Tuesday, May 11, 2010

Topic Discussion: ANCA Disease

The current JASN 2010 issue  has a special article on ANCA disease. A nice historical notation of the disease and where it stands currently
Few things I learned from this article
1. It was first mentioned in 1982
2. Awareness of Friedrich Wegener's connection to the Nazi has prompted efforts to remove his name from the disease entity. Initially, this disease used to be called Rhinogenic granulomatosis
3. Churg Strauss used to be called allergic granulomatosis
4. What activates the neutrophils by ANCA? A theory of second hit is thought about.  You have these antibodies ( ANTI PR3, ANTI MPO) and they are just floating around. A second hit, perhaps an infection or alteration in the immunologic mileau might trigger the ANCA disease.  
5. ANCA causes disease but what produces ANCAs? There  are three theories regarding this topic
           ---> Theory of autoantigen complement theory: the protein complementary to the autoantigen initiates an immune response and leading to increased risk of thrombosis
          ---> LAMP 2 theory: Patients with anti PR3 and MPO have been noticed to have antibodies to another neutrophil protein , lysosome associated membrane protein 2 or LAMP-2 ( analogous to fimH peptides on bacteria). So anti LAMP-2 antibodies could result from molecular mimicry and lead to anti PR3 and MPO antibodies. 
           ----> Neutrophils are surrounded by neutrophil nets and perhaps the MPO and PR3 may be available on the net for initiating an autoimmune response.
6. Summary of some major trials

1. MEPEX trial: JASN 2007 showed that for patients with ANCA vasculitis and Creatinine > 5.8 and on dialysis, plasmapheresis was helpful in taking them off dialysis and for renal recovery.
2. CYCLOPS trial: Large trial that compared oral vs IV cytoxan in ANCA vasculitis and there was no difference in end points for renal outcomes but there was less cumulative dose of cytoxan in IV dosing and less side effects.
3. CYCAZAREM trial: compared changing to Imuran after 6 months of induction with PO cytoxan to continuing cytoxan PO for 12 months, no difference in remission.
4. RITUXVAS:- RCT (small) IV cytoxan to Rituxan + initial 2 months of cytoxan IV — no difference in remission. More adverse events in rituxan arm
5. RAVE:- Rituxan + azathioprine for maintenance vs IV cytoxan plus azathioprine, induction part completed:- similar rates of remission and no major advantage with rituxan
6. NORAM:- compared Methotrexate in lieu of cytoxan, more relapse with Methotrexate.

In terms of maintenance, two trials, one comparing MMF to AZA showed AZA to be safer and less side effects. 
SO it the best treatment even till date for induction :- cytoxan and maintenance imuran?

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