RHEUMATOLOGY (WWW.MEDICINENOTES.

IN)

VASCULITIS
BY DR. OM LAKHANI , MD
IMPORTANT POINTS These notes are made from Standard Textbook of Medicine The current notes corresponds to Chapter 326 of Harrisons Internal medicine The Yellow shades refer to things you have to revise frequently (atleast once a week) The Blue shades refers to concepts The Pink shades refers to concepts that are not required for undergraduate level but useful for Postgraduate level.

Q. What is Vasculitis? Vasculitis is quite simply inflammation of the blood vessals. Inflammation of blood vessals leads to Ischemia of the tissue involved depending on the size and site of blood vessal involved. Q. Classify vasculitis Based on Primary and Secondary vasculitis Primary vasculitis Wegners granulomatosis Churg Struss syndrome Takayasus arterities etc Secondary Vasculitis Drug induced vasculitis Infection associated Associated with other connective tissue disorder Associated with malignancy

Q. Classify Vasculitis on basis of size of vessel involved Large vessel vasculitis Takayasus arteritis Giant cell arteritis Medium vessel vasculitis

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Kawasakis disease Polyarterities Nodosa Small vessel vasculitis Henoch Scholein Purpura (ANCA negative) Wegeners granulomatosis Chugg Strauss syndrome Microscopic polyangiitis

PATHOGENESIS OF VASCULITIS

Q. What is the basis of pathogenesis of Vasculitic syndrome ? The basic etiology of vasculitis is attributed to some sort of reaction to known or unknown antigen. Other factors are also involved in the process. There are three types of pathogentic process observed.

1. Deposition of Immune complexes 2. Production of Antineutrophilic cytoplasmic antigens (ANCA) 3. Pathogenic T cell response and Granuloma formation

Q. What is the process of Immune complex deposition ? The immune complex deposition theory is similar to Serum sickness like phenomenon As a result of allergic reaction to antigen vasoactive amines like histamine, bradykinin etc are released from mast cell and platelets They increase the permeability of the vessel walls There is also antigen-antibody reaction taking place with formation of complexes that are not cleared from the body by the phagocytic system. This is because initially there are excess antigen and less antibodies and small complexes are formed that donot fix compliment and are not cleared off. With the increase permeability of vessels wall Ag-Ab complexes enter the vessel wall and get deposited on the vessel wall. The antigen-antibody complex deposits cause activation of compliment pathway The compliment is chemotactic for neutrophils and it attracts the neutrophils The neutrophils release enzymes which cause damage to the vessel wall as a collateral damage. This is a Type III hypersensitivity reaction Page 2

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Two classical examples of this are hepatitis B and Hepatitis C (Cryoglobinemia) These are also associated with Glomerulonephritis with reduced serum compliment

Q. Which are the ANCA Associated vasculitis ? The small vessel vasculitis like Chugg Strauss, Wegners granulomatosis and Microscopic polyangiitis are referred to as ANCA Associated vasculitis. Q. What are the different type of ANCA (Anti-neutrophilic cytoplasmic antibody)? cANCA- Cyctoplasmic ANCA o In vasculitis it is associated with Proteinase 3 hence it is called Anti Proteinase 3 antibody o In seen in 90% cases of Wegners granulomatosis pANCA Perinuclear ANCA o It is associated with various different types of antibodies againt various targets o The pANCA associated with vasculitis is against Myleoperoxidase and it is anti myeloperoxidase antibody o Non Myleoperoxidase pANCA are associated with other diseases like Inflammtory bowel disease

Q. Does the level of ANCA correlate with severity of the vasculitis ? No The level of cANCA may not correlate with the severity of the vasculitis. ANCA titres should not be used for judging progress of the disease and response to treatment.

CLINICAL FEATURES Q. Which clinical features lead you to think about vasculitis syndrome ? These are some typical clinical features of vasculitis Palpable purpura Unexplained ischemic event Chronic sinusitis Mononeuritis multiplex Microscopic hematuria Glomerulonephritis with systemic manifestations

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Q. Which disease mimic the typical symptoms of vasculitis ? Infectious diseases Bacterial endocarditis Disseminated gonococcal infection Pulmonary histoplasmosis Coccidioidomycosis Syphilis Lyme disease Rocky Mountain spotted fever Whipple's disease

Coagulopathies/thrombotic microangiopathies Antiphospholipid antibody syndrome Thrombotic thrombocytopenic purpura Neoplasms Atrial myxoma Lymphoma Carcinomatosis Drug toxicity Others Sarcoidosis Atheroembolic disease Antiglomerular basement membrane disease (Goodpasture's syndrome) Amyloidosis Migraine Cocaine Amphetamines Ergot alkaloids Methysergide Arsenic

CLINICAL VIGNETTE A 40 year old Microbiologist had history of chronic progressive dyspnea. Recently she had hemoptysis. Her X ray was suggestive of multiple bilateral cavitary infiltrates. She was initially DR. OM LAKHANI (WWW.MEDICINENOTES.IN) Page 4

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thought to have sputum negative tuberculosis and was treated with AKT for 6 months. However despite her treatment she continued to have occasional hemoptysis. On urine examination she was also found to have microscopic hematuria. Her physician suspected Wegners granulomatosis. What is test his doctor should ask for diagnosis of Wegners granulomatosis

WEGNERS GRANULOMATOSIS Q. What are the organs involved grossly in Wegners granulomatosis ? Organs involved in Wegners granulomatosis include o Upper respiratory tract o Lower respiratory tract o Kidney - Glomerulonephritis Q. What are the current preferred name for Wegners granulomatosis ? Wegners is preferably called as Granulomatosis with polyangiitis. Q. What is the characteristic pathological finding in Wegners granulomatosis ? Characteristic pathological finding of Wegners is Necrotizing vasculitis. It is associated with Granuloma formation which may be extravascular or intravascular Q. What is the characteristic of lung lesion in Wegners ?

Lung lesion in Wegners consists of multiple, bilateral and cavitary infiltrates. Patient may present with hemoptysis or chronic progressive dyspnea

Q. What is the characteristic lesion in the kidney ? In kidney initially there is focal segmental glomerulitis which may evolve sometimes to RPGN Granuloma may or may not be found in the kidney. Renal involvement dominates the clinical picture is often the cause of death It is found in 77% cases of Wegners Those without renal involvement are said to have Limited Wegners granulomatosis

Q. True or false- Chronic carrier of Staphyloccus aureus have increased risk of replase of Wegners granulomatosis ?

True. Chronic carriers of Staph aureus have higher risk of relapse DR. OM LAKHANI (WWW.MEDICINENOTES.IN) Page 5

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However, it is not the etiological agent for Wegners.

Q. What are the features of upper respiratory tract involvement in Wegners ?

Saddle nose deformities Epistaxis Serous otitis media Severe tracheal stenosis- leading to severe respiratory tract obstruction Paranasal sinus pain

Q. What is characteristic of ANCA in Wegners ?

90% of patients with Wegners have cANCA positive (anti proteinase 3) Few may have Anti MPO (pACNA) also positive though it is rare Few may be ANCA negative as well Q. Which disease is a close differential of Wegners granulomatosis ?

Idiopathic Midline granuloma is a close differential of Wegners granulomatosis It is associated with erosion through skin and face which is rare in Wegners It is treated with local irradiation (Radiation never used in Wegners ) Q. Which drug has revolutionized the management of Wegners granulomatosis ?

Cyclophosphamide. Q. How is the treatment of Wegners started ?

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Wegner's

Severe disease

Mild disease

Induction

Maintenence

Methotrexate + Steroids

Cyclophsophamide + Steroids

Methotrexate, Azathioprine, MMF

Patients with severe disease are started on induction regimen with Cyclophosphomide 2 mg/kg daily (for 3-6 months) along with Prednisolone 1 mg/kg for first month followed by gradual tapering of the dosage to alternate day over 6-9 months. Patient with RPGN and Lung hemorrhage above regimen is sometimes combined with adjunctive plasmapheresis if the S. Creat is >5.8 Once induction regimen is completed maintence of remission is done with Methotrexate, Azathioprine or Mycophenolate mofetil Duration of therapy is for 2 years after which it is gradually tapered.

Q. Is there an advantage of IV cyclophosphamide over oral therapy ? IV Cyclophosphamide given every 2 weeks is an alternative to daily oral therapy This reduces risk side effect of Cyclophosphamide However the rate of relapse is higher with IV cyclophosphamide. Q. What is the risk of relapse after remission ? Relapse rate is high in tune of 50-70% after remission ANCA is not used for determination of relapse Q. What are the side effects with cyclophosphamide ?

Cyclophosphamide can lead to o Hemorrhagic cystitis o Risk of Bladder carcinoma on long use o Bone marrow suppression DR. OM LAKHANI (WWW.MEDICINENOTES.IN) Page 7

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o Infertility

Q. Is there a role of Rituximab ? In a recent trial Rituximab with steroids was found to be equally efficacious as cyclophosphamide plus steroids. However the long term rate of relapse with Rituximab is not known There is a risk of Hepatitis B activation and small risk of PMFL as Opportunistic infection with JC virus with Rituximab. These complications have to be kept in mind.

Q. Which organ involvement in Wegners does not respond to systemic therapy ?

Endobronchial disease and subglottic stenosis does not respond to systemic therapy

Q What is the role of Cotrimoxazole as therapy in Wegners ?

Isolated sinus disease in Wegners can be treated with Cotrimoxazole therapy.

ANSWER TO CLINICAL VIGNETTE cANCA (Anti Proteinase 3) would be the test to go for to diagnose Wegners granulomatosis

MICROSCOPIC POLYANGIITIS

Q. What is the difference between Wegners granulomatosis and Microscopic polyangiitis ? WEGNERS Seen Seen cANCA Present MICROSCOPIC POLYANGIITIS Not seen Not seen pANCA Absent

Lung parenchymal involvement Upper Respiratory tract involvement ANCA Granulomas

Q. What is the mean age of occurrence of Microscopic polyangiitis DR. OM LAKHANI (WWW.MEDICINENOTES.IN) Page 8

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Microscopic polyangiitis is often seen at age of around 50-60 year.

Q. Microscopic polyangiitis is part of Polyarterities nodosa. True or false False. Renal involvement of PAN was considered microscopic polyangittis. However, many now considered it as a different entitiy.

Q. Since there is no lung parenchymal involvement in MP, there is no hemoptysis. True or false. False. Hemoptysis is not an uncommon presentation of MP. It is because of pulmonary capilitis.

Q. What are the other clinical features of MP ? MP presents with Renal involvement, with renal lesions similar to that seen in Wegners granulomatosis. They also have hemoptysis occasionally. Other features typical to vasculitis may also be present. As noted before pANCA (anti MPO) are positive with MP. Q. What is the treatment of MP ? Treatment of MP is similar to that of Wegners granulomatosis

CHURG STRAUSS SYNDROME

Q. What are the features of Churg strauss syndrome ? Features of Churg struss syndrome include Asthma Peripheral and tissue eosinophilia Extravascular granuloma Vasculitis of multiple organ system

Q. What are the clinical features of CSS ? CSS the lung picture dominates with patient presenting with Asthma Other features of vasculitis are also present Mononeuritis multiplex is not uncommon Renal involvement is less common compared to other small vessel vasculitis Myocardial involvement often is the cause of death in these patients.

Q. What is THE characteristic lab findings in CSS ?

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Striking Peripheral eosinophlia is characteristic of CSS Eosinophil counts are often >1000 /ul

Q. What is the drug of choice in treatment of CSS ? CSS is treated classically with steroids.

POLYARTERITIS NODOSA

Q. Which vessels are preferentially involved in PAN and which are spared ?

PAN preferentially involves small to medium vessels like Renal arteries. Involvement of pulmonary artries is rare. Bronchial artery may be involved. Lesions typically seen in bifurcations and branches of vessels Veins are involved but venules are not and involvement of venules should suggest MP

Clinical Pearl : Aneurysmal dilatation of vessel wall is typical of PAN

Q.True or false : Glomerulonephritis is typically seen in PAN ? False. Renal involvement of PAN is typically arteritis without Glomerulonephritis. Renal involvement in form of vasculitis of renal artery leading to hypertension is the most common clinical organ involvement in PAN. Q. Which two diseases are strongly associates with PAN ? Hepatitis B and Hairy cell leukemia have strong association with PAN. Q. Is there any specific serological test for PAN ? No. PAN does not have any serological test. pANCA is rarely positive in PAN. Q. How is the diagnosis of PAN established ? Since the symptoms of PAN are often vague and no serological test is positive, diagnosis of PAN is very difficult. The only consistent way of diagnosing PAN is by biopsy. Biopsy is done of tissue involved. Sometimes demonstration of aneurysmal dilatation on angiography may be helpful However, aneurysmal dilatations are not pathognomic of PAN and neither are they always found in PAN.

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Q. Describe the treatment of PAN

PAN

Without HEpatitis B

With Hep B

Mild Disease

Severe Disease

Antiviral therapy for Hep B

Steroids

Cyclophsophamide + Steroids

GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA

Q. What are the other names of Giant Cell arteritis ? Giant cell arteritis is also called Cranial Arteritis Temporal arteritis Q. Which vessels are preferentially involved in GCA ?

Carotid and its branches esp temporal artery Q. What is Polymyalgia Rheumatica ?

It is related it GCA It is associated with pain in o Neck o Shoulder o Lower back DR. OM LAKHANI (WWW.MEDICINENOTES.IN) Page 11

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o Hips o Thighs It can occur in isolation, however occurs in 40-50% cases with GCA Q. What is epidemiology of GCA ?

It is more common in Females than males Generally seen in older people after age 40 yrs Associated with HLA- DR4

Q. What is the typical clinical profile of GCA ?

Patient with age >50 yrs presents with o Fever o Headache o Anemia o High ESR o Polymyalgia rheumatica Q. What is the typical characteristics of headache associated with GCA ? Headache is associated with tender, pulsatile, thickened artery. Scalp pain and Jaw claudication are often associated.

Q. What is the dreaded complication of headache associated with GCA ? Headache associated with GCA can lead to Ischemic optic neuropathy. This often leads to blindness. This is an important complication of Giant cell arteritis.

Q. How is diagnosis of GCA confirmed ? To confirm the diagnosis of GCA, biopsy of the Temporal artery is often required. Ultrasound of the artery is sometimes useful. Q. True or false. Patient with GCA are at risk of developing abdominal arotic aneurysm ? False. Patients with GCA are at high risk of developing thoracic aortic aneurysm. Q. What is the treatment of choice for GCA ?

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Patients with GCA are treated with Prednisolone. Asprin is added to patients to reduce risk of ischemic complications. Prednisolone is also useful for Polymyalgia rheumatica. ESR is used to monitor progress of disease.

TAKAYASUS ARTERITIS Clinical Vignette Dr. Rahul an intern in Medicine was asked to take the pulse and blood pressure of all patients in the ward by his registrar. Dr. Rahul got stuck at a third patient, Miss Suhasini , an 18 year old girl admitted for right sided hemiparesis . CT scan was showing an infarct. Dr. Rahul tried his best to feel the radial pulse of his patient but did not succeed. He used stethoscope and could clearly hear the heart beat of the patient but the pulse eluded him again. His asked his registrar, why couldnt he feel his patients pulse ? In a broader sense, why did this young girl develop a cerebral infarct in the first place ? His Registrar gave his just one answer Which is ? Q. Which vessels are preferential involved in Takayaus arteritis ? TA preferentially involves the branches of the arch of aorta. Hence it is also called as aortic arch syndrome. Q. In which group of patients is TA common ? TA is common in young girls and young women especially in Asia. Q. Which vessel are most commonly involved in TA ? 1. Subclavian artery most commonly involved- can lead to arm claudication and Raynauds phenomenon. Often these patients donot have a palpable radial pulse and hence called Pulseless disease. 2. Carotid artery are second most common involvement- can lead to TIA and syncope. Many other vessels including the pulmonary artery can be involved. Renal artery involvement often contributes to hypertension

Q. How is the diagnosis of Takayasus arteritis established ? The diagnosis of Takayasus is established by the characteristic picture on an arteriogram. It is characterised by irregular vessel wall, post stenotic dilatation and aneurysm formation on an arteriogram.

Q. How is Takayasus arterities treated ?

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Takayasus is treated with steroids. In some cases methotrexate is added to the regimen. The disease has a chronic relapsing course.

HENOCH SCHONLEIN PURPURA Q. What is the other name of HSP ? It is also known as anaphylactoid purpura. Q. What are the clinical features of HSP ? HSP is characterized by the following features 1. 2. 3. 4. 5. Small vessels vasculitis ANCA negative More common in children in 1st decade of life Palpable purpura- more in lower limbs and buttocks GI manifestations (70% cases) a. Colicky abdominal pain b. Passing blood and mucus per rectum 6. Polyarthralgia without arthritis 7. Glomerulonephritis 1/3rd cases a. Mild glomerulonephritis b. Resolves without treatment c. Rarely RPGN can develop Q. What are the features of disease in adults ? Adults have more of polyarthralgia. Renal involvement is often insidious. Myocardial involvement is sometimes seen in adults. Q. How is diagnosis of HSP established ? Diagnosis of HSP is established by skin biopsy which shows leukocytoclastic vasculitis with characteristic IgA deposition. Q. How is HSP treated ? HSP is self resolving and generally does not require treatment. Predinsolone is given in some cases to reduce edema, discomfort and arthralgia. However, steroids donot reduce the skin or renal manifestations and does not reduce the risk of recurrence.

BEHETS SYNDROME

Q. What is the diagnostic criteria for Behet's syndrome ? DR. OM LAKHANI (WWW.MEDICINENOTES.IN) Page 14

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Diagnostic criteria for Behet's syndrome are Recurrent oral ulceration plus two of the following: Recurrent genital ulceration Eye lesions Skin lesions Pathergy test

Q. In which group of Patients is this disease common ? This disease in common in patients in the old silk route ie from Middle east to Far east. Q. What are the clinical features of Behets syndrome ? 1. Recurrent oral ulceration a. Classical symptom of the disease b. Usually small ulcers c. Heal without scar 2. Genital ulcerations- often painfuk 3. Arthralgias 4. Eye involvement a. Bilateral panuveatitis- dreaded complications b. Can cause blindness. 5. Increase risk of superficial and deep vein thrombosis 6. Arterial involvement- pulmonary artery can also be involved 7. CNS vasculitis a. Parenchymal Lesion is often seen b. IL6 levels are elevated in CSF c. MR spectroscopy is useful in diagnosis 8. GI involvement similar to Crohns disease often seen

Q. What is Pathergy s test ? The pathergy test is a simple test in which the forearm is pricked with a small, sterile needle. Occurrence of a small red bump or pustule at the site of needle insertion, 1 to 2 days after the test, constitutes a positive test.

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OTHER CONDITIONS

Q. Which is the most common vasculitis seen in clinical practice ? Cutaneous vasculitis (leukocytoclastic vasculitis) is the most common form of vasculitis seen in clinical practice. Q. What are the features of skin involvement in Vasculitis ? Skin lesions in vasculitis are Palpable purpura Pruritic More in lower extremities

Q. What are features of Cogans syndrome ?

Interstitial Keratitis Vestibuloauditory symptoms Systemic vasculitis- especially aortic valve involvement

Q. What are features of Kawasakis disease ? Kawasakis disease is mainly seen in children <5 yr It is associated with o Bilateral conjunctival injection without exudates o Fever o Erythema of palms and soles o Edema of hands and feet o Periungual peeling of finger and toes o Polymorphous exanthem o Strawberry tongue o Cervical adenopathy Most most dreaded complication is involvement of Coronary artery which can produce aneurysms and even Myocardial infarction Apart from cardiac involvement, the disease is generally benign. Q. Which are the drugs implicated in vasculitis ? Drugs implicated to cause vasculitis include DR. OM LAKHANI (WWW.MEDICINENOTES.IN) Page 16

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Allopurinol Gold Sulphonamides Penicillin Phenytoin Hydralazine PTU

Q. Which infections can cause vasculitis ? Rickettsia Bacterial endocarditis HIV EBV

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