection; 15 \200\22325% of patients with con nective tissue diseases; 40 \200\22350% of patients with HCV infection). Hepatitis C virus and cryoglobulinemia There is now convincing evidence of a role for HCV i n the production of B-cell clonal expansion and mixed CG pro- duction. HCV-related CG usual ly contains IgM monoclonal anti- body that associates with anti-HCV IgG. HCV RNA can also be identi \201 ed in the cryoprecipitates. B-cell stimulation may occur either by direct engagement of B-cell CD81 by HCV, or via chronic stimulation by anti- HCV \200\223HCV virio n complexes. Etiology and pathogenesis Clinically signi \201 cant cryoglobulinemia results from several events: \200 chronic immune stimulation or lymphoproliferation resulting in production of CG; CHAPTER 4.6 Mixed cryoglobulinemia and hepatitis C infection 177 Clinical features The majority of patients with circulating CGs are probably asymptomatic. The clinical manifestations are often dependent on the underlying type of CG that is presen t. It usually develops after a systemic prodrome, but can be the presenting manifestation of d isease in a minority of patients. More than 50% have proteinuria and/or hematuria. 20% have nephrotic syndrome. 20% have an acute nephritic syndrome. 10% present with acute oliguric renal failure. 50% are hypertensive, and this may be malignant and asso- ciated with acute renal dysfunction. Type I cryoglobulinemia Symptomatic patients usually present with hyperviscosity- related p roblems (neurological symptoms of blurring or loss of vision, headache, vertigo, nystagmus, dizziness, sud- den deafness, diplopia, ataxia, confusion, and signs of Raynaud \200\231s phenomenon, digital ischemia, livedo reticularis and purpura). Other manifestations A variety of other symptoms/signs can be identi \201 ed. Raynaud \200 \231s phenomenon is seen in 50% of patients (usually associated with connective tissue dise ases). Sj gren \200\231s syndrome is seen in up to 20%. Hepatomegaly and/or abnormal liver function tests in up to 90%. Lymphadenopathy in 20%. Splenomegaly in up to 50%. Vasculitic involvement of the heart, central nervous sys- tem, and eye is very uncommon. Type II and III cryoglobulinemia This typically presents with features related to systemic vasculitis. Common symptoms and signs are palpable purpura (most common sign), arthralgias, myalgia, fatigue, and numbness and weakness related to peripheral neuropathy. These sympto ms often are present for several years before a diagnosis is made and over this time it is common for the symptoms to spontaneously wax and wane. Cutaneous Purpura is the commonest cutaneous manifestation (present in 90% of patients). I t usually occurs on the extremities, less commonly on the buttocks and trunk, and very rare ly on the face. Skin biopsy usually demonstrates a leukocytoclastic vascu- litis. Other les s common skin manifestations include an urticarial rash due to venulitis, a deep cutaneous vas- culitis leading to necrotic lesions, and digital ischemia/ gangrene. Investigation The following investigations should be undertaken when CG-related disease is suspected. Cryoglobulins. The identi \201 cation of a CG is clearly of fundamental impor- tance. The detection of a CG requires care in blood sample col- lection, transportation, and processin g. Blood must be collected into prewarmed syringes and bot- tles, and then transported to t he laboratory at 37 C. The serum is separated by centrifugation at 37 C. The serum is tra nsferred to a graduated tube and placed at 4 C for 5 days. The serum is centrifuged and th e volume of the precipitate is reported as a percentage of the serum volume (cry- ocrit). T he precipitate is then rewarmed (it should redissolve) and then subjected to further invest igation (e.g. immun- o \201 xation, ELISA) to determine the concentration and con- stituen ts of the CG. False-negative results can be caused by mishandling of the sample. If it cool s at any time before serum separation, the CG may be lost. A negative result therefore need s to be interpreted in the clinical context, and repeat testing with appropriate sample han dling may be necessary. Cryocrits vary between 1 and 70% (higher values typically seen with type I cryoglobulinemia). There is poor correlation between the cryocrit and the severity of clinical disease. Musculoskeletal Arthralgia is present in >70% of patients. It is typically symmetrical and involves knees, hips, shoul- ders, metacarpophalangeal, and proximal interphalangeal joints . Arthritis is uncommon. Exacerbation in cold conditions is described by some patients. Neuropathy Symptomatic neuropathy is seen in up to 40% of patients. Subclinical disease can be detected in up to 80% of patients by electrophysiological studies. Neuropathy may be mo re common in non-HCV-related disease. Pulmonary 40 \200\22350% of patients will have respiratory symptoms (cough, dyspnea, pleuri tic pain). Severe pulmonary disease with bronchiolitis obliterans organizing pneumonia (BOO P), lung hemorrhage, pulmo- nary vasculitis is uncommon but can seen when patients present with fulminant CG-related disease. Complements Type I disease usually leads to no complement abnormality. Type II and III dise ase is associated with reduced C1q, C4 and CH50. C3 is usually unaffected. Autoantibodies Renal This usually results from immune complex deposition in type II and III disease, or fr om hyperviscosity in type I disease. Up to 60% of patients will have renal disease. Rheumatoid factor is typically present in type II and III disease. P. TOPHAM 178 Antinuclear antibodies with multiple specificities (e.g. smooth muscle, microsomal, Ro, La, Sm, mitochondrial) are often present re \202 ecting the association with connective tissu e diseases. Viral studies Serological studies for HCV, HBV, HIV, and EBV, should be undertaken. Other investigations If a lymphoproliferative disorder is suspected, bone mar- row biopsy, CT scanning for lymphadenopathy, and lymph node biopsy may be necessary. Histology In the evaluation of patients with cryoglobulinemia, biopsy of an affected organ is appropriate. This may be skin, peripheral nerve, or kidney (in those with abnormal uri- nalysis or renal function). Fig. 4.6.1 Methanamine-silver-stained glomerulus showing hyaline deposits in capillaries an d in the subendothelial compartment. Arrows indicate the position of the glomerular basemen t membrane. Endocapillary proliferation is also visible. (Courtesy of Dr Nick Mayer, Univer sity of Leicester Hospitals, UK.) Renal biopsy In patients with type II or III cryoglobulinemia, the histo- logical appearanc es are usually those of mesangiocapillary glomerulonephritis (MCGN) type I. Endocapillary p rolifer- ation is invariable and in two-thirds GBM thickening/redu- plication is seen. Less commonly a focal and segmental pattern of injury, or mesangial proliferative GN can be see n. Findings that differentiate cryoglobulinemic GN from idio- pathic MCGN are: \200 Corticosteroids and cyclophosphamide can be used for nonmalignancy-associated type I diseas e during acute \202 ares. Types II and III cryoglobulinemia Mild symptoms (arthralgias, myalgia, fatigue) without evi - dence of end-organ damage can be treated conservatively with analgesia and cold avoidance . NSAIDs can be helpful, and low-dose corticosteroids can be used in those without symptoma tic relief from NSAIDs. Disease with evidence of end-organ damage requires immunosuppressiv e therapy. hyaline thrombi in the subendothelial space or in capillary lumen (seen in 70% of cases) (F ig. 4.6.1); intense leukocytic (monocyte) in \201 ltration of glomeruli; \201 brinoid ne crosis of extraglomerular arterioles/arteries (seen in up to 30% of cases). \200 Immuno \202 uorescence microscopy demonstrates IgM, IgG and C3 in a granular capillary wal l distribution. Electron microscopy reveals subendothelial and mesangial electron-dense dep osits. These deposits may have an organized substructure ( \200\230fingerprint-like \200 \231 appearance). These are not speci \201 c and can be seen in others situations, e.g. lu pus nephritis. Immunosuppression/plasmapheresis For an acute flare with progressive renal dysfunction, sev ere neuropathy, or necrosis of extremities, the following regimen may be used: \200 IV methylprednisolone 1 g/day for 3 days then 60 mg prednisolone/day followed by a slow tap er over 2 \200\2233 months. Cyclophosphamide 2 mg/kg/day orally for 2 months. Plasmapheresi s: 1 plasma volume exchange on alternate days for 2 \200\2233 weeks. Alternatively, cryo \201 ltration (double \201 ltration plasmapheresis with a cooling unit on the sec- ond \201 lter) can be used in order to selectively remove the CG. Management The optimal management of CG-related disease has not been well-de \201 ned. The disease tends to follow a relapsing and remitting pat- tern. Data suggest that prolonged i mmunosuppression has no effect on the risk of developing progressive renal dys- function; t herefore such treatment is usually reserved for acute \202 ares. Treatment of the underly ing disease process (i.e. lympho- proliferative disorder, viral disease, connective tissue dis- ease) is important, however. The general management principles for patients with glome rular disease should be adopted, i.e. blood pressure control, treatment of hyperlipidemia, and reduction of pro- teinuria using renin \200\223angiotensin system inhibition. \200 Improved renal function can be seen in 50 \200\22380% of patients with this regimen. Monito ring of the cryocrit is not necessarily helpful given the poor correlation between the cryo crit and the severity of disease. Therefore the length of the course of plas- mapheresis is determined by the clinical response. Immunosuppression may theoretically be complicated by enhanced replication of underlying HCV, and exacerbation of low-grade non-Hodgkin lymphoma (in addition to the conventional risks of treatment, i.e. infection, bone marrow suppressi on, late malignancy, etc.). Type I cryoglobulinemia Chemotherapy (and radiotherapy) for the underlying lymphoproliferat ive disease is required. CHAPTER 4.6 Mixed cryoglobulinemia and hepatitis C infection 179 Antiviral therapy For HCV-related disease, antiviral therapy is appropriate. Antiviral trea tment should be delayed for 3 \200\2234 months after an acute \202 are that requires immu nosuppressive treatment. The treatment of choice is a combination of: \200 \200 Approximately 5 \200\22310% of patients with type II cryoglob- ulinemia develop a lymphopro liferative disorder (usually B-cell non-Hodgkin lymphoma), usually 5 \200\22310 years after diagnosis. This risk is 35 times higher than that of the gen- eral population. Risk factor s for a poor outcome are: renal failure, infection, hypertension, and four or more extra-re nal manifesta- tions. Pegylated interferon-A 1 g/kg weekly for 48 weeks. Ribavirin 1000 mg/day for 48 weeks. This regimen should not be used in those with a GFR <50 mL/min (ribavirin is contraindicate d and the prolonged half-life of pegylated interferon-A in this setting raises con- cerns a bout its use). For those with renal impairment, nonpegylated interferon- A can be used alon e. The optimal dose is unclear but inter- feron-A 3 million units 3 times a week for 12 mon ths has been used with success. This regimen is less effective than combination therapy, bu t can lead to a virological and clinical response in 60% of patients. Cessation of treatmen t almost invariably results in viral relapse. HCV-related renal disease (without cryoglobulinemia) HCV infection can also cause MCGN type I without evi- dence of CG production. It has also been associated with membranous nephrop athy in some patients. In both conditions if there is evidence of severe, progressive glome rular disease (i.e. severe nephrosis, progressive renal function decline), antiviral therap y (as described above) should be considered (although in membranous nephropa- thy a causal role for HCV has not been established). Further reading Braun GS, Horster S, Wagner KS, Ihrler S, Schmid H. Cryoglobulinaemic vascu litis: classi \201 cation and clinical and thera- peutic aspects. Postgrad Med J 2007; 83: 87 \200\22394. Other treatments Rituximab (monoclonal anti-CD20 antibody) has been evaluated in small stud ies with apparent clinical success, although at the expense of increased HCV RNA levels. It s role remains to be determined but it can be considered in patients who do not respond to the treatments described above. Fabrizi F, Colucci P, Ponticelli C, Locatelli F. Kidney and liver involve- ment in cryoglobulinemia. Semin Nephrol 2002; 22: 309 \200\223318. Kamar N, Rostaing L, Alric L. Treatment of hepatitis C-virus-related glomerulonephritis. Kidney Int 2006; 69: 436 \200\223439. Meyers CM, Seeff LB, Stehman-Breen CO, Hoofnagle JH. Hepatitis C and renal disease: an upda te. Am J Kidney Dis 2003; 42: 631 \200\223657. Dialysis and renal transplantation The outcome on hemodialysis or peritoneal dialysis is si milar to that seen in the matched dialysis population. Renal transplantation should not be precluded in patients with CG-related disease even though 50 \200\22370% of renal allo- gra ft recipients develop clinically signi \201 cant disease. This is not usually a cause of g raft failure. The transplant immunosuppression appears to have no clinically signi \201 ca nt effect on HCV replication. Internet resources Review article about cryoglobulinemia: http://www.kidneyatlas.org/book4/adk4-09.pdf See also Immunological investigation of the patient with renal disease, p. 36 Proteinuria a nd/or hematuria, p. 76 Nephrotic syndrome, p. 80 Mesangiocapillary glomerulonephritis, p. 1 12 Infection-related glomerulonephritis, p. 128 Prognosis Overall survival at 10 years after symptom onset and time of diagnosis is 70% and 50% respectively. Death is usually due to liver disease, cardiovascular disease or infecti on. The risk of developing renal failure appears to be highest in those with HCV-related di sease (up to 40%). D. JAYNE 180 Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is the most common multisystem autoimmune disease. It ha s variable presentations and outcomes and can poten- tially be fatal. Kidney involvement is the most frequent severe manifesta- tion and it can lead to end-stage renal disease. Immune complexes such as anti-dsDNA \200\223nucleosome complexes, deposit in tissues and: \200 \200 \200 activate complement; attract in \202 ammatory cells; initiate acute in \202 ammation. Lymphocyte activation There is increased T-cell:B-cell activation and interaction through c o-stimulatory ligands (e.g. CD40:CD40 ligand), antigen presentation, and B-cell-stimulating cytokines (e.g. Blys, APRIL).