Systemic vasculitis 2 Dr.

Overview ► Wegener’s granulomatosis  Epidemiology  Clinical features  Pathogenesis  Diagnosis  Treatment  Prognosis

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 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 SymptomAt OnsetTotal SymptomAt OnsetTotal ► ENT 75%95% ► Lung ► Joints ► Fever ► Kidney ► Cough ► Eye ► Skin ► Weight Loss ► Nervous System (Central/Peripheral) 0 10/15 One-third of patients may be without symptoms at onset of disease

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 presentation. Lung involvement: Lung involvement:  Infiltrates  Nodules  Hemoptysis  Pleuritis 33% with lung involvement are asymptomatic. 33% with lung involvement are asymptomatic. About 80% have no renal involvement at presentation. About 80% have no renal involvement at 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

► 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) Criteria for Classification Diagnosis

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) (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 ► % 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

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 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 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%CKD 42% Hearing Loss 35%Hearing Loss 35% Nasal Deformity 28%Nasal Deformity 28% Tracheal Stenosis 13%Tracheal Stenosis 13% Severe Infection 50% (Treatment)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)

► Oral cyclophosphamide mg/kg BW + corticosteroids 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 Conclusion (Contd)

HENOCH-SCHÖNLEIN PURPURA

DEFINITION ► Also called “anaphylactoid purpura” ► HSP is a systemic vasculitic syndrome with:  Palpable purpura  Arthralgias  GI involvement  Glomerulonephritis

BACKGROUND ► First described in 1801 by William Heberden, a physician in London, who wrote about a case of a 5 year old boy with hematuria, abdominal pain, joint pains and a skin rash. ► In 1837, Johann Schönlein and later in 1874, Edouard Henoch described multiple case reports of similar cases. They also showed an association of an upper respiratory infection preceding development of symptoms.

EPIDEMIOLOGY ► 90% of cases reported in children  Peak in children aged 4-7 ► Male:Female (1.5:1) ► 50% follow a URI ► Renal disease is more severe in adults

PATHOGENESIS ► Likely mechanism thought to be an immune-complex mediated disease with deposits in the glomerular capillaries, dermal capillaries and GI tract. ► Mesangial deposits of IgA are the same as those seen in IgA nephropathy

PRECIPITATING ANTIGENS ► INFECTIONS  URI  Measles  Rubella  Parvovirus B19  Mycoplasma  Coxsackie virus  Toxocara  Amebiasis  Salmonella  C.difficile  H.pylori  Adenovirus  Legionella  Tuberculosis  Mumps  Streptococcus  Morganella morganii

PRECIPITATING ANTIGENS ► Drugs  Vancomycin  Streptokinase  Ranitidine  Cefuroxime  Diclofenac  Enalapril  Captopril

PRECIPITATING ANTIGENS ► Other:  Food hypersensitivity  Cold exposure  Autosomal recessive Chronic granulomatous disease  Myelodysplastic syndrome  Small cell lung cancer  Breast cancer

PATHOLOGIC FEATURES DERMATOLOGIC FINDINGS: Leukocytoclastic vasculitis with IgA deposition

Direct Immunofluorescence of skin biopsy. Granular IgA and C3 staining of cutaneous vasculature.

H & E stain of skin biopsy showing leukocytoclastic vasculitis with infiltration of neutrophils.

Skin biopsy: Leukocytoclastic vasculitis with mononuclear and polymorphonuclear cell infiltrates in the perivascular space

PATHOLOGIC FEATURES RENAL FINDINGS: Granular deposits of IgA, mesangioproliferative glomerulonephritis and crescent formation

Renal biopsy: sclerosis and fibrous crescents in the glomerulus.

Immunofluorescence: Glomerular deposits of IgA

CLINICAL FEATURES ► Tetrad of symptoms  Abdominal pain  Renal disease  Palpable purpura  Arthritis/arthralgias – more common in adults and most common in knees and ankles. Generally self-limiting

CLINICAL FEATURES ► PALPABLE PURPURA: most commonly seen on lower extremities and buttocks, however can also been seen on the trunk and arms.  Lesions begin as erythematous macules and progress to purpuric, non-blanching, nonpruritic lesions that may become confluent

CLINICAL FINDINGS ► GI INVOLVEMENT: more common in children. Symptoms include abdominal pain, nausea, vomiting, diarrhea, constipation or bowel intussusception. May present with GI bleeding.

CLINICAL FEATURES ► RENAL INVOLVEMENT:  in up to 50% of patients  Usually more rapidly progressive in adults. Rare in children  May present with hematuria  Can have mild glomerulonephritis leading to microscopic hematuria and can lead to a rapidly progressive glomerulonephritis with RBC casts  Usually resolve spontaneously.

DIAGNOSTIC EVALUATION ► May have mild leukocytosis ► Normal platelet count ► Normal serum complement levels ► Elevated IgA in 50%

DIAGNOSIS ► Generally a clinical diagnosis ► Skin Biopsy: can be helpful and used to confirm IgA and C3 deposits and leukocytoclastic vasculitis. ► Renal Biopsy: not usually needed for diagnosis. Will show mesangial IgA deposits and segmental glomerulonephritis

MANAGEMENT ► Usually self-limiting (1-6 weeks) ► Steroids:  may decrease tissue edema, may aid in arthralgias and some abdominal pain  Has not been shown to be beneficial in kidney disease or dermal manifestations  Does not lessen chance of recurrence  Does not shorten duration of disease

MANAGEMENT ► if rapidly progressive glomerulonephritis  Multidrug regimens with cytotoxic drugs however not many reports with treatment in adults.  Plasmaphoresis  IVIG ► Symptomatic management of GI symptoms and surgical intervention if warranted.

PROGNOSIS ► Prognostic factors:  generally a milder course in children with shorter duration and fewer recurrences  Proteinuria >1gm/day with worse prognosis if develop nephrotic syndrome ► 1-5% children progress to ESRD ► Recurrence in up to 40% of patients