1. Vasculitis Bshar Al-Ktoot Qais Al-Omari Yara Rashed Emad Al-Nimer

2. Vasculitis primary or secondary May involve several organs

3. Vasculitis  inflammation of and damage to blood vessels  lumen is usually compromised → ischemia of the tissues supplied by the involved vessel  any type, size, and location of blood vessel may be involved so heterogeneous syndromes may result.  primary or may be a secondary component of another primary disease( as in SLE, Sjögren's syndrome, RA).  May confined to a single organ or involve several organs.

4. PATHOPHYSIOLOGY AND PATHOGENESIS  genetic predisposition, environmental exposures, and the regulatory mechanisms associated with immune response to certain antigens.

5. Mechanisms of vasculitis (1) Pathogenic Immune-Complex Formation  deposition of antigen-antibody complexes in vessel walls → affect vascular permeability and cause neutrophils chemotaxis → These cells then infiltrate the vessel wall and release their enzymes, which damage the vessel wall

6. (2) ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCA) ANCA in small-vessel vasculitis

7. con’t (2) ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCA) cANCA directed against Proteinase-3 antigen pANCA directed against myeloperoxidase antigen

8. How ANCA cause vasculitis?

9. con’t (2) ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCA)  Important in small-vessel vasculitis  If ANCA is + ( present ) ⇨ called ANCA associated vasculitis  ANCA are autoantibodies directed against certain proteins/enzymes in the cytoplasmic granules of neutrophils and monocytes  two major categories of ANCA  1- cytoplasmic ANCA (cANCA) → due to diffusely binding of ANCAs to antigen targets throughout the neutrophil so that cause diffuse, granular cytoplasmic staining pattern observed by immunofluorescence microscopy cytoplasm, Proteinase-3 is the major cANCA antigen

10.  2- peri nuclear ANCA(pANCA) →more localized perinuclear or nuclear staining, pANCA mostly directed against myeloperoxidase antigen  when neutrophils or monocytes are primed, proteinase-3 and myeloperoxidase translocate to the cell membrane, where they can interact with extracellular ANCA, ANCAs activate neutrophils to adhere to endothelial cells, resulting in local production of reactive oxygen species (ROS) and release of proteolytic enzymes that damage vascular endothelial cells

11. (3) Pathogenic T Lymphocyte Responses and Granuloma Formation direct Ab toxicity

12. (3) Pathogenic T Lymphocyte Responses and Granuloma Formation  delayed hypersensitivity and cell- mediated immune injury in granulomatous vasculitis.  Vascular endothelial cells can express HLA class II molecules (in a manner similar to antigen-presenting macrophagese), these form interaction with CD4+ T lymphocytes, endothelial cells activate T lymphocytes→ granulomas can form in the setting of persistent T-cell response to certain stimuli

13. But what is granulomatou inflammation?  It is chronic inflammation that form granuloma.  Granulomas are collections of specialized macrophage referred to as epitheliod cells often surrounded by a rim of lymphocyte.  Antigens are presented by Macrophages to CD4 lymphocytes →lymphocytes release cytokines especially interferon-y →activation of macrophages that assume epithelioid appearance ( epithelioid cells )→may coalesce to form multinucleate giant cells.

15. Classification of vasculitis Large vessel vasculitis refers to the aorta and its major branches.

16. Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR)  Giant cell arteritis = temporal A  CGA almost exclusively in individuals >50 years, rare under 60.  F:M is 3:1.  severe headaches often localised to the temporal or occipital region.  tenderness of the scalp

17. Con’t /Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR)

18.  GCA referred to as cranial arteritis or temporal arteritis  GCA is inflammatory granulomatous arteritis ( giant cell formation ) of large vessels of the head and neck particularly the temporal artery which occurs in association with PMR.  systemic disease that can involve arteries in multiple locations, particularly the aorta and its main branches.  Clinical features result from the ischemia related to the involved vessels  symptoms of GCA include severe headaches ( involvement of the cranial arteries ) often localised to the temporal or occipital region, tenderness of the scalp, may Jaw pain ( claudication of the jaw when eating) due to ischaemia of the masseter muscles

19. Con’t /Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR)  Visual disturbance can occur the most feared manifestation is sudden painless temporary or permanent loss of vision in one eye due to Involvement of the ophthalmic artery  features of systemic inflammation including fever, malaise, fatigue, anorexia, weight loss…  Rarely, neurological involvement may occur, with transient ischaemic attacks, strokes, brain-stem infarcts and hemiparesis.

20. Con’t /Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR)  PMR : symmetrical muscle pain and stiffness(shoulder and pelvic girdles), worse in the morning.  in 40–50% of patients with GCA

21. Con’t /Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR)  PMR: inflammatory disorde cause sudden onset symmetrical muscle pain and stiffness affecting the shoulder and pelvic girdles( limb girdle pattern)→ inflammatory activity seems to be concentrated in tissues surrounding the affected joints, worse in the morning, also the Constitutional symptoms such as weight loss, fatigue, malaise and night sweats are common.  polymyalgia rheumatica occurs in 40–50% of patients with GCA and management of both is similar.  studies has increasingly supported that giant cell arteritis and polymyalgia rheumatica represent differing clinical spectrums of a single disease process.

22. Investigations  A raised ESR and/or CRP  The diagnosis is usually based on clinical features, raised ESR and response to steroid.  Anaemia ( normochromic, normocytic)  Liver function abnormalities particularly increased alkaline phosphatase levels.  Temporal artery biopsy (definitive diagnostic test) taken before, or within 7 days of starting, high doses of Corticosteroids→ shows giant cell arteritis, negative biopsy does not exclude the diagnosis because the lesions are focal

23. Management  Corticosteroids should be commenced urgently in suspected GCA because of the risk of visual loss(dramatic response )→symptoms will have completely resolved within 48-72 hours in virtually all patients (40-60 mg prednisolone daily ), i f this improvement does not occur, the diagnosis should be questioned and need biopsy.  Then dose should be progressively reduced, guided by symptoms and ESR→reaching a dose of 10-15 mg by about 8 weeks.  Thereafter, slower reduction by 1 mg per month until 5-7.5 mg daily

24. Takayasu's Arteritis Asia Female Pulseless disease upper extremity claudication may involve thoracic and abdominal aorta and may renal arteries

25. Takayasu's Arteritis  most common in Asia( esp Japan)  most prevalent in young females.  8:1 female preponderance  often affects the ascending aorta and aortic arch, causing obstruction of the aorta and its major arteries.  termed as pulseless disease because of →occlusion of the large arteries originating from the aorta.  may involve thoracic and abdominal aorta and may occlude large branches such as the renal arteries.  Cause intimal hyperplasia, medial and adventitial thickening, →may fibrotic occlusion.  During the acute stage, fever, malaise, weight loss, and other systemic symptoms

26.  chronic stages of the disease may cause large artery occlusion and present as upper extremity claudication, cerebral ischemia, and syncope.  In investigation: cause raised ESR and CRP, normocytic, normochromic anaemia  Treatment : Glucocorticoids and immunosuppressive agents have been reported to be effective in some patients during the acute phase. may require a surgical bypass

27. MEDIUM VESSLE VASCULITIS INCLUDE: 1- POLYARTERITIS NODOSA. 2- KAWASAKI DISEASE.

28. Polyarteritis Nodosa: * It is a multisystem, necrotizing vasculitis of small and medium- sized muscular arteries in which involvement of the renal and visceral arteries is characteristic. * A rare condition,which is common in male * Affect any age group but peak incidence is btw 40-50. * Imp risk factor is Hepatitis B, increase risk 10X. * Pathologically there is a fibinoid necrosis of vessels walls with microaneurysm formation, thrombosis and infarction.

29. - Presentation is with fever, malaise, weight loss and myalgia. & manifestation of multisystem disease: symptoms duo to organ infarction: * Skin : palpable purpura, ulceration, infarction + livedo reticularis

30. * Renal : presents with haematuria and proteinuria. Hypertension and acute/chronic renal failure occur * Cardiac: coronary arteritis causes myocardial infarction and heart failure. * Neurological: in 70% of pt arteritis of the vasa nervosa leads to neuropathy,affect sensory + motor. * Abdominal : pain due to arterial involvement of the abdominal viscera, mimicking acute cholecystitis, pancreatitis or appendicitis.

31. Investigations of PAN: 1-Blood count (Anaemia, leukocutosis, and raised ESR). 2-Biobsy from an affected organ. 3-Angiography (Demonstration of microaneurysms in hepatic, intestinal, or renal vessels if necessary). 4-Other investigations: ECG “ cardiac involvement” and abdominal ultrasound depending on the clinical problem. Treatment of PAN: Corticosteroids, usually in combination with immunosuppressive drugs such as azathoprine.

32. Kawasaki Disease

33. Kawasaki`s disease - acute systemic vasculitis affecting children under 5 years of age..- worldwide distribution but more frequent in Japan.- there may be an infective trigger Clinical feature - fever lasting more than 5 days. - bilateral conjuctival congestion. - dryness and redness of the lips and oral cavity. - cervical lymphadenopathy..- polymorphic rash.- redness and oedema of the palms and soles

34. Diagnosis & treatment - 5/6 of the above features are essential for the diagnosis or - 4/6 if there is coronary artery aneurysm - tests shows albuminurea, leucocytosis, thrombocytopenia, and raised CRP - anti-endothelial cell autoantibodies are often present - treatment with high dose iv immuno- globulin followed by aspirin 200-300 mg. daily

35. SMALL VESSEL VASCULITIS Divided into: positive or negative anti-neutrophilic cytoplasplasmic antibody (ANCA) ANCA- positive vasculitis - Wegner`s granulomatosis - Churg-Strauss granulomatosis - Microscopic polyangitis ANCA- negative vasculitis - Henoch-Schonlein purpura - Cryoglobulinaemic vasculitis - Cutaneous leucocytoclastic vasculitis.

36. GRANULOMATOSIS WITH POLYANGIITIS (WEGENER'S) Definition :Granulomatosis with polyangiitis (Wegener's) characterized by * granulomatous vasculitis of the upper and lower respiratory tracts + * glomerulonephritis + * variable degrees of disseminated vasculitis involving both small arteries and veins may occur. unknown aetiology Incidence and Prevalence * an uncommon disease *estimated prevalence of 3 per 100,000. *The disease can be seen at any age, the mean age of onset is 40 years. Pathology and Pathogenesis The histopathologic hallmarks are - necrotizing vasculitis of small arteries and veins together with - granuloma formation, which may be either intravascular or extravascular.

37. Lung involvement typically appears as multiple, bilateral, nodular cavitary infiltrates which on biopsy almost invariably reveal the typical necrotizing granulomatous vasculitis. - CXR shows (single or multiple nodular masses or pneumonic infiltrates with cavitation) in migratory pattern Upper airway lesions, particularly those in the sinuses and nasopharynx, typically reveal inflammation, necrosis, and granuloma formation, with or without vasculitis. renal involvement is characterized by a focal and segmental glomerulitis that may evolve into a rapidly progressive crescentic glomerulonephritis In addition to the classic triad of disease of the upper and lower respiratory tracts and kidney, virtually any organ can be involved with vasculitis, granuloma, or both.

38. Involvement of the upper airways occurs in 95% of patients with granulomatosis with polyangiitis (Wegener's). Patients often present with severe upper respiratory tract findings such as paranasal sinus pain and drainage and purulent or bloody nasal discharge, with or without nasal mucosal ulceration. Nasal septal perforation may follow, leading to saddle nose deformity. Serous otitis media may occur as a result of eustachian tube blockage..Subglottic tracheal stenosis resulting from active disease or scarring Eyes 55% Conjunctivitis Dacryocystitis Scleritis Proptosis Eye pain Visual loss Retinal lesions Corneal lesions Iritis Kidney 77% Glomerulonephritis Ear/nose/throat 95% Sinusitis Nasal disease Otitis media Hearing loss Subglottic stenosis Ear pain Oral lesions Lung 85 % Pulmonary infiltrates Pulmonary nodules Hemoptysis Pleuritis - the typical histological changes are seen in the kidneys ( necrotising microvascular glomerulonephriti)

39. (“saddle nose” deformity). saddle nose deformity wegener's The centers of both are necrotic & cavitating

40. Diagnosis The diagnosis of granulomatosis with polyangiitis (Wegener's) is made by the demonstration of necrotizing granulomatous vasculitis on tissue biopsy in a patient with compatible clinical features. The specificity of a positive antiproteinase-3 ANCA for granulomatosis with polyangiitis (Wegener's) is very high, especially if active glomerulonephritis is present However, if all the typical features are not present at once, it needs to be differentiated from the other vasculitides, (Goodpasture's syndrome), relapsing polychondritis, tumors of the upper airway or lung, &infectious diseases such as histoplasmosis. The cornerstone of diagnosis in Wegener's granulomatosis remains the correlation of typical clinical features with histopathologic patterns.

41. Treatment : (Wegener's) was universally fatal within a few months of diagnosis. treatment with cyclophosmide, also rituximab is used S.E of daily cyclophosphamide is very toxic: pancytopenia, infection, hemorrhagic cystitis bladder cancer (increased 33-fold) lymphoma (increased 11-fold) Monthly IV cyclophosphamide -- less toxic but less effective

42. Microscopic polyangitis * MPO p- ANCA ( 70%). *Characterized by: 1- Nongranulomatous, necrotizing vasculitis with few or no immune deposits. 2- involves the kidneys and lungs. * Typical presentation is : rapidly progressive glomerulonehritis + alveolar hemorrhage. * Without prompt treatment, rapidly progressive glomerulonehritis leads to irreversible renal damage.

43. the most common disease manifestations: - Glomerulonephritis (79%), - weight loss (73%), - mononeuritis multiplex (58%), - fever (55%). Treatment : The first-line induction therapy consists of oral or intravenous administration of high dose corticosteroids with immunosuppressive treatment (e.g. cyclophosphamide, or rituxan). In case of severe renal disease and major alveolar hemorrhage, plasma exchange is beneficial. Maintenance treatment consists in continuation of cyclophosphamide or rituxan, or substitution with azathioprine. Relapses are treated with increased or reinstituted immunosuppression. In case of renal failure, dialysis and/or renal transplantation are appropriate.

44. Churg-Strauss Syndrome: referred to as allergic angiitis and granulomatosis. Several phases of Churg-Strauss syndrome are described as follows: 1- a prodromal phase, characterized by the presence of allergic disease (typically asthma or allergic rhinitis), which may last months to many years. 2- an eosinophilia–tissue infiltration phase, in which remarkably high peripheral eosinophilia may occur and tissue infiltration by eosinophils is observed in the lung, gastrointestinal tract, and other tissues. 3- a vasculitic phase

45. Pathology and Pathogenesis - The necrotizing vasculitis involves small and medium-sized muscular arteries, capillaries, veins, and venules. -A characteristic histopathologic feature is granulomatous reactions. These are usually associated with infiltration of the tissues with eosinophils This process can occur in any organ in the body; lung involvement is predominant, with skin, cardiovascular system, kidney, peripheral nervous system, and gastrointestinal tract.

46. Clinical Manifestations nonspecific manifestations: Allergic rhinitis and sinusitis develop in up to 61% of patients and are often observed early in the course of disease. The pulmonary findings in Churg-Strauss syndrome clearly dominate the clinical picture with severe asthmatic attacks and the presence of pulmonary Infiltrates. Mononeuritis multiplex is the second most common manifestation and occurs in up to 72% of patients. Skin lesions occur in 51% of patients and include purpura in addition to cutaneous and subcutaneous nodules. fever, malaise, anorexia, and weight loss, which are characteristic of a multisystem disease.

47. laboratory finding eosinophilia, which reaches levels >1000 cells/L in >80% of patients. elevated ESR, fibrinogen, or alpha 2 -globulins can be found in 81% of patients. Approximately 48% of patients have circulating ANCA that is usually antimyeloperoxidase. Diagnosis Biopsy. Treatment - Glucocorticoids.

48. Henoch-Schönlein Purpura Definition referred to as anaphylactoid purpura. characterized by: 1. palpable purpura (most commonly distributed over the buttocks and lower extremities). 2. arthralgias 3. gastrointestinal signs and symptoms (abdominal pain) 4. glomerulonephritis. Approximately 30–70% have clinical evidence of renal disease with haematuria and/or proteinuria. Incidence and Prevalence usually seen in children and Young adult

49. Pathology and Pathogenesis : Immune complexes deposit in the small vessels (IgA). It often occurs after upper respiratory tract infections.

50. Laboratory studies generally show : -Mild leukocytosis. -Normal platelet count. -Eosinophilia. -Normal Serum complement components. -IgA levels are elevated in about one-half of patients. Diagnosis 1.based on clinical signs and symptoms. 2.Skin biopsy may show IgA deposition by immunofluorescence. 3.Renal biopsy is rarely needed for diagnosis but may provide prognostic information in some patients. Treatment The prognosis of HSP is excellent. Most patients recover completely, and some do not require therapy Treatment is similar for adults and children. When glucocorticoid therapy is required, prednisone

51. Idiopathic Cutaneous Vasculitis ( Cutaneous Leukocytoclastic Angiitis ) Definition - Inflammation of the blood vessels of the dermis. - Is not one specific disease but a manifestation that can be seen in a variety of settings. - In >70% of cases occurs either as part of a primary systemic vasculitis or as a secondary vasculitis related to an inciting agent or an underlying disease. - In the remaining 30% of cases, cutaneous vasculitis occurs idiopathically.

52. Pathology and Pathogenesis - Postcapillary venules are the most commonly involved vessels; capillaries and arterioles may be involved less frequently. - This vasculitis is characterized by a leukocytoclasis, a term that refers to the nuclear debris remaining from the neutrophils that have infiltrated in and around the vessels during the acute stages. subacute - In the subacute or chronic stages, mononuclear cells predominate; in certain subgroups, eosinophilic infiltration is seen. - Erythrocytes often extravasate from the involved vessels, leading to palpable purpura.

53. Clinical Manifestations This usually appears on the lower legs as a symmetrical palpable purpura. - The skin lesions may be pruritic or even quite painful, with a burning or stinging sensation. - Edema may accompany certain lesions, and hyperpigmentation often occurs in areas of recurrent or chronic lesions. Diagnosis -biopsy. -An important diagnostic principle in patients with cutaneous vasculitis is to search for an etiology of the vasculitis : either it an exogenous agent, such as a drug or an infection, or an endogenous condition, such as an underlying disease.

54. Treatment 1. Some cases of idiopathic cutaneous vasculitis resolve spontaneously, while others remit and relapse. 2. antimicrobial therapy 3. Glucocorticoids are often used in the treatment of idiopathic cutaneous vasculitis.

55. Cryoglobulinemia - Cryoglobulins are cold-precipitable monoclonal or polyclonal immunoglobulins. - They are classified into 3 type.type II+III are associated with Cryoglobulinemia vasculitis - May be associated with a systemic vasculitis characterized by palpable purpura, arthralgias, weakness, neuropathy, and glomerulonephritis. - It can be observed in association with a variety of underlying disorders: multiple myeloma, lymphoproliferative disorders, connective tissue diseases, infection, and liver disease. - In many instances it appeared to be idiopathic.

57. 5% of patients with chronic hepatitis C will develop cryoglobulinemic vasculitis. Pathology and Pathogenesis - Skin biopsies reveal an inflammatory infiltrate surrounding and involving blood vessel walls, with fibrinoid necrosis, endothelial cell hyperplasia, and hemorrhage. - Deposition of immunoglobulin and complement is common. - Membranoproliferative glomerulonephritis is responsible for 80% of all renal lesions in cryoglobulinemic vasculitis.

58. Laboratory Manifestations The fundamental finding is The presence of circulating cryoprecipitates. Rheumatoid factor is almost always found and may be a useful clue to the disease when cryoglobulins are not detected. An elevated ESR and anemia occur frequently. Hypocomplementemia occurs in 90% of patients. Evidence for hepatitis C infection must be sought in all patients by testing for hepatitis C antibodies and hepatitis C RNA. Treatment The majority of cases are associated with hepatitis C infection, treatment with interferon-alpha (IFN-α) and ribavirin.

59. Goodpasture`s syndrome :  It is an autoimmune disease  Goodpasture's syndrome appears in two age groups: - in young men in their late 20s - in men and women in their 60–70s.  It mainly affects the lung (hemorrhaging) and the kidney (glomerulonephritis)hemorrhagingglomerulonephritis  the first lung symptoms usually develop days to months before kidney damage is evident.  Renal involvement follows as acute glomerulo- nephritis  The disease starts with symptoms of an upper respiratory tract infection followed by cough and intermittent haemoptysis, difficulty breathing, fatigue and anaemia.  Dignosis : Renal biopsies typically show focal or segmental necrosis  The chest X-ray shows transient shadows  Treatment : with steroids, sometime plasmophoresis Treatment