ANCA vasculitis
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ANCA vasculitis diagnosis and management
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ANCA vasculitis
- 1. ANCA-Associated Vasculitis Diana Girnita, MD, PhD Rheumatology
- 2. VASCULITIS Group of diseases that cause inflammation of blood vessels Systemic diseases that can affect multiple organs Challenging clinical pictures even for experience physicians Can be life threatening
- 4. General approach MULTISYSTEMs Severe Constitutional symptoms Rapidly progressive organ dysfunction Very high ESR/ CRP, anemia, thrombocyosis >500K
- 5. ANCA-Associated Vasculitis (AAV) • Group designation for several types of small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA) Granulomatosis with polyangiitis (GPA, Wegener’s) Microscopic polyangiitis (MPA) Renal-limited vasculitis (RLV) (considered part of MPA) Eosinophilic granulomatosis with polyangiitis (EGPA, Churg- Strauss)
- 6. Similar, but different also!! GPA MPO EGPA Granulomas NO Granulomas NO necrotizing vasculitis Asthma Eosinophilia Organ eosinophilic infiltration Eosinophilic granulomas Biopsy: NO immune depositions
- 7. Epidemiology • Uncommon diseases, I=20/106, P=90/106 • All ages, but middle age predominantly • Men> women, 1.5:1 • Racial differences, White >> Non-white, especially for GPA • GPA>MPA>EGPA
- 8. HISTORY • Scottish ENT Peter McBride (1854–1946) -1897 in a BMJ article entitled "Photographs of a case of rapid destruction of the nose and face” • Friedrich Wegener (1907–1990) a German pathologist, in two reports in 1936 and 1939
- 9. Discovery of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) 1982- ANCA+ First described in 8 pts with necrotizing pauci-immune glomerulonephritis 1984 –ANCA+ in 4 patients with systemic vasculitis 1985 - association between ANCA and GPA; MPA, EGPA Davies DJ, et al: Br Med J 285:606, 1982; Hall JB, et al: Aust NZ J Med 14:277, 1984 van der Woude FJ, et al: Lancet 1:425, 1985 Jennette CJ, Falk R: New Eng J Med 337:1512, 1997
- 10. CLINICAL FEATURES UPPER/LOWER AIRWAYs RENAL SKIN
- 11. Most common manifestations in AAV Mansi IA etal. ANCA-associated small-vessel vasculitis. Am Fam Physician. 2002;65(8):1615-1620; Hamidou MA et al Systemic antineutrophil cytoplasmic antibody vasculitis associated with lymphoid neoplasia. Ann Rheum Dis. 2001;60(3):293-295.
- 12. ORGAN GPA MPA Constitutional 60% 90% Musculoskeletal 60% 60% ENT 70% 10-20% Renal 20% 90% Pulmonary 50% 40% DAH 5% 10-20% ILD/PF <5% 10%-15% GPA vs MPA
- 13. ORGAN GPA MPA Skin 15% 20% PNS 20% 20% Eye 15% 5-10% Heart 5-10% 5-10% GI 5-20% 5-20% CNS 10% 3-10% GPA vs MPA
- 15. ENT manifestations Nasal crusting, sinusitis, otitis media, earache, otorrhea, persistent rhinorrhea, purulent/bloody nasal discharge, oral and/or nasal ulcers, and polychondritis. Conductive and/or sensorineural hearing impairment/ loss
- 16. Cartilage destruction -Saddle Nose American College of Rheumatology Image Bank
- 17. Sinusitis American College of Rheumatology Image Bank
- 18. GPA-Bony Destruction Mohamed Haris, MBBS et al. CMAJ 2008;178:25-26 CT paranasal sinuses: patchy bone destruction of the nasal septum, medial walls of the maxillary sinuses (arrows); the irregular mucosal thickening (asterisks).
- 19. Hyperplastic gingivitis “strawberry gums” American College of Rheumatology Image Bank
- 20. Palate perforation 30 yo F with GPA with perforation of her palate with surrounding erythema and induration American College of Rheumatology Image Bank
- 21. Tracheal involvement Hoarseness Cough Dyspnea Stridor Wheezing Tracheal or subglottic stenosis
- 22. Subglotic stenosis American College of Rheumatology Image Bank Vocal cord thickening Subglotic stenosis
- 23. LUNG Hemoptysis Pleuritic pain Pulmonary consolidation/ infiltration, cavities Hilar adenopathy ILD/PHTN American College of Rheumatology Image Bank
- 24. GPA-Multiple Pulmonary Nodules American College of Rheumatology Image Bank
- 25. Pulmonary Hemorrhage American College of Rheumatology Image Bank
- 26. Renal involvement GN- only 18% patients at presentation, but within 2 years of onset 77- 85% Asymptomatic hematuria A rise creatinine (hematuria; cellular casts, subnephrotic proteinuria) Can lead to renal failure if not treated aggressively
- 27. SKIN involvement American College of Rheumatology Image Bank Leukocytoclastic vasculitis
- 28. SKIN involvement Purpura Cyanosis and necrosis of toes American College of Rheumatology Image Bank
- 29. PNS involvement -Mononeuritis Multiplex American College of Rheumatology Image Bank Foot Drop Wrist drop
- 30. EYES
- 31. EYES GPA • Scleritis/keratitis • Orbital mass with optic nerve involvement/ with ptosis/ ophtalmoplegia/Loose sight (optic nerve compression) • Uveitis 3% • Proptosis 2-15% Harper SL et al. Wegener's granulomatosis: the relationship between ocular and systemic disease. J. Rheumatol. 28(5),1025–1032 (2001).
- 32. Musculoskeletal • 28% patients with arthritis (monoarticular, migratory oligoarthritis, symmetric or asymmetric polyarthritis of small and large joints) • +RF-50-60% • In contrast to RA, arthritis is nonerosive and nondeforming
- 33. Rare manifestations GI: abdominal pain, bloody diarrhea Heart: pericarditis, myocarditis, conduction system abnormalities; Pagnoux C et al Presentation and outcome of gastrointestinal involvement in systemic necrotizing vasculitides: analysis of 62 patients with polyarteritis nodosa, microscopic polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, or rheumatoid arthritis-associated vasculitis. Medicine (Baltimore) 2005; 84:115.
- 34. AAV-increased incidence of DVT The etiology of the hypercoagulable state in such patients is not clear, although circulating antiplasminogen antibodies have been demonstrated in patients with AAV and DVT. Weidner S et al. Thromboembolic events as a complication of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2006; 55:146.Stassen PM et al. Venous thromboembolism in ANCA-associated vasculitis- -incidence and risk factors. Rheumatology (Oxford) 2008; 47:530.Bautz DJ, et al. Antibodies with dual reactivity to plasminogen and complementary PR3 in PR3-ANCA vasculitis. J Am Soc Nephrol 2008; 19:2421.
- 35. DIAGNOSIS
- 36. When to suspect small vessel involvement? ENT/LUNG: pulmonary infiltrates/ hemorrhage KIDNEY: active urinary sediment NEURO: foot drop/wrist drop SKIN: palpable purpura
- 37. Labs and Imaging • Anemia and thrombocytosis • Elevated markers of inflammation • Renal function deterioration • ANCA testing • CXR, CTs • BAL (DAH) • Biopsy (skin, lung, kidney) Guillevin L et al. MPA: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999; 42:421.Finkielman JD et al. ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis. Am J Med 2007; 120:643.e9.
- 38. ANCA ANTIBODIES Anti-Neutrophil Cytoplasmic Antibodies
- 39. Immunofluorescence and ELISA (PR3 and MPO) MPO
- 41. ANCA C-ANCA/PR3 P-ANCA/MPO Hagen EC, Daha MR, Hermans J, et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. Kidney Int 1998; 53:743.
- 42. ANCA Test Characteristics IF ELISA IF + ELISA Sensitivity 67% 55% 52% Specificity 93% 99% 99% PPV* 45% 83% 88% NPV* 97% 96% 96% Stone et al. Arth Care Res.13(6):424.2000 856 patients –median F/up 1.8 years, definitive dg of AAV, prevalence of AAV only 9%;
- 43. Take home message • 1/3 of pts with confirmed AAV: negative ANCA by IF • ½ had negative ELISA. • So, it is certainly possible to have AAV without either test being positive • 40% of limited GPA disease is ANCA negative
- 44. ANCA In AAV Types AAV Sensitivity C- ANCA* P- ANCA* αPR3* αMPO* GPA 60-90 % 75% 25% 80-90% 10-20% MPA 70% 15% 85% 10-20% 80-90% RLV (NCGN) 80-90% <5% 95% <5% 75-80% EGPA 50% 15% 90% 5% 95% * Percent of those with + ANCA Stone et al. Arth Care Res.13(6):424.2000
- 45. ANCA Frequencies in Vasculitis 0 10 20 30 40 50 60 70 80 90 100 WG MPA iRPGN CSS P-ANCA C-ANCA Hagen EC, et al: Kidney Int 53(3):743–753, 1998.
- 46. C-ANCA and P-ANCA • GPA ---C-ANCA/ PR3 (neutrophil proteinase 3) • MPA----P-ANCA ---MPO (myeloperoxidase), but may also be caused by antibodies to elastase, lactoferrin, LAMP-2. • EGPA --- P-ANCA --- MPO
- 47. Other Causes of +ANCA Drugs (PTU, methimazole, hydralazine, minocycline, allopurinol, cocaine (+ levamisole) - P-ANCA pattern (MPO+) Infections (Infective endocarditis, EBV, TB) Connective tissue disease (SLE, Scleroderma, RA, poly/dermatomyositis) Cystic fibrosis (90% p-ANCA, MPO and PR3 negative) Inflammatory bowel diseases (atypical ANCA)
- 48. Cocaine-Induced Purpura Cocaine+levamisone Cutaneous infarction and necrosis (ears; nose) P-ANCA/ MPO; Combination of anti-MPO and PR3 is very suggestive of the syndrome American College of Rheumatology Image Bank
- 49. LUNG Biopsy Lung Biopsy (thoracoscopic) Transbronchial and nasal bx are usually unhelpful MPA: pulmonary capillaritis American College of Rheumatology Image Bank
- 50. a. severe interstitial inflammation Zagelbaum N et al. (2016) GPAcase report outlining the importance of urinalysis in patients presenting with pulmonary cavitary lesions Pulm Crit Care Med Renal biopsy b.severe, with multifocal necrotizing interstitial granulomas and arteriolitis
- 52. Pretest probability of vasculitis – a Bayesian Analysis H K Choi,et al. Diagnostic performance of antineutrophil cytoplasmic antibody tests for idiopathic vasculitides: metaanalysis with a focus on antimyeloperoxidase antibodies. J Rheumatol 2001;28;1584-1590
- 53. TREATMENT
- 56. Induction Rx • NIH study (CYC) • EUVAS study (CYC vs Methotrexate) • RITUXVAS (CYC+RITUX vs CYC ) • RAVE trial (CYC vs RITUX)
- 57. 158 pts with GPA followed up to 24 years ( 8 years mean follow-up) 84% received "standard” low dose daily CYC (2mg/kg/day) and GC (1mg/kg/day)
- 58. Complete remission (CR) 75%, PR-16% Survival rate of 80% at 5 yrs. 50% of CR had relapse Side effects of Rx -Serious infections (21%/yr, zoster 8%/yr ) -cystitis (43%), bladder CA (3%), myelodysplasia (2%), -amenorrhea (57% of 28 pt) -2.4 x SIR of malignancy Mortality of 20% -13% vasculitis, 7% Rx related Cyclophosphamide induces remission, but relapses are common, and causes toxicity Hoffman et al. 1992 Ann Int Med 116(6):488, 1992
- 59. Looking for less toxic therapy….
- 60. Induction Rx: CYC vs Methotrexate (NORAM) • 101 patients RCT • 49 pts CYC 2 mg/kg/d vs 51 pts MTX 20-25/wk, continued for 12 mos • Prednisone 1 mg/kg/d → 15 mg/d (12 weeks) → 7.5 (24 wks) • Non life-threatening and non organ-threatening Dz • Excluded pts with DAH/ serum Cr >2.5 mg/dl • 1º Endpoint: remission at 6 mos • 2º Endpoints: relapses at 18 mos, side effects De Groot et al. 2005. Arth & Rheum 52(8):2461.
- 61. Induction Rx CYC vs Methotrexate De Groot et al. 2005. Arth & Rheum 52(8):2461. 89.8% vs 93.5% 46.5% vs 69.5% CYC probably more effective; should be used in more active dz and in pts with significant pulmonary dz; use Methotrexate in limited disease
- 62. Rationale for Rituximab in AAV Rituximab depletes CD20+ B-cells (and pre-B-cells) Rituximab had shown significant efficacy in a small number of cases of refractory GPA B-lymphocytes are activated during flares of GPA but not in quiescent GPA
- 63. RITUXVAS trial
- 64. 44 pts ANCA- RENAL vasculitis 3:1 ratio IV MP 1g, then po MP (1 mg/kg per day with reduction to 5 mg per day by the end of six months) rituximab (375 mg/m2per weekx 4 weeks) in combination with 2 intravenous cyclophosphamide pulses (15 mg/kg) IV cyclophosphamide (15 mg/kg every 2 weeks for three doses followed by infusions every three weeks) for three to six months followed by azathioprine Patients who received rituximab who had progressive disease within the first 6 months were given a third dose of cyclophosphamide (15 mg/kg).
- 65. RITUXVAS • At 12 and 24 months --there was no difference in the rate of sustained remission (76% vs 82%) • No difference the rate of SAE at 12 months.
- 66. RAVE trial Stone et al. 2010; NEJM 363:221.
- 67. Stone et al. 2010; NEJM 363:221.
- 68. RAVE trial: CYC vs RTX 197 patients; Double blind, RCT CYC 2 mg/kg/d (for 12 weeks) vs RTX 375 mg/m2 x 4 doses IV solumedrol 1 g x 1-3 days Prednisone 1 mg/kg/d → 40 mg/d (4 weeks) → 0 (20) wks 1º Endpoint: complete remission at 6 mos 2º Endpoints: duration of remission, side effects Stone et al. 2010; NEJM 363:221.
- 69. RAVE Trial Outcome CYC RTX Difference Remission 53% 64% NI, NS Severe Flares 0.011/mo 0.018/mo NS DAMAGE 1.5 1.3 NS Remission (in relapsing Dz) 42% 67% P=0.01 ANCA →negative 24% 74% P=.004 Serious AE’s 59% 54% NS Deaths (n) 2 1 NS Stone et al. 2010; NEJM 363:221.
- 70. Stone et al. 2010; NEJM 363:221.
- 71. Complete Remission at 12 &18 months RTX (N=51) CYC/AZA (N=51) Complete Remission 12 months 23 (45%) 24 (47%) Complete Remission 18 months 21 (41%) 22 (43%)
- 72. Stone et al. 2010; NEJM 363:221.
- 73. Stone et al. 2010; NEJM 363:221.
- 74. Stone et al. 2010; NEJM 363:221.
- 77. PR3+ patients Stone et al. 2010; NEJM 363:221.
- 78. Patients prone to flare • GPA • History of previous flare • PR3+
- 79. RAVE Trial • RTX not inferior to CYC at 6 mos • RTX superior in relapsing disease and PR3+ disease • Similar results in DAH and AKF pts • At 18 mos, only 39% and 33% still in remission • Improvement in maintenance therapy needed Stone et al. 2010; NEJM 363:221.
- 81. PLEX recommendations 1.Rapidly deteriorating kidney function or severe kidney dysfunction (Cr>4.0 mg/dL or who require dialysis) 2.+ anti-GBM autoantibody disease 3. Diffuse pulmonary hemorrhage
- 82. PLEX IN AAV • MEPEX trial: RCT of 137 pts with AAV • RPGN, Cr ≥ 5.8 • IV solumedrol 1 g q mo x 3 vs PLEX x 7 over 14 days • All pt’s got oral CYC x 6 mos and oral prednisone 1 mg/kg/d • CYC changed to AZA and pred ≤ 10 mg/d at 6 mos Jayne. 2007; J Am Soc Neph 18: 2180
- 83. MEPEX Jayne. 2007; J Am Soc Neph 18: 2180 69% vs 49%, p< .02 59% vs 43%, p< .008 PE MP PE MP Survival did not differ 73% vs 76%, NS
- 84. CYC oral vs CYC IV RTC 149 patients Pulse CYP- 15 mg/kg every 2 to 3 weeks (76 pts) Daily oral CYC 2 mg/kg per day (73 pts) + prednisolone. RESULTS No difference in time to remission No difference in % of patients who achieved remission at 9 months (88.1% vs. 87.7%). Cumulative CYP dose in the daily oral group was greater than that in the pulse group The pulse group had a lower rate of leukopenia
- 86. Maintenance RX • Cyclophosphamide (CYP) • Azathioprine (AZA) • Methotrexate (MTX) • Rituximab (RTX) • Mycophenolate mofetil (MMF)
- 87. Maintenance Rx in AAV Study n Length Rx Efficacy Toxicity (SAE’s) CYCAZAREM1 155 12 (18) mos CYC vs AZA Relapses: 13.7% vs 15.5% (ns) 10% vs 11% (ns) WEGENT2 126 12 (18) mos MTX vs AZA Relapses: 13.6% vs 15.5% (ns) 18% vs 8% (ns) IMPROVE3 156 24 (42) mos AZA vs MFM Relapses: 38% vs 55%* 16% vs 8% MAINRITSAN4 115 28 mos RTX vs AZA Relapses: 5% vs 29%* 79% vs 76% (ns) 1.Jayne.NEJM 2003;349:36; 3. Heimstra.JAMA 2010; 304:2381 2.Pagnoux. NEJM 2008; 359:2790 4. Guillevan. NEJM 2014; 371:1771 *: p <.05
- 88. Maintenance Rx: CYC vs AZA (CYCAZAREM) Jayne et al. 2003; NEJM 349 (1):36. CYC 13.7% vs. AZA 15.5%, NS •RCT of 155 pts with AAV (60% GPA, 40% MPA) •90% with CKD , Cr ≤ 5.7 •CYC 2 mg/kg (x 3 mos) and pred 1mg/kg/d → 10 mg/d at 3 mos •At 3 mos, those in remission → CYC or AZA •Primary endpoint: relapse at 12 mos •RESULTS: no difference in relapse rate
- 89. Maintenance Rx: RTX vs AZA MAINRITSAN Guillevan et al. 2014; NEJM 371:1771. • RCT of 115 pts with AAV (76% GPA, 20% MPA, 4% RLV) • Induction with IV CYC q 2-3 weeks x 4-6 mos, pred 1 mg/kg/d → 5 mg/d at 6 mos • At remission, randomized → RTX or AZA • RTX 500mg Day 1, 14, then every 6 months • AZA 2mg/kg/day • Primary endpoint: relapse at 28 mos
- 90. MAINRITSAN 5% vs 29%; P=.002 Guillevan et al. 2014; NEJM 371:1771. 16% vs 45%; P=.04 HR =0.18 (0.09 -0.42) P<0.001
- 91. Treat even in severe renal failure- at least 4 months Among CYC-treated patients, the likelihood of treatment response was >14% even with highest chronicity index score and eGFR<10 ml/min/ 1.73 m2. 155 pts pauciimmune GN and crescentic GN Within 4 months after biopsy, treatment response was attained in 51% of patients, 35% remained on dialysis, and 14% died Lee T et al. Predictors of treatment outcomes in ANCA-associated vasculitis with severe kidney failure. Clin J Am Soc Nephrol.2014 May;9(5):905-13. doi: 10.2215/CJN.08290813. Epub 2014 Feb 27.
- 92. Relapses in AAV remains a real concern… 40-50% of patients Associated with increased risk of ESRD and extra-renal damage Risk factors: previous relapse, PR-3+, lung involvement (GPA)
- 93. Still many unanswered questions… Would RTX induction followed by regular RTX maintenance be more effective? What is optimal dose and interval for RTX? Would combination therapy be more effective? Can damage be prevented? Can AAV be cured?
- 94. THANK YOU!
Notas del editor
- Group together because of similar clinical manifestations, relapsing courses and pathology (especially renal findings), long term morbidity and similar RX response
- Since these are the most closely related, and have been studied more extensively, in the interest of time, I’ve elected to limit my discussion to these two entities.
- Rare disease but from my experience we see about 6 cases/yr on the inpatient service and about 2-3x as many cases in whom the diagnosis is entertained. GPA is seen 2-3 times as often as MPA.
- The key to making a diagnosis of AAV is to suspect it. To be able to do so, it is necessary to be familiar with more common and more characteristic clinical features and presentations. GPA and MPA have overlapping Clinical Features such that often it is difficult, if not impossible, to distinguish. In addition, GPA and MPA have overlapping ANCA profiles which, as you will see, determine to a greater extent prognosis than does clinical diagnosis. In practice we often consider a pt to have GPA if they destructive upper airway disease, lower airway disease, and granulomas demonstrated on biopsy. However, not every patient has a biopsy and not every patient with otherwise typical GPA has a biopsy with sufficient tissue to demonstrate granulomas. Because of this, many prefer to use the more general term of AAV and subset according to ANCA type. When one thinks of vasculitis, one things of an acute fulminant process, but these diseases may present subacutely, or in a chronic, indolent manner. Mean and median time to diagnosis for GPA has been 4.7 and 15 mos respectively. Only 42% of pts had a diagnosis in less than 3 mos with some cases requiring years. With MPA, there is oftentimes a more acute presentation, but the median time to diagnosis was 3 mos with a mean of 9.8 mos in a large French cohort. Constitutional symptoms like fatigue, malaise, fever, decreased appetite, and weight loss occur in the vast majority of patients. More commonly in MPA. May occur weeks to months prior to onset of specific organ system involvement. Fever may be significant in 25% and suggest infection. Weight loss of greater than 10% occurred in 15% of patients, sufficient to suggest an underlying malignancy. At times these were the only clinical manifestations when pts first seek attention. Musculoskeletal symptoms occurred in majority of patients and consisted primarily of arthralgias and myalgias. Joint swelling with signs of inflammation was much less common occurring in no more than 10-20% of pts. ENT manifestations occurred in 70% of pts with GPA at onset and in a minority, but not insignificant number of pts with MPA. Most commonly, they consisted of chronic, recurrent, or refractory sinusitis. Viral rhinosinusitis is common, on average 3 episodes per year in adults. Acute bacterial sinusitis is much less common accounting for less that 2% of all cases of acute rhinosinusitis/year. Bacterial sinusitis usually will respond to a appropriate antibiotic within 3-5 days, if it doesn’t respond to an alternative antbiotic in 3-5 days. Bacterial infection is frequent with GPA and commonly coexists with active disease. So that, if one has many more that the usual number of viral RS/year, more than a single bout of bacterial sinusitis, or doesn’t respond as described above, then one needs to think of other possible explanations. While GPA certainly isn’t the most common cause of complicated or refractory sinusitis, in fact it is probably among the least common causes, nonetheless, it is the differential. The next slide shows some of the clues that might lead one to suspect GPA on exam… ____________________________________________________________________________________________________________________________________________________________________________________ In addition, epistaxis, chronic nasal ulceration, nasal septal perforation, and tracheal abnormalities were frequent presenting complaints. 15 % of patients in the NIH series had tracheal stenosis. This usually was subglottic and resulted in SOB. At times it produced stridor and acute respiratory failure. This has been a presenting manifestation of several pts that I have seen and has been the sole manifestation is some with more limited disease. Skin is involved in the minority of patients with AAV, but the presence of typical palpable purpuric lesions should raise the suspicion of small vessel vasculitis and AAV. Some of the purpuric lesions may also have areas of necrosis/infarction. Large ulcers, subcutaneous nodules, vesicles and bullae may occasionally be found. Renal involvement is seen in about 20% of pts with GPA on presentation although 70% will ultimately develop it. In contrast 90+ % of pts with MPA have renal involvment at onset. This may range from asymptomatic hematuria to RPGN. Proteinuria is moderate with an average of approximately 2g/24 hrs although nephrotic range is occasionally seen. For the Primary care physician, microscopic hematuria with or without rbc casts, moderate proteinuria, and modest but progressive decrease in GFR are the most common presentations likely to be encountered. Renal biopsies are shown on the next slide. The characteristic lesion is a a or diffuse necrotizing glomerulonepritis with or without crescents and in the absence of immune deposits as is seen in panel 3. Periglomerular and interstitial infiltrates may also be found. Curiously, vasculitis is seen in less than 20% of cases. Pulmonary involvement is seen in approximately 50% of patients at onset of the disease in both GPA and MPA. In GPA, the most common findings were nodules or infiltrates which may be solitary or multiple. As many as a third of patients may be asymptomatic and have findings on chest xray or CT. Typical findings in GPA are shown in the next slide. As was mentioned, the nodules may be solitary and may or may not cavitate. They may also be lobulaed or spiculated as can be seen from the next slide from a patient I saw recently. Finally, infiltrates and ground glass opacities are relatively common as well. In contrast, MPA typically has more diffuse disease such as pulmonary hemorrhage. But it is increasingly appreciated that pts with MPA pay also present with ILD or pulmonary fibrosis as is shown on the next slide. Additional presenting manifestations are shown and include PNS, eye, heart, GI, and CNS. I will just highlight a few more characteristic features which, if present, should lead you to immediately suspect the diagnosis.... The next is scleritis: most common presenting manifestation found in 10% of pts, scleritis is a very painful eye condition as opposed to episcleritis or conjunctivitis, deep vessels are involved which produces a violaceous red coloration which don’t blanche on application of phenylephrine. Less common at presentation, but more suggestive of GPA is proptosis or pseudotumor of the orbit. There are few conditions which cause, and GPA is one. Shown is an example. PNS is involved often in both GPA and MPA. A characteristic finding and one that should suggest a vasculitis is mononeuritis multiplex which is asymmetrical involvement of all modalities of 2 or more peripheral nerves. It commonly presents as a wrist drop or foot drop as is seen on the following slide which is usually quite profound.
- Here is one of the more characteristic ENT manifestations—the saddle nose deformity. Saddle nose is seen in approximately 10% of pts with GPA. It is oftentimes painful and is as you can see, quite disfiguring.The differential is limited if one excludes trauma and surgery. It includes relapsing polychondritis, congenital syphilis, lymphoma, or paranasal sinus malignancy. In the later two conditions, mass like lesions are usually found and in the case of relapsing polychondritis, no nasal mucosal or sinus abnormalities occur, but multifocal cartilage involvement is the rule.
- The axial CT scan on the left shows destruction of the medial wall of the maxillary sinus and loss of the nasal septum. The coronal view on the right shows inflammatory changes and ethmoid sinusitis.
- In pts with complicated or refractory sinusitis, a CT scan is usually indicated. Here is an example of what can be seen in nearly 50% of pts with GPA– bony erosions Now other things may cause such erosions like malignancy and invasive infections, but oftentimes in GPA it is multifocal as shown here suggesting a systemic process.
- 30 year-old woman with granulomatosis with polyangiitis has perforation of her palate with surrounding erythema and induration
- This 17 year-old woman with granulomatosis with polyangiitis developed stridor after 18 months of nasal obstruction, recurrent epistaxis, and progressive hearing loss. Bronchoscopy showed vocal cord thickening and subglottic stenosis (left images). She had resolution of her symptoms with oral corticosteroids and balloon dilatation (right images).
- On average, they are between 2 and 3 cm in diameter, but some can be quite large as in this pt.
- While nodules can be seen with MPA, more diffuse pulmonary disease is more common. Most suggestive of MPA is DAH shown here. DAH is seen in approximately 30% of pts with MPA and is usually acute, but may be more indolent or recurrent. And, alveolar hemorrhage may at time also be localized.
- Palpable purpura due to cutaneous leukocytoclastic vasculitis is seen in a significant minority of pts with AAV, more commonly in MPA than GPA but frequently enough that it should be carefully sought for as a skin biopsy is perhaps the least invasive way of making a diagnosis. Although not common, granulomas may also be found in addition to vasculitis.
- has purpuric lesions of his hands and feet with cyanosis and superficial necrosis of several toes.
- PNS is involved often in both GPA and MPA. Approximately 15% will have neuropathy as one of the first manifestations of the disease. A characteristic finding and one that should suggest a vasculitis is mononeuritis multiplex which is asymmetrical involvement of both motor and sensory functions of 2 or more peripheral nerves. It commonly presents as a foot drop as is seen on the right, or a wrist drop, on the left. This is due to infarction of the sciatic or common peroneal nerves and the radial nerve respectively. This involvement is usually quite profound and results in significant disability.
- Proptosis was present in 2% of pts with GPA an onset but eventually affected 15%. It may be unilateral or bilateral. It is due to infiltration of retroorbital space with granulation tissue and produces a picture of orbital pseudotumor. It is significant in that approximately 50% of pts loose sight due to compression of the optic nerve. Patients could prsent to the primary care physician with mild unilateral proptosis. Apart from Graves disease, sarcoid, and idiopathic orbital myositis, GPA is the most likely cause. Occasionally, lymphoma may
- Normochromic normocytic anemia Thrombocytosis >400K
- Strongly cationic proteins are attracted to and arrange themselves in close proximity to the negatively charged nuclear membrane, where as the weakly cationic or neutral proteins do not.
- The next step in assessing pts suspected of AAV, is obviously to order an ANCA. On the left is the cytoplasmic staining pattern, the C-ANCA and on the right is the P-ANCA or perinuclear ANCA with accentuated staining around the nuclei. These different staining patterns are actually an artifact of the method of fixation, but a useful artifact nonetheless.
- The largest and perhaps the most carefully performed study involved 856 patients who were followed from 6 mos to 4 years with a median duration of 1.8 yrs to establish a definitive diagnosis Prevalence of AAV in this population was only 9% even though this was an academic institution with a vasculitis center. As can be seen, the sensitivity of IF was highest at 67% vs ELISA at 55% and vs the combination of positive tests at 52%. So, 1/3 of pts who were ultimately diagnosed with AAV were ANCA negative The specificity was high for all assays, but especially for ELISA and it combinations. The PPV of the ELISA turns out to be quite reasonable even with a low prevalence of disease, and the negative predictive value was even higher. If prevalence of the disease were 20%, then the PPV would increase to 92% and the NPV would decrease slightly. And, by analogy, if applied to an individual with a higher pretest liklihood, then the PPV would similarly increased. (The take home is that a.) Other studies have reported higher sensitivities. Most of these have involved groups of patients followed at specialized centers with established disease. This population is probably enriched for more severe disease and diseases of longer duration. I believe the current study best addresses the question at hand—how good is ANCA as a diagnostic test in someone suspected of having AAV.
- As can be seen, those with clinical picture most suggestive of GPA are 3 times more likely to have a C-ANCA than a P-ANCA. The opposite is true for MPA. If one looks at PR3 vs MPO most with clinical dx of GPA will have PR3 antibodies although 10-20% will have MPO. And, for those with clinical picture of MPA, 80-90% will have MPO, but 10-20% will have PR3. The question that arises is: does it make a difference. The answer is yes and will discussed in more detail when we discuss treatment. (The sensitivity of ANCA has been variously reported as I have indicated. The Stone paper placed it as 60% for both GPA and MPA. However, others have reported frequencies as high as 90% in pts with well established disease. That may be the difference. In addition, the extent and activity of the disease may influence the sensitivity of the test. In those with multisystem, active disease, the sensitivity is higher and may approach 90-95%.)
- PR3 is a serine proteinase found in the azurophilic granules of PMNs and lysosomes of Monos. It has enzyme activity similar to elastase and can degrade, elastin, laminin, and collagen and promote containment of invading microorganisms. It stimulates the production of pro-inflammatory cytokines, like TNF, IL8 and IL18 and is pro-apoptotic for PMN’s and endothelial cells. MPO is a enzyme which catalyzes the production of hypochlorous acid from H2O2 and chloride. HOCl is a potent antibacterial agent which also can oxidize/chlorinate host proteins, lipids, and DNA. Antibodies to PR3 and to MPO are more specific than ANCA staining patterns and can be tested for by ELISA.
- The most frequently reported association of ANCA and drugs is with cocaine. Since 70% of cocaine is now adulterated with levamisole, a veterinary anti-heminth with immunostimulatory properties, it is unclear if it is the cocaine, the levamisole, or both that are responsible. The combination has been associated with typical features of MPA including GN but a more common presentation is shown here with cutaneous infarction and necrosis, with predilection for the ears and nose. These pts also have fever, neutropenia, and arthralgias. They usually have a very high titer of P-ANCA but only modest titers of anti-MPO. They may also have anti-PR3 and the combination of anti-MPO and PR3 is very suggestive of the syndrome.
- The GN in AAV is considered to be pauci-immune as can be seen on this slide. The bottom panel, shows faint staining of C3 and negative staining for the other immunoreactants. This would be consistent wih pauci-immune GN. The top panel shows linear deposition of igg consistent with ani-GBM disease. The middle panel has granular deposition of immune reactants consistent with immune complex disease, such as SLE or cryoglobulinemia.
- As you know the predictive value of a test is what is most relevant to a particular patient. This depends on the sensitivity and specificity of the test but also on the patient in terms of the pretest likelihood of having the disease in question. Here are some older estimates from the literature reported in a metaanalysis done by Hyon Choi in 2001. Sinus + lung + GN has a pretest likliehood of 85%.
- This was the paper that changed everything for AAV. In 1971, Fauci, Wolf, and Johnson reported on the immune and clinical response to CYC in 9 pts with WG. Prior to that pts were primarily treated with steroids and had a 10% 2 year survival rate. 9 cases: 6 complete remissions, 2 partial remissions, 1 treatment failure. This started a new age in the treatment of GPA. On the basis of this report and others that followed from the NIH, cyc became the standard of care for GPA.
- At 6 mos, 89.8 vs 93.5 (NS) MTX: remission delayed in those with more extensive disease and pulmonary disease (p<.04) At 12 mos: relapse rate in MTX was 69.5% vs 46.5% (p< .04)
- There was still the need for more effective induction of remission, given the fact that 25% of pts did not respond to standard induction regimen. Attention turned to rituximab for the following reasons:
- RAVE trial was a double blind, RC non-inferiority trial of 197 pts from 9 different vasculitis centers with ANCA + AAV who were randomized to receive IV Rituxan or oral cyc together with iv and then oral steroids. The primary endpoint was remission off prednisone at 6 mos. As can be seen … However, in the subset of pt who had relapsing disease at baseline, which was approximately half of the total, RTX proved to be superior. Adverse events, both serious and non-serious, were however comparable as were deaths. Withdrawals were also comparable between treatment groups. This was something of a surprise. Single course of RTX treatment resulted in remission in the majority of pts off prednisone. These patient had no maintenance rx whereas the cyc pt’s followed with azathioprine maintenance. Have been followed up to 18 mos without retreatment with RTX in the original RTX group and aza in the control group. The rates of complete and partial remissions declined but did so in parallel in the two treatment groups. At 18 mos, 39 % were still in remission in the RTX vs. 33 in the Cyc-Aza group. The superiority of RTX over CYC-AZA in patients with relapsing disease at baseline was still apparent at 12 mos but was only a trend at 18 mos. Surprisingly, side effects were again similar including all infections and all serious infections. No new malignancies were identified.
- Severe AE: 50% vs 48%, NS Probs with trial: MP vs PE not MP+PE vs MP alone MP every month not qd Types of PE varied by treatment center, 13 across Europe
- Relapse rate at 12 mos was comparable, both for severe and non-severe. Cumulative activity scores were also comparable as were VDI
- New (80%) or relapsing (20%)
- The major problem in AAV
- So, while we now have some answers, we still have many questions. And, while we have come a long way, we have not yet arrived. Hopefully, we will do so in the not to distant future.