Recent advances in the classification and management of ...

Recent advances in the classification and management of ...

Recent advances in the classification and management of pulmonary small vessel vasculitides Dr. Aditya Jindal 5/8/11 The vasculitides are a set of related disorders characterized by blood vessel inflammation leading to tissue or end-organ injury Differentiated from other vascular disorders by

the presence of inflammation of the vessel wall as compared to bland vasculopathy Frankel SK, Jayne D. The Pulmonary Vasculitides. Clin Chest Med 31 (2010) 519536 Classification To understand a name you must be

acquainted with the particular of which it is a name - Bertrand Russel Explanation of terminology used for naming, defining classifying, and diagnosing diseases Frankel SK, Jayne D. The Pulmonary Vasculitides. Clin Chest Med 31 (2010) 519536 ACR classification criteria

Sensitivity 710% - 953% Specificity 787% - 997% Frankel SK, Jayne D. The Pulmonary Vasculitides. Clin Chest Med 31 (2010) 519536 Limitations 1. ANCA developed afterwards 2. No distinction made between poly arteritis nodosa and MPA

3. Evolving diagnostic techniques and pathophysiology has made distinction easier 4. Not intended to be used as diagnostic but as classification criteria Chapel Hill Consensus Conference (CHCC) Held at Chapel Hill, North Carolina Goals To reach consensus on the names for some of the most common forms of noninfectious systemic vasculitis To construct root definitions for the vasculitides so

named Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37:187 Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37:187 Wegeners granulomatosis Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels

(e.g., capillaries, venules, arterioles, and arteries) Necrotizing glomerulonephritis is common Churg-Strauss syndrome Eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels, and associated with asthma and eosinophilia. Microscopic polyangiitis Necrotizing vasculitis, with few or no immune deposits,

affecting small vessels (i.e., capillaries, venules, or arterioles) Necrotizing arteritis involving small and medium sized arteries may be present Necrotizing glomerulonephritis is very common Pulmonary capillaritis often occurs Recognised that histological samples would not be always available Introduced concept of surrogate markers and ANCA Limitations

Neither diagnostic nor classification criteria Sorensen etal tested the CHCC for diagnosis and found that only 8 of 27 patients were diagnosed with Wegeners granulomatosis, and 3 of 12 cases with microscopic polyangiitis Surrogate parameters for vasculitis New diagnostic criteria: Wegeners granulomatosis

1. Biopsy or surrogate parameter for granulomatous inflammation in the respiratory system 2. Biopsy verified necrotising vasculitis in small to medium sized vessels or biopsy/surrogate parameter for glomerulonephritis or positive PR3-ANCA test 3. Lack of eosinophilia in blood and biopsy samples Microscopic polyangiitis 1. Biopsy verified necrotising vasculitis in small vessels and/or glomerulonephritis with few or no immune deposits 2. Involvement of more than one organ system as indicated

by biopsy verified vasculitis in small to medium sized vessels or surrogate parameter for glomerulonephritis 3. Lack of biopsy and surrogate parameter for granulomatous inflammation in the respiratory system Sorensen SF, Slot O, Tvede N, Petersen J. A prospective study of vasculitis patients collected in 5-year period: evaluation of the Chapel Hill nomenclature. Ann Rheum Dis 2000;59:47882. Lane etal evaluated the Sorensen criteria and found that They were not useful for MPA

The exclusion of eosinophilia limited the usefulness of the criteria for WG Lane SE, Watts RA, Barker THW, Scott DGI. Evaluation of the Sorensen diagnostic criteria in the classification of systemic vasculitis. Rheumatology 2002;41:113841. An algorithm to classify ANCA associated vasculitis for epidemiological studies was developed that included MPA and incorporated ANCA Known as the EMEA (European Medicine Agency)

algorithm However, this was too cumbersome to use in individual patients Watts R, Lane S, Hanslik T et al. Development and validation of a consensus methodology for the classification of the ANCA associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis 2007; 66:2227 Recent revision of the classification scheme based on 1. The traditional approach of classifying vasculitis by size of predominant vessel involved

2. Diagnostic auto-antibodies (ANCA) 3. Current understanding of pathogenesis Watts RA, Suppiah R,Merkel PA, Luqmani R. Systemic vasculitis is it time to reclassify? Rheumatology 2011;50:643-645 Diagnostic and Classification criteria in Vasculitis (DCVAS) A major international effort to use data-driven methods to develop A revised single classification system for the vasculitides A validated set of diagnostic criteria for the vasculitides in

accordance with standards established by the ACR and the European League Against Rheumatism (EULAR) NCT01066208 Started in Feburary 2010 and expected to be complete by July 2012 Granulomatosis with polyangiitis (Wegeners) The term Wegeners granulomatosis was introduced into the Englishlanguage literature by Drs Godman and Churg in 1954 Godman GC, Churg J. Wegeners gra ulomatosis: pathology and review of the literature. AMA Arch Pathol 1954;58:53353.

The name change was triggered by evidence that Dr Friedrich Wegener was a memberof the Nazi party before and during World War II Woywodt A, Haubitz M, Haller H, et al. Wegeners granulomatosis. Lancet 2006; 367:13626 The parenthetical reference to Wegeners will be phased out after several years as the new usage becomes more widely known Falk RJ, Jennette JC. ANCA disease: where is this fi eld heading? J Am Soc Nephrol 2010;21:74552 Falk RJ, Gross WL, Guillevin L et al. Granulomatosis with polyangiitis (Wegeners): an alternative name for Wegeners granulomatosis. A joint proposal of the American College of

Rheumatology, the American Society of Nephrology, and the European League against Rheumatism. Ann Rheum Dis 2011 70: 704 Management Treatment protocols have changed in the last two decades after the first wave of the EUVAS (European vasculitis study group) trials EUVAS criteria are objective disease classification instruments that have been developed to assist the clinician in categorizing disease severity so that

therapies may be appropriately titrated to disease activity and the associated risk of end-organ injury and/ or mortality. Mukhtyar C etal. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009;68:310317. A. Localised disease Refers to isolated upper or lower airway disease and a complete absence of other end organ involvement or constitutional symptoms

Managed with topical therapy, corticosteroids, and/or a single moderate potency cytotoxic agent such as methotrexate or azathioprine B. Early generalised disease Presence of constitutional symptoms and active vasculitis but without any specific threat to organ function Standard therpay Cylophosphamide + steroids NORAM (Non-Renal Alternative with Methotrexate) trial

Compared methotrexate with cyclophosphamide for the induction of remission in early disease Time to remission (5 m vs 3 m) Relapse rate (74% vs 42%) favored cyclophosphamide Methotrexate was better tolerated and had less side affects de Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005;52:2461

MYCYC (Mycophenolate Mofetil Versus Cyclophosphamide for Remission Induction ANCA Associated Vasculitis) trial EUVAS sponsored randomised contolled trial Compares mycophenolate mofetil with cyclophosphamide for the induction of remission Currently underway C. Generalised active disease Presence of constitutional symptoms and threatened organ function caused by vasculitic activity

Oral cyclophosphamide plus steroids standard therapy since the 1970s CYCLOPS (Daily Oral Versus Pulse Cyclophosphamide for Renal Vasculitis) trial 149 patients with newly diagnosed generalized active AAV were randomized to pulse intravenous cyclophosphamide (15 mg/kg every 23 weeks) or daily oral cyclophosphamide (2 mg/kg/d) plus prednisolone No difference in time to remission or proportion of patients who achieved remission (88.1% vs 87.7% at 9

months) Pulse group had a lower rate of leukopenia and received a lower total cumulative dose of cyclophosphamide de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009;150:670 D. Severe disease Presence or threat of immediate organ failure and/or death

Rapidly progressive glomerulonephritis and renal failure (creatinine >5.7 mg/dL) Alveolar hemorrhage associated with respiratory failure Cardiomyopathy with heart failure Life-threatening arrhythmias Central nervous system disease Gastrointestinal disease with bowel schemia or life-threatening hemorrhage Standard treatment Plasma exchange + i/v cyclophophamide + steroids

MEPEX (Plasma Exchange or High-Dosage Methylprednisolone as Adjunctive Therapy for Severe Renal Vasculitis) EUVAS sponsored randomised controlled trial 137 patients with a new diagnosis of AAV and a serum creatinine level greater than 500 mmol/L (5.8 mg/dL) were included All patients received standard therapy with oral cyclophosphamide and oral prednisolone and were then randomized to either 7 plasma exchanges or 3000 mg of

intravenous methylprednisolone At 3m 69% of patients treated with plasma exchange were alive and independent of dialysis compared with only 49% in the methylprednisolone group Jayne DRW, Gaskin G, Rasmussen N, et al. Randomised trial of plasma exchange or high dose methyl prednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 2007; 18:2180 A 20 patient case series showed the efficacy of this

treatment strategy in alveolar hemorrhage also Klemmer PJ, Chalermskulrat W, Reif MS, et al. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small vessel vasculitis. Am J Kidney Dis 2003;42:1149 PEXIVAS (Plasma exchange and glucocorticoid dosing in the treatment of ANCA-associated vasculitis) EUVAS sponsored Largest international multicenter trial in vasculitis to date Will include 500 patients with ANCA-associated vasculitis with glomerular filtration rate of less than 50ml/min or lung

hemorrhage Started in June 2010, E. Refractory disease Disease that does not respond to conventional accepted therapy Investigational or unproven therapies are used 1. Rituximab Targets the CD20 antigen on the surface of B cells and clears circulating B cells from the circulation

Evaluated in two recent trials RAVE (Rituximab in ANCA-Associated Vasculitis) trial Multicenter, randomized, double-blind, double-dummy, noninferiority trial Compared rituximab with standard cytotoxic therapy for the induction of complete remission by 6 months in patients with severe ANCA-associated vasculitis 64% of the patients achieved complete remission compared to 53% in the cyclophosphamide control arm More efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in

the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) (P = 0.01) As effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage No significant differences between the treatment groups with respect to rates of adverse events Stone JH, Merkel PA, Spiera R et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010; 363:22132 RITUXVAS (rituximab versus cyclophosphamide in ANCA

associated vasculitis) trial 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomly assigned, in a 3:1 ratio, to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group) or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group) 76% patients in the rituximab group and 82% patients in the

control group had a sustained remission (P = 0.68) Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P = 0.77) Rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis Sustained-remission rates were high in both groups Rituximab-based regimen was not associated with reductions in early severe adverse events Jones RB, Tervaert JW,Hauser T et al. Rituximab versus

cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010; 363:21120 Further work is still needed before rituximab is integrated into the standardised mangement of vasculitis 2. Other agents a. Infliximab - chimeric IgGk monoclonal antibody against soluble and membrane-bound TNF

Has given positive benefit in small trials b. Anti thymocyte globulin Studied in the EUVAS sponsored SOLUTION trial 15 patients received ATG for refractory vasculitis Partial disease remission was induced in 9/15 and complete disease remission in 4/15 2 patients died after drug administration 1 of pulmonary hemorrhage 1 of infection Serum sickness and nonfatal infections were among the

notable complications Schmitt WH etal. Treatment of refractory Wegener's granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients. Kidney Int. 2004 Apr;65(4):1440-8 c. Intravenous immunoglobulin (IVIg) Studied in small clinical trials

Effect is generally short-lived Most appropriate in acute situations where conventional therapy is contraindicated especially if severe infection is present d. WEGENT (Wegeners Granulomatosis-Entretien) trial 32 induction-refractory (24 WG and 8 MPA) patients were treated with oral CYC in 20 patients, combined with infliximab in 1 15 (75%) achieved remission or low disease activity state, 3 subsequently

died of uncontrolled disease and 2 entered remission using several other agents including biological agents Seror R, Pagnoux C, Ruivard M, et al. Treatment strategies and outcome of induction-refractory Wegeners granulomatosis or microscopic polyangiitis: analysis of 32 patients with first-line induction-refractory disease in the WEGENT trial. Ann Rheum Dis 2010;69:21252130 e. Alemtuzumab f. Deoxyspergualin

F. Remission maintenance Less aggressive regimens are used for maintenance of disease remission CYCAZAREM (Cyclophosphamide versus Azathioprine for Remission in Generalized Vasculitis) trial EUVAS sponsored randomised controlled trial Patients were initially treated with oral cyclophosphamide and oral prednisolone for induction They were then randomised to Either oral cylophosphamide for 12 m followed by azathioprine

Or directly to azathioprine No difference in relapse rates (15.5% in the AZA group and 13.7% in the CYC group) [P 0.65; 95% confidence interval (CI) 9.9 to+13.0%] up to the end of the study at 18 months after treatment outset Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:36. IMPROVE (International Mycophenolate Mofetil to Reduce Outbreaks of Vasculitides trial

EUVAS sponsored Open-label randomized controlled trial Directly compared mycophenolate mofetil with azathioprine for the maintenance of remission in renal vasculitis 156 patients were assigned to azathioprine (n=80) or mycophenolate mofetil (n=76) and followed up for a median of 39 months Relapses were more common in the mycophenolate mofetil group (42/76 patients) compared with the azathioprine group (30/80 patients), with an unadjusted hazard ratio (HR) for mycophenolate

mofetil of 1.69 (95% confidence interval [CI], 1.062.70; P=.03) Severe adverse events did not differ significantly between groups Hiemstra TF, Walsh M, Mahr A, et al; European Vasculitis Study Group (EUVAS). Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA 2010;304(21):23812388 WGET (Wegener Granulomatosis Etanercept Trial)

Concluded that Etanercept has no role Wegeners Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegeners granulomatosis. N Engl J Med 2005;352(4): 351361 REMAIN (Randomized Trial of Prolonged Remission Maintenance Therapy in Systemic Vasculitis ) Ongoing EUVAS trial Will compare 24 months of therapy with 48 months

of therapy Leflunomide A small trial compared leflunomide with methotrexate Showed superiority in the leflunomide arm Metzler C, Miehle N, Manger K, et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegeners granulomatosis. Rheumatology (Oxford) 2007;46:1087

Frankel SK, Jayne D. The Pulmonary Vasculitides. Clin Chest Med 31 (2010) 519536 EULAR recommendations for the management of primary small and medium vessel vasculitis 1. Patients with primary small and medium vessel vasculitis should be managed in collaboration with, or at centres of expertise 2. ANCA testing (including indirect immunofluorescence and ELISA) should be performed in the appropriate clinical context 3. A positive biopsy is strongly supportive of vasculitis and the procedure is recommended to assist diagnosis and further evaluate patients suspected of having vasculitis

4. A structured clinical assessment, urine analysis and other basic laboratory tests at each clinical visit for patients with vasculitis should be done 5. Patients with ANCA-associated vasculitis should be categorised according to different levels of severity to assist treatment decisions 6. A combination of cyclophosphamide (intravenous or oral) and glucocorticoids is recommended for remission induction of generalised primary small and medium vessel vasculitis 7. A combination of methotrexate (oral or parenteral) and

glucocorticoid as a less toxic alternative to cyclophosphamide for the induction of remission in non-organ threatening or non-life threatening ANCA-associated vasculitis is recommended 8. The use of high-dose glucocorticoids as an important part of remission induction therapy is recommended 9. Plasma exchange for selected patients with rapidly progressive severe renal disease in order to improve renal survival is recommended 10.Remission-maintenance therapy with a combination of low-dose

glucocorticoid therapy and, either azathioprine, leflunomide or methotrexate is recommended 11.Alternative immunomodulatory therapy choices should be considered for patients who do not achieve remission or relapse on maximal doses of standard therapy: these patients should be referred to an expert centre for further management and enrolment in clinical trials Mukhtyar C etal. EULAR recommendations for the management of primary

small and medium vessel vasculitis. Ann Rheum Dis 2009;68:310317 Additional points Dosage and schedule of cyclophosphamide 15 mg/kg (maximum 1.2 g) iv infusion every 2 weeks for first three doses f/b every 3 weeks for next 3 6 doses Dose adjustment can be made based on creatinine levels Oral prednisolone or prednisone at 1 mg/kg/day is started alongside and maintained for 1 month, and should not be reduced to less than 15 mg/day for the first 3 months then tapered to a maintenance

dose of 10 mg/day or less during remission When a rapid effect is needed, intravenous pulsed methylprednisolone may be used in addition to the oral prednisolone as part of remission induction therapy Remission maintenance therapy should be continued for at least 18 months The addition of trimethoprim/sulphamethoxazole (800/160 mg twice daily) to standard remission maintenance can reduce the risk of relapse in WG Prophylaxis against Pneumocystis jiroveci in all patients

being treated with cyclophosphamide; with trimethoprim/sulphamethoxazole (800/160 mg on alternate days or 400/80 mg daily) is recommended Thromboembolic disease in the setting of AAV The Wegeners Clinical Occurrence of Thrombosis (WeCLOT) study identified that the incidence of thromboembolic disease in patients with WG was 7.0 per 100 person-years, which is the same rate of venous thromboembolic (VTE) disease as for patients with a known prior history of VTE Clinicians should consider patients with AAV to be at higher risk

for VTE Merkel PA, Lo GH, Holbrook JT, et al. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegeners Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann Intern Med 2005; 142:620 Alveolar hemorrhage(AH) Defined as bilateral alveolar infiltrates on radiological imaging without an alternative explanation plus at least one of the following Hemoptysis

Increased carbon monoxide diffusing capacity Bronchoscopic evidence of hemorrhage Unexplained drop in hemoglobin Casian A, Jayne D. Management of Alveolar Hemorrhage in Lung Vasculitides. Semin Respir Crit Care Med 2011;32:335345 Vasculitis was the third most common cause of AH requiring intensive care support (19% of patients), after thrombocytopenia (27%) and sepsis (22%) Rabe C, Appenrodt B, Hoff C, et al. Severe respiratory failure due to diffuse alveolar hemorrhage: clinical characteristics and outcome of intensive care. J Crit Care

2010;25(2): 230235 The majority (80%) of these vasculitis cases with AH are due to ANCA associated vasculitis (AAV) Papiris SA, Manali ED, Kalomenidis I, Kapotsis GE, Karakatsani A, Roussos C. Bench-to-bedside review: pulmonary-renal syndromesan update for the intensivist.. Crit Care 2007;11(3):213

AH is the most common respiratory manifestation of AAV, occurring in 24% 95% of AH due to pauci immune vasculitis are ANCA + Casian A, Jayne D. Management of Alveolar Hemorrhage in Lung Vasculitides. Semin Respir Crit Care Med 2011;32:335345 AH appears similar in the PR3-ANCA and MPO ANCA groups with regard to clinical features and severity of

respiratory failure Mild AH is more common (in 24 to 28% of AAV) 28% of patients may retrospectively reportprevious symptoms suggestive of AH for >12 months before diagnosis Treatment Treatment decisions are made based on the EUVAS disease severity grading AH may fit into almost any of the categories depending on the disease severity

Mild AH without impairment of pulmonary function Moderate AH resulting in impaired pulmonary function but not requiring mechanical ventilation Severe AH requiring respiratory support Refractory AH Mild moderate AH Treated in the same way as mentioned earlier Rituximab has been used in this setting Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med 2010;363(3):221

232 Severe AH Cyclophosphamide + glucocorticoids + /- Plasma exchange Recombinant, activated factor VII useful in case reports in life threatening, uncontrollable AH Henke D, Falk RJ, Gabriel DA. Successful treatment of diffuse alveolar hemorrhage with activated factor VII. Ann Intern Med 2004;140(6):493494 Heslet L, Nielsen JD, Levi M, Sengelv H, Johansson PI. Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage. Crit Care 2006;10(6):R177

Extracorporeal membrane oxygenation (ECMO) At the end The prognosis of the pulmonary small vessel vasculitides has improved markedly in the last few years provided timely diagnosis is made and adequate treatment instituted The results of the various trials going on would probably lead to major changes in the nomenclature, classification and management of these disorders

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