Vasculitides

Question 1

What diseases mimic Behcet’s disease ?

Answer 1

Crohn’s disease, ulcerative colitis, and familial Mediterranean fever mimic many of the features suggestive of Behcet’s disease.

Question 2

What complications occur in Behcet’s disease that cause excessive morbidity and mortality?

Answer 2

The greatest morbidity and mortality comes from neurologic, ocular, and large vessel arterial or venous disease.

Question 3

What medications effectively treat Behcet’s syndrome ?

Answer 3

Therapeutic agents that have proven effective in Behcet’s disease include glucocorticoids, colchicine, azathioprine, anti-TNF therapy, interferon alfa-2a and interferon alpha-2b at 3 to 19 million units three times weekly, thalidomide, and rituximab.Smaller trials of cyclophosphamide, cyclosporine, show some benefit as well.

Question 4

What treatment is used to manage glomerulonephritis seen in Behcet’s syndrome?

Answer 4

Renal disease seems to behave like granulomatosis with polyangiitis, so that rituximab might be effective if glomerulonephritis is present. Those patients with amyloidosis do better with colchicine.

Question 5

What are the usual signs and symptoms of granulomatosis with polyangiitis (GPA) ?

Answer 5

Granulomatosis with polyangiitis (GPA , formerly Wegener’s granulomatosis), was initially recognized due to nasal or oral inflammation with ulceration and crusting, pulmonary infiltrates or nodules, abnormal urinary sediment with red cell casts with acute glomerulonephritis, and granulomatous inflammation with capillaritis on biopsy. ANCA Testing typically shows antibodies to proteinase 3 (C-ANCA). Antibodies to myeloperoxidase (P-ANCA) are more typical of microscopic polyangiitis wherein biopsies usually show capillaritis without the granulomas. Both patterns are pauci-immune.
GPA relapses much more frequently than MPA.

Question 6

Is retinal vein thrombosis a sign of temporal arteritis?

Answer 6

Temporal arteritis is associated with amaurosis fugax in 26% with central retinal artery occlusion, branch retinal artery occlusion, and non-arteritic anterior ischemic optic neuropathy. 5% of central retinal vein occlusion is related to amurosis fugax-sudden onset of blurred vision in one eye but not temporal arteritis.
Central retinal vein occlusion increases with age, hypertension, smoking, obesity, and the presence of diabetes and glaucoma, and decreases with alcohol and physical activity.

Question 7

IgG4 related disease (IgG4RD) may affect what systems?

Answer 7

IgG4RD may involve salivary and lacrimal glands, autoimmune pancreatitis, cholangitis, retroperitoneal fibrosis, aortitis and periaortitis, thyroid disease, lung and pleural disease, and renal disease.

Question 8

What is unique about IgG4 antibodies?

Answer 8

The disulfide bonds linking the heavy chains in IgG4 can link multiple molecules together and form unusual immune complexes. Levels of IgG4 above135 mg percent occur in about 90% of patients with IgG4RD.

Question 9

What are the common causes of angioedema?

Answer 9

Drug reaction to Ace inhibitors are the most common cause, but NSAID’s, calcium channel blockers, estrogens, fibrinolytic agents, any new medication or significant increase in dosage should also be suspect. Complement factor 1 inhibitor (C1-INH) deficiency either inherited (Types 1, 2 or 3) or acquired are not as common. Inherited forms are due to absent protein, defective protein, or inherited problems with clotting factors causing bradykinin release. Aquired C1-INH deficiency can occur with malignancies where autoantibodies develop to C1-INH.

Question 10

What are the diagnostic criteria for Behcet’s disease?

Answer 10

Behcet’s disease is characterized by the presence of recurrent aphthous ulcers with at least 3 episodes in any 12 month period. There must be at least 2 additional features such as: recurrent genital ulceration, eye lesions, skin lesions, or positive pathergy test. Anterior or posterior uveitis on slit lamp examination or retinal vasculitis documented by an ophthalmologist, erythema nodosum or papulopustular skin lesions or pseudo-folliculitis with characteristic achneiform nodules observed by a physician. Other features commonly explained by Behcet’s disease include arterial aneurysms in the heart, kidney, or pulmonary vasculature, oligo or polyarticular non deforming arthritis, renal amyloidosis or glomerulonephritis, pericarditis or myocarditis. A positive pathergy test is defined by a papule 2 mm or more mm in size developing within 48 hours after the insertion of a 20 gauge needle 5 mm into the forearm skin. Aseptic meningoencephalitis, cerebral vasculitis, recurrent phlebitis, arteritis, synovitis, or focal bowel ulceration might substitute for pathergy in European or North American populations.

Question 11

What sort of ANCA occurs in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) ?

Answer 11

ANCA testing is positive to proteinase 3 (C-ANCA) in GPA (90%) and antimyeloperoxidase (P-ANCA) in MPA (70%). 20% have the wrong antibody and 10% are negative. Renal biopsies usually show pauci-immune capillaritis.
Deep venous thrombosis is associated with anti-plasminogen antibodies.

Question 12

What is unique about the histopathology of IgG4RD?

Answer 12

There is marked infiltration by plasma cells and lymphocytes with storiform fibrosis (spoke wheel distribution).Biopsy showing increase in IgG4 plasma cells are specific.

Question 13

What treatments work for IgG4RD?

Answer 13

Prednisone at 0.5 mg per kilogram for months with additional methotrexate, azathioprine, mycophenolate, or rituximab if necessary. There are no randomized controlled trials.

Question 14

Is retinal vein thrombosis a sign of temporal arteritis?

Answer 14

Temporal arteritis is associated with amaurosis fugax in 26% with central retinal artery occlusion, branch retinal artery occlusion, and non-arteritic anterior ischemic optic neuropathy. 5% of central retinal vein occlusion is related to amurosis fugax, but not temporal arteritis.

Question 15

What factors indicate a poor response to cytotoxan in primary angiitis of the central nervous system (PACNS)?

Answer 15

Increased gadolinium enhancement of the meninges is more common 80% vs 19% and absence of seizures upon presentation is also more common 47% vs 17%.
A&R 5/14.

Question 16

What are the respiratory tract signs of GPA?

Answer 16

Respiratory system involvement may produce hoarseness, cough, dyspnea, strider, wheezing, hemoptysis or pleuritic pain as well as tracheal or symbolic stenosis, pulmonary consolidation/pleural effusion.
Chest x-rays may show pulmonary fibrosis, pulmonary arterial hypertension, nodules, patchy or diffuse opacities, fleeting pulmonary infiltrates, and hilar adenopathy.
ENT manifestations occur in 90% of GPA and 35% of MPA.

Question 17

What are the renal manifestations of GPA?

Answer 17

Renal involvement is present initially in 18% and eventually an 85%. Proteinuria is usually subnephrotic. Renal biopsy usually shows pauci-immune necrotizing glomerulonephritis. ANCA positivity occasionally shows immune complex deposition and has a worse prognosis.
Changes are described as focal if at least 50% of glomeruli are normal, crescentic if at least 50% show cellular or fibrotic crescents, sclerotic with at least 50% globally sclerotic, and mixed if less than 50% are normal, crescentic, or sclerotic.
ANCA-associated glomerulonephritis may complicate unrelated nephropathy, lupus nephritis, anti-glomerular basement membrane antibody disease, IgA nephropathy, and bacterial infection-related glomerulonephritis.

Question 18

What skin changes occur in GPA?

Answer 18

Skin involvement with leukocytoclastic angiitis occurs in about 50% but may also include urticaria, livedo reticularis, erythema nodosum, pyoderma gangrenosum, and Sweet syndrome.

Question 19

What are the features of Limited GPA?

Answer 19

Limited GPA with slower disease progression are usually young, female, less likely to be ANCA positive and more likely to have recurrent upper respiratory tract disease.

Question 20

What antigens are responsible for P-ANCA positivity?

Answer 20

P-ANCA immunological testing is an artifact of alcohol fixation which permits positively charged granule proteins to circle around the negatively charged nucleus. The most common target is myeloperoxidase, but other proteins include lactoferrin, elastase, cathepsin G, bactericidal permeability inhibitor, catalase, lysozyme, beta-glucuronidase, and others.
C-ANCA is usually due to antibodies to protinease 3.
Formalin fixed neutrophils avoid confusion with ANA + sera. Both types of fixation need to be checked by Eliza testing for specific antigens PR3-ANCA, and MPO-ANCA.

Question 21

What sort of ANCA develops in renal Limited vasculitis, and anti-GBM antibody disease?

Answer 21

Renal limited vasculitis shows MPO-ANCA in 80%. Lesser numbers have a specificity for lysosome associated membrane protein-2 (LAMP-2). Some LAMP-2 positive cases are ANCA negative. Extra renal manifestations often develop later.
Anti-GBM antibody disease is positive and up to 40%. Studies on stored serum show the presence of ANCA positivity years prior to development of anti-GBM antibody disease.
Rapidly progressive glomerulonephritis may be considered as ANCA induced even when testing negative if other forms of pauci-immune glomerulonephritis such as Churg-Strauss vasculitis can be excluded.

Question 22

What form of ANCA positivity develops in Churg-Strauss vasculitis, and ulcerative colitis?

Answer 22

In Churg-Strauss syndrome 50% are ANCA positive, 70% were MPO-ANCA.
80% of patients with ulcerative colitis are P-ANCA positive usually against myeloid cell specific 50-kD nuclear envelope protein or lactoferrin, cathepsin G, elastase, lysozyme, PR3.

Question 23

What drugs commonly cause ANCA positivity?

Answer 23

Levamisole contaminated cocaine induces MPO-ANCA and in 50% PR3-ANCA. Leukopenia 28% and often abnormal urinalysis and pulmonary hemorrhage.
Antithyroid drugs especially propylthiouracil (OR 11.8) are associated with MPO-ANCA. Hydralazine, and minocycline, penicillamine, allopurinol, clozapine, phenytoin, rifampicin, cephotaxime, isoniazid, and indomethacin. Drug-induced lupus and/or interstitial nephritis might well have drug-induced ANCA-associated vasculitis.

Question 24

What treatment is effective in acute renal failure due to ANCA positive vasculitis?

Answer 24

Pulse prednisone followed by cyclophosphamide or rituximab with plasmapheresis is usually effective initially.
Even when anuric with markedly elevated creatinine, a trial of therapy for weeks, often results in return of renal function enough to discontinue dialysis.

Question 25

How are renal crescents formed?

Answer 25

Glomerular damage is due to breaks in the glomerular capillary wall resulting in release of fibrinogen, macrophages and T cells which then produce IL-1 and TNF. Collagen deposition is driven by fibroblast growth factors especially TGF-beta. Crescents are unlikely to respond to immunosuppressive treatment.