"Update on classification of vasculitis and Wegener�s "
Update on classification of vasculitis and Wegener’s granulomatosis Dr. Overview Classification of vasculitis Wegener’s granulomatosis Epidemiology Clinical features Pathogenesis Diagnosis Treatment Prognosis Vasculitis classification– the first step Primary Systemic Vasculitis classification Classification of systemic vasculitis Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis Small vessel Medium-sized vasculitis vessel vasculitis Wegener’s granulomatosis Polyarteritis nodosa Churg-Strauss Kawasaki disease syndrome Microscopic polyangiitis Henoch-Schonlein purpura Large-vessel Essential vasculitis cryoglobulinemic vasculitis Cutaneous Giant cell (temporal) leukocytoclastic arteritis angiitis Takayasu arteritis Classification of systemic vasculitis 2 major groups based on clinical and histopathological features of vasculitis 1. Large vessel vasculitis: aorta and major branches Giant cell arteritis / temporal arteritis Takayasu arteritis 2. Medium-sized vasculitis: medium arteries Polyarteritis nodosa (PAN) Kawasaki disease Classification of systemic vasculitis 2. medium-sized vasculitis: arterioles, capillaries and venules Wegener’s granulomatosis (WG) Churg-Strauss syndrome (CSS) Microscopic polyangiitis (MPA) 3. small vessel vasculitis: venules, capillaries Henoch Schonlein purpura (HSP) Cryoglobulinaemic vasculitis Pathogenesis of vasculitis Antibody mediated inflammation Wegener’s granulomatosis (WG) Churg-Strass syndrome (CSS) Microscopic polyangiitis (MPA) Pathogenesis of vasculitis Immune complex-mediated inflammation Henoch SchÖlein purpura (HSP) Cryoglobulinaemic vasculitis Polyarteritis nodosa (PAN) Cell-mediated inflammation Giant cell arteritis Takayasu arteritis Wegener’s granulomatosis (WG) Churg-Strass syndrome (CSS) Small vessel pauci-immune vasculitis Wegener’s granulomatosis: Necrotizing granulomatous inflammation, most often affecting respiratory tract Churg-Strauss syndrome: Occurs in association with asthma, eosinophilia, and necrotizing granulomatous inflammation Microscopic polyangiitis: Pauci-immune systemic vasculitis occurring in the absence of asthma and eosinophilia with no evidence of granulomatous inflammation Wegener’s Granulomatosis Wegener’s Granulomatosis Vasculitis and Granulomas in Lung and Upper Airway and also Glomerulonephritis History of Wegener’s In 1931 Two patients died from prolonged sepsis with inflammation of blood vessels scattered throughout the body In 1936 Wegener first described a distinct syndrome in three patients found to have necrotizing granulomas involving the upper and lower respiratory tract In 1954 Seven more patients described, resulting in definate criteria Wegener’s granulomatosis Epidemiology: Prevalence in US estimated at 3 per 100,000 Male : Female = 1 : 1 80-97% are Caucasian Mean age at diagnosis: 41-56 Definitions Wegener’s granulomatosis is a systemic vasculitis of the medium and small arteries, as well as venules, arterioles and occasionally large arteries “Classic” Wegener’s primarily involves the upper and lower respiratory tracts and the kidneys Definitions (Contd) “Limited” form have clinical findings isolated to the respiratory tract- can occur in ¼ of cases, although 80% may go on to develop glomerulonephritis Specifically, pts with limited disease are younger at disease onset, and more likely to be women The Controversy Wegener’s vs PR3-ANCA vasculitis Lancet, 22 April 2006 Suggestion that using Wegener’s name “needs balanced discussion within the scientific community” Reiter's syndrome- reactive arthritis The Problem with Changing Multiple ANCA+ diseases: microscopic polyangiitis (MPA) "renal-limited" vasculitis (pauci-immune glomerulonephritis without evidence of extrarenal disease) Churg-Strauss syndrome (CSS) Drug-induced vasculitis Goodpasture’s Rheumatic disorders Autoimmune GI disorders CF Diagnostic Criteria primarily clinical Criteria for Classification Nasal or oral inflammation Development of painful or painless oral ulcers or purulent or bloody nasal discharge Abnormal chest radiograph Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities Abnormal Urinary sediment Microhematuria (>5 red blood cells per high power field) or red cell casts in urine sediment Granulomatous inflammation on biopsy Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole) * For purposes of classification, a patient shall be said to have Wegener's granulomatosis if at least 2 of these 4 criteria are present. The presence of any 2 or more criteria yields a sensitivity of 88.2% and a specificity of 92.0% Classic Symptoms Upper respiratory tract sinuses Nose ears trachea Lungs Kidneys Eye Scleritis Uveitis Orbital pseudotumor /proptosis Upper Respiratory Tract Ear Ear infections that are slow to resolve Recurrent otitis media Decrease in hearing Upper Respiratory Tract Nose Nasal crusting Frequent nosebleeds Erosion and perforation of the nasal septum. The bridge of the nose can collapse resulting in a “saddle–nose deformity”. Upper Respiratory Tract Sinuses/Trachea Sinuses Chronic sinus inflammation Trachea subglottic stenosis Lungs Nodules (which may cavitate) Alveolar opacities Pleural opacities Diffuse hazy opacities (which may reflect alveolar hemorrhage) Kidney Glomerulonephritis w/ associated hematuria and proteinuria Can lead to renal failure if not treated aggressively Renal masses (rare) Active urine sediment: red blood cell casts RBC casts Skin “palpable purpura” most common Raynaud’s phenomenon—due to inadequate blood flow to fingers and toes Ulcers Miscellaneous Joints Arthritis can occur, with joint swelling and pain Nerves Peripheral nerve involvement leads to numbness, tingling, shooting pains in the extremities, and sometimes to weakness in a foot, hand, arm, or leg Meninges Prostate gland Genito–urinary tract Constitutional symptoms of fatigue, low– grade fever, and weight loss Incidence of symptoms Symptom At Onset Total ENT 75% 95% Lung 50 85 Joints 30 70 Fever 25 50 Kidney 20 75 Cough 20 50 Eye 15 50 Skin 15 45 Weight Loss 10 35 Nervous System (Central/Peripheral) 0 10/15 One-third of patients may be without symptoms at onset of disease Update on vasculitis: J Allergy Clin Immunol 2009 Update on vasculitis: J Allergy Clin Immunol 2009 Wegener’s continued. . . Renal involvement is manifested by acute renal failure with red cells, red cell and other casts , and proteinuria Pts with microscopic polyangitis have a renal lesion that is essentially indistinguishable from that of pts with classic Wegener’s, the principle difference is the absence of granulomatosis inflammation, although some experts consider the presence of any significant upper respiratory tract involvement to be indicative of Wegener’s In addition to pulmonary and renal… Upper and lower airways, including subglottic region or trachea Joints (myalgias, arthralgias, arthritis) Eyes (conjuctivitis, corneal ulceration, episcleritis/scleritis, optic neuropathy, nasolacrimal duct obstruction…) In addition to pulmonary and renal… (Contd) Skin (hemorrhagic lesions, palpable purpura) Nervous system(cranial nerve abnormalities) GI tract/Heart, lower GU Wegener’s Granulomatosis About 50% have no lung involvement at 100% presentation. 90% 80% • Lung involvement: Infiltrates 70% Nodules 60% Hemoptysis At Initial 50% Presentation Throughout Pleuritis • 40% Disease Course 30% 33% with lung involvement 20% are asymptomatic. 10% • About 80% have no renal 0% involvement at ENT Lung Kidney presentation. Klippel, 1998 Pathogenesis Risk factors and inciting events Exact events obscure Infectious—staph? Genetic single nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) AAT deficiency Environmental—inhalational? Silica lead mercury Pathogenesis ANCA ANCAs may be not only markers for Wegener's granulomatosis and related disorders, but they may also be actors in pathogenesis Neutrophils exposed to cytokines such as TNF, express PR3 & MPO (the targets for ANCAs) Adding ANCAs to these cytokine- primed neutrophils causes them to generate oxygen radicals and release enzymes capable of damaging blood vessels Pathogenesis (Contd) “Priming” of Neutrophils Exposing PR3 and MPO epitopes ANCA binding Degranulation/ROS production/neutrophil-endothelial cell interaction Increased ANCA = Increased degranulation rate Pathogenesis (Contd) Production of ANCA (anti-neutrophil cytoplasmic antibodies) is one of the hallmarks of WG and related forms of vasculitis(Churg-strauss, MPA, pauciimmune glomerulonephritis, drug –induced). ANCA are directed against antigens present within the primary granules of neutrophils and monocytes, and thus produce tissue damage via interactions with primed neutrophils and endothelial calls. ~90% of pts with active generalized WG are ANCA positive, but some do not have ANCA, and those with limited forms of the dz, up to 40% may be ANCA negative, thus the absence of ANCA does not exclude the diagnosis of Wegener’s. Pathogenesis (Contd) Most common targeted antigens in WG : Proteinase 3 (PR3), observed in 70- 80% of pts Myeloperoxidase (MPO)-target in approximately 10% Dual postivity is rare and , and generally indicated the presence of another condition such as SLE ~70% of pts with MPA are ANCA positive and most have MPO-ANCA, with only a minority having PR3 Diagnosis Criteria for Classification Nasal or oral inflammation Development of painful or painless oral ulcers or purulent or bloody nasal discharge Abnormal chest radiograph Chest radiograph showing the presence of nodules, fixed infiltrates, or cavities Abnormal urinary sediment Microhematuria (>5 red blood cells per high power field) or red cell casts in urine sediment Granulomatous inflammation on biopsy Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole) Diagnosis (Contd) American College of Rheumatology –not intended to be used in routine clinical practice and established before ANCA. Presence of 2 or more yield 88% sensitivity and 92% specificity Nasal or oral inflammation Abnormal chest radiograph (nodules, alveolar opacities) Abnormal urine sediment Granulomatous inflammation on biopsy of an artery or perivascular area Diagnosis (Contd) Routine Labs-nonspecific- Leukocytosis, thrombocytosis (>400,000), marked ESR, and normocytic,normochromic anemia, mildly elevated RF ANCA- as previously described Tissue Biopsy- dx should be confirmed by tissue bx at site of active disease .Nasopharyngeal bx less invasive, but may not see full pathogenesis due to small amount of tissue- acute and chronic inflammation Renal bx-segmental necrotizing glomerulnephritis w or w/o cresents Skin-leukocytoclastic vasculitis with little or no complement and immunoglobulin Lung-granulomatous and vasculitis Diagnosis (Contd) Biopsy specimens showing the triad of vasculitis, granulomata, and large areas of necrosis Sinuses Nose Skin--leukocytoclastic vasculitis with little or no complement and immunoglobulin on immunofluorescence Kidney--segmental necrotizing glomerulonephritis that is usually pauci-immune on immunofluorescence / EM Lung--vasculitis and granulomatous inflammation (Only large sections of lung tissue obtained via thoracoscopic or open lung biopsy are likely to show all of the histologic features) Seropositivity for C-ANCAs Antineutrophil cytoplasmic antibodies Focal or diffuse necrotizing extracapillary glomerulonephritis is the histological hallmark of ANCA-associated Vasculitis Massive necrosis is usually associated to diffuse circumferential extracapillary proliferation. From a clinical point of view, the patient is affected by rapidly progressive renal failure . The biopsy specimen of a lung from a patient with Wegener granulomatosis showing evidence of vasculitis and inflammation C-ANCA staining pattern of ethanol-fixed normal human neutrophil ANCA ~90% of Wegener's cases are ANCA+ In limited dz, up to 40% may be ANCA neg 80 - 90 % PR3-ANCA Remaining MPO-ANCA Is ANCA sufficient? Concensus is that tissue dx is necessary Rarely may initiate tx w/o biopsy Should attempt to confirm w/ biopsy when able Differential Dx of Vasculitis Fibromuscular dysplasia Cholesterol emboli Atrial myxoma with emboli Infective endocarditis Malignancies,ie lymphamatoid granulomatosis Bacteremia Rickettsial dz Amyloid SLE Differential of Pulmonary Renal Syndrome Goodpasture’s Disease Systemic Vasculitis Wegener’s Granulomatosis Microscopic Polyangiitis Churg-Strauss Syndrome Cryoglobulinemia Henoch-Schonlein Purpura Connective Tissue Disease Polymyositis/Dermatomyositis Progressive Systemic Sclerosis SLE Primary Glomerular Disease IgA Nephropathy Post-Infectious GN Membranoproliferative GN Treatment Traditional Prednisone (initiated at 1 mg/kg daily for 1 to 2 months. then tapered) Cyclophosphamide (2mg/kg daily for at least 12 months) >90% improve and 75% remit Treatment (Contd) Many physicians favor use of daily oral cyclophosphamide/corticosteroid combination therapy in the initial treatment of all pts dx with Wegener’s, and Once remission is induced (which requires a minimum of 3-6 months for most pts), other less toxic immunosuppressives can be employed Treatment (Contd) Use of aggressive immunotherapy is justified b/c survival in untreated generalized Wegener’s is extremely poor, with up to 90% of pt’s dying with in 2 yrs from respiratory or renal failure, but mortality is markedly diminished with introduction of cyclophosphamide/corticosteroid therapy Treatment (Contd) Response to therapy-partial or complete resolution of inflammatory manifestations, such as inactive urine sediment, although renal failure can persist Treatment (Contd) IV Cyclophosphamide monthly- lowers the overall cumulative dose-role is incompletely defined, and both equal and decreased efficacy has been described in Wegener’s, which may be due to different pt populations in the studies, nonresponders had more severe disease, and those with incomplete response- switching to oral daily regimen may induce remission Treatment (Contd) Methotrexate-mild dz, higher relapse rate, can’t use in Cr >2.0 Plasmapharesis-pts with renal dz needing dialysis, pulmonary hemorrhage, or also with anti-GBM Treatment (Contd) In one of largest nonrandomized prospective single center studies, outcomes of 158 pts with Wegener’s treated with varying regimens at NIH were reported Standard low dose cyclophosphamide plus prednisone(133), cyclophos alone (8), glucocorticoids alone(10), or other cytotoxic agents plus steroids(6). Cyclophos administered for a mean of 2 yrs. Treatment (Contd) Mean follow up 8 yrs-In cyclophos and steroids: Survival 80%, with deaths due to Wegners, side effects or both Significant clinical improvement was observed in more than 90% of pts, with 75% achieving complete remission Among the 98 pts followed for more than 5 yrs, more than half experienced remission of greater than 5 yrs Treament (Contd) So, based on studies, first line is daily oral cyclophosphamide/corticosteroid. Cyclophos at 1.5-2 mg/kg/day, steroid (1mg/kg/day). IV Cyclophosphamide can be used, not well studied, but associated with higher relapse and longer to remission Methotrexate-maybe used in mild disease, or in maintenance, but either way, higher relapse rate Azathioprine-maintence, esp in pts with renal insuffiency Steroids- no significant benefit in maintenance Treatment (Contd) Duration of maintenance therapy- 12-18 months after stable remission May need more long term maintenance esp if ANCA continues to be positive Treatment (Contd) 50% in remission relapse AND daily cyclophos is very toxic pancytopenia, infection, hemorrhagic cystitis bladder cancer (increased 33-fold) lymphoma (increased 11-fold) Treatment (Contd) Monthly IV cyclophosphamide -- less toxic but less effective Weekly methotrexate -- maintains remission Trimethoprim-sulfamethoxazole -- controversial (?effective for disease limited to the respiratory tract), reduces the relapse rate Steroids —prednisone vs solumedrol Plasmapheresis -unproven, awaiting MEPEX trial Recommended for anti-GBM+, pulm hemmorhage, renal failure IVIG— recommended in the setting of infection during PLEX Prognosis Overall, the morbidity and mortality associated with Wegener’s granulomatosis and microscopic polyangiitis, results from the combined effects of irreversible organ dysfunction b/c of inflammatory injury occurring before and the early phase of effective therapy, consequences of immunsuppressive therapy, and natural hx of disease Prognosis (Contd) Morbidity-consequences of therapy (glucocorticoid toxicity, increased risk of malignancy ie bladder cancer, skin ca, sterility, organ failure); disease related damage (partial hearing loss and persistent proteinuria);increased risk of DVT/PE in ANCA Prognosis (Contd) Renal –ESRD eventually occurs in 20-25% of pts. Poor renal outcome associated with more severe renal dysfunction at presentation, lack of response to initial treatment,and enhanced amount of fibrotic changes on renal bx Mortality- Major causes of death are complications of underlying disease and therapy. 90% mortality rate in 2 yrs in untreated. Higher mortality in elderly, those with florid organ failure at presentation. Prognosis (Contd) Poorer outcomes with advanced age, severe renal impairment, DAH. Mortality >75% if untreated with median survival of 5 months. Drastic improvement since 1970s in mortality. Permanent morbidity: • CKD 42% • Hearing Loss 35% • Nasal Deformity 28% • Tracheal Stenosis 13% • Severe Infection 50% (Treatment) Conclusions One of the most frequent pulmonary-renal syndromes Granuloma’s in upper respiratory tract: rhinitis, sinusitis, pharyngits, stomatitis, pulmonary infiltrates (nodules with cavitations) with hemoptoe, respiratory insufficiency, diffusion disturbances Most frequently RPGN-crescentic GN with pauci –immune GN ANCA positive (large majority C-ANCA) Conclusion (Contd) Oral cyclophosphamide 1 - 2 mg/kg BW + corticosteroids 0.6 -1 mg/kg BW. I.V. pulse of cyclophosphamide 500 mg/m² every month for 3 months + corticosteroids- results are not better? Follow ANCA titers In case of dialysis need, plasmapheresis is to be considered, together with pulses of cyclophophamide. Maintenance therapy: low dose of cyclophophamide,methotrexate for pulmonary or upper respiratory tract manifestations: trimetoprim-sulfamethoxazole