1. Case conference
Samer banihani
2/16/2011

2. 73 yr WM presented to ER c/o increasing sob and generalized weakness that has been going on for about 4 days. He said he had been coughing bld since 2 days. Pt denied cp or fever

3. PAST MEDICAL HISTORY
1. HTN
2. HLP.
3. CAD
PAST SURGICAL HISTORY
The patient had a 3-vessel coronary artery bypass.
ALLERGIES
No known drug allergies.
FAMILY HISTORY
Positive for HTN , DM
MEDICATIONS
1. Metoprolol.
2. Norvasc.
3. Simvastatin.
4. Niacin.
5. Aspirin
SOCIAL HISTORY
Denies smoking, alcohol use, or illicit drug use.

4. BP 132/68, T 97.4 , oxygen saturation 94% on 10 L by Venturi mask, P 78, RR 18.
HEENT: NCAT, EOMI, MMM, no perioral cyanosis
Chest: CTAB, no w/r/r
CV: regular rate with irregularly irregular rhythm, no m/r/g
Abdm: +BS, nondistended, nontender
Extremities: 2+ radial and DP pulses, no edema, cyanosis; some ecchymoses on UE
Neuro: CN2-12 intact, pupils unequal with 4mm on L, 2 mm on R but reactive; sensation intact and strength 5/5 to BUE/BLE

5. Differential Diagnosis:

6. CBC: wbc 23 , Hb 8.7 , Hct 25, Plt 133
BMP: Na135, K 3.9, Cl 97, Hco3 17 , Cr17.3, BUN 124, Ca 8.9 , phos 6.1
LFT: AST 22 ,ALT 26 , TP4.6, Albumin 3.1 , Al.phos 41,
LDL 285 , Haptoglobin 115
INR 1.2 , Fibrinogen 267
UA: RBC 25-30, wbc 2-3 , albumin +4,

7. Hepatitis Panel negative C-ANCA negative P-ANCA positive 958
Serology:
HIV negative
Hepatitis Panel negative
C-ANCA negative
P-ANCA positive 958
Anti-GBM negative
C3 , C4 normal
ANA neg
CXR: Diffuse pulmonary infiltration

8. Differential Diagnosis: Pulmonary-Renal Syndrome
Goodpasture’s disease
Microscopic polyangitis
Wegener’s granuloma
Churg-Strauss syndrom
SLE
Behcet’s syndrome
Essential mixed cryoglobulinemia
Rheumatoid vasculitis
Drugs: penicillamine, hydralazine, propylthiouracil
Acute renal failure with hypervolemia
Severe cardiac failure
Hantavirus infection
Opportunistic infections
ARDS w/ renal failure in multi-organ failure
Renal vein/IVC thrombosis w/ PE
Henoch-Schonlein purpura

9. ANCA associated Vasculitis

13. Renal involvement *hematuria, proteinuria and renal failure
*less frequent in Churg-Strauss
*hematuria, proteinuria and renal failure
*renal failure usually has characteristics of rapidly progressive glomerulonephritis

14. Skin
*Purpura most common in lower extremities, occurs as recurrent crops.
*Nodular lesions occur more frequently in Churg-Strauss and Wegener’s

15. Upper and lower respiratory tract
*pulmonary hemorrhage
*nodular or cavitary lesions in Wegener’s and Churg-Strauss
*subglottic stenosis, sinusitis, rhinitis, otitis media, ocular inflammation most common in Wegener’s
Pulm hemorrhage caused by hemorrhagic capillaritis
CXR and CT from Wegener’s showing bilateral nodules and masses primarily at bases

16. Cardiac *identified in 50% of pts with Churg- Strauss
*<20% in Wegener’s and microscopic polyangiitis
*transient heart block, ventricular hypokinesis, infarction, myocarditis, endocarditis, pericarditis
17yo Wegener’s aortic valve insufficiency found to have two perforations in the aortic valve leaflets

17. Nerves *central: vasculitis within the meninges
*peripheral: mononeuritis multiplex
*central: vasculitis within the meninges
31yo ANCA vasculitis + headaches + positive ANCA titer, MRI shows enhancing leptomeningeal thickening of the cerebellum with extension into the falx. Meningeal biopsy c/w leptomeningeal involvement of Wegener’s. Mayo Clinic proceedings

18. Gastrointestinal
*typically abdominal pain, blood in the stool, mesenteric ischemia and rarely perforation
*can also mimic pancreatitis and hepatitis
Small bowel loops are edematous, inflamed, and hemorrhagic

19. Diagnosis

21. Demonstration (C-ANCA) by indirect immunofluorescence with normal neutrophils. There is heavy staining in the cytoplasm while the multilobulated nuclei (clear zones) are nonreactive. These antibodies are usually directed against proteinase 3 and most patients have Wegener's granulomatosis.
Demonstration of (P-ANCA) by indirect immunofluorescence with normal neutrophils. Staining is limited to the perinuclear region and the cytoplasm is nonreactive. Among patients with vasculitis, the antibodies are usually directed against myeloperoxidase

22. Anti-neutrophil cytoplasmic autoantibodies
Serologic testing for ANCA is useful diagnostic test, but should be interpreted in the context of other patient characteristics
Sensitivity for pauci-immune small vessel vasculitis and GN is 80-90%
¼- 1/3 of patients with anti-GBM crescentic GN and ¼ of patients with idiopathic immune-complex crescentic GN are ANCA positive
Pts with concurrent ANCA and anti-GBM antibodies have worse prognosis than those with ANCA alone

23. Anti-neutrophil cytoplasmic autoantibodies
Proteinase 3
(PR3/c-Anca)
Myeloperoxidase
(MPO/p-ANCA)
Negative
Wegener’s granulomatosis
70%
25% 5%
Microscopic polyangiitis
40%
50%
10%
Churg-Strauss syndrome
60%
30%
Pauci-immune glomerulonephritis
20%

24. Pathologic diagnosis Biopsy of involved site Skin Muscle Nerve Gut
Kidney

25. Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of Wegener granulomatosis
Light micrograph showing fresh segmental necrotizing lesions with bright red fibrin deposition (arrows). A necrotizing glomerulonephritis can be seen in a variety of inflammatory disorders including vasculitis and lupus nephritis. The latter has prominent immune complex deposition which is generally absent in vasculitis

27. European League Against Rheumatism (EULAR)

28. Birmingham Vasculitis Score

29. Initial Therapy cyclophosphamide and glucocorticoids Rituximab
Methotrexate
plasma exchange
The use of aggressive initial immunosuppression is justified because the mortality rate in untreated generalized WG is as high as 90 percent at two years, usually due to respiratory or renal failure

34. Rituximab
Two randomized trials have suggested that rituximabmay be an effective alternative to cyclophosphamidefor the initial treatment of patients who have newly diagnosed disease or have relapsed following treatment with cyclophosphamide or other immunosuppressive therapy
A) RAVE trial
B) RITUXVAS

37. RAVE
Multicenter, randomized, double-blind, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction.
Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis.
Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups.
The primary end point was a BVAS/WG of 0 and successful completion of the prednisone taper at 6 months
Secondary end points included rates of disease flares, a BVAS/WG of 0 during treatment with prednisone at a dose of less than 10 mg per day and rates of adverse events

39. Result
The rituximab-based regimen was 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%) reached the primary end point (P=0.01).
Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage
There were no significant differences between the treatment groups with respect to rates of adverse events
Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease

40. Limitation
These studies suggest that rituximab is as effective as cyclophosphamidefor the initial treatment of WG and MPA or for patients with relapsing disease. However, both studies are limited in the duration of follow-up . Longer-term results from the RAVE trial are expected in 2011.

41. Role of plasma exchange
Several controlled trials of patients with WG, MPA, or the related disorder segmental necrotizing glomerulonephritis with no immune deposits on pathologic examination (which is thought to represent renal-limited vasculitis) have demonstrated no overall benefit for the renal disease from plasma exchange, with the possible exception of patients who one or more of the following :
Severe renal disease, which has been variably defined
Concurrent anti-glomerular basement membrane (GBM) antibody disease
Severe pulmonary hemorrhage

44. CYCAZAREM trial Patients Vasculitis / crt < 5.7
At least 3 mos of CYC, then with remission switch to AZA or CYC, fu for 18 mos
ANCA (+), mostly WG
GFR >50 cc/min
After induction of remission, randomized to Continued CTX (1.5 mg/kg) for 12 mos total Change to AZA (2 mg/kg)
18 mos fu
N Engl J Med. 2003;349(1):36-44

45. Time to first relapse
Eleven patients in the azathioprine group had relapses
10 patients in the cyclophosphamide group

46. CYCAZAREM – renal recovery
There were similar increases in the glomerular filtration rate from study entry to 18 months in the two groups:
an increase of 17.5 ml per minute (95 percent confidence interval, 11.9 to 23.1) in the azathioprine group (r2=0.57)
and an increase of 23.5 ml per minute (95 percent confidence interval, 18.2 to 29.0) in the cyclophosphamide group (r2=0.56)
End-stage renal failure developed in two patients in each group

47. CYCAZAREM - conclusion
No difference in relapse rate
CTX (14%) vs AZA (15%)
Only predictor of relapse was
MPA (8%) vs WG (18%)
No difference in serious adverse events

48. MMF vs Azathioprine for Remission Maintenance (IMPROVE)
Randomized multicenter Trail
All patients received cyc and steroid for induction
Primary Outcome:
Relapses were more common in the MMF group (42/76 patients) compared with the azathio group (30/80 patients)
Result:MMF was less effective than azathioprine for maintaining disease remission
N=156
JAMA. 2010;304(21):

49. Methotrexate versus azathioprine
 Azathioprine and methotrexate provide comparable efficacy and are similarly safe when administered for maintenance therapy.
In the only well-designed trial (WEGENT) that directly compared these agents, both drugs were associated with a similar number of adverse effects that required drug discontinuation (11 and 19 percent for azathioprine and methotrexate, respectively) and a similar relapse rate (36 and 33 percent). The majority of relapses (73 percent) occurred after the cessation of maintenance therapy.

50. Duration of maintenance therapy
no randomized trials that have compared different durations of maintenance therapy.
Maintenance therapy in patients with newly diagnosed WG or MPA is usually given for 12 to 18 months after stable remission has been induced.

51. Solution study
Fifteen patients with histologically proven active refractory Wegener (seven unresponsive to cyc, (eight intolerant) were treated with ATG
During a follow-up of months, seven patients relapsed after a mean of 8.4 months .Six patients are free of relapse for 22.3 months.
Anti-T-cell–directed treatment with ATG may be a therapeutic option for severe refractory Wegener’s
Kidney Int Apr;65(4):

52. Summary

53. Renal transplantation
Frequency of recurrence about 20%
Graft loss caused by recurrence < 5%
Positive ANCA titer at time of transplant does not increase risk of recurrent disease in transplant
Recurrent ANCA GN in transplant responds to therapy similarly to recurrent disease in native kidneys