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Approach to a Patient with Vasculitis A student Perspective

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1 Approach to a Patient with Vasculitis A student Perspective
Mohammed A. Omair Consultant Rheumatologist Assistant Professor King Khalid University Hospital King Saud Unversity

2 Objectives Review the classification of vasculitis
Epidemiology, manifestations and treatment of different types of vasculitis Vasculitis mimickers

3 Introduction Vasculitis refers to a group of heterogeneous diseases characterized by inflammation within the wall of the blood vessels, resulting in occlusion and/or thrombosis of vessel lumen and, ultimately, tissue ischaemia and/or organ injury. Classification of systemic vasculitides is mainly based on histological features and the size of the vessel predominantly involved, from large- to medium and finally small-sized vessel vasculitides according to the Chapel Hill nomenclature.

4 Size Matters

5 Chapel Hill Nomenclature (1994) Revised in 2012

6 Types of Vasculitides Large vessel vasculitis (LVV)
Takayasu arteritis (TAK) Giant cell arteritis (GCA) Medium vessel vasculitis (MVV) Polyarteritis nodosa (PAN) Kawasaki disease (KD) Small vessel vasculitis (SVV) Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) Microscopic polyangiitis (MPA) Granulomatosis with polyangiitis (Wegener’s) (GPA) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Immune complex SVV Anti–glomerular basement membrane (anti-GBM) disease Cryoglobulinemic vasculitis (CV) IgA vasculitis (Henoch-Schonlein) (IgAV) Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis) Variable vessel vasculitis (VVV) Behcet’s disease (BD) Cogan’s syndrome (CS) Single-organ vasculitis (SOV) Vasculitis associated with systemic disease Vasculitis associated with probable etiology Hepatitis C virus–associated cryoglobulinemic vasculitis Hepatitis B virus–associated vasculitis Syphilis-associated aortitis Drug-associated immune complex vasculitis Drug-associated ANCA-associated vasculitis Cancer-associated vasculitis Others

7 Large Vessel Vasculitis GCA
Giant cell arteritis (GCA) is the most common of the vasculitis syndromes and, being a disease of the elderly, its incidence is increasing with the general ageing of the population. GCA is most feared for its early complications, namely blindness and stroke, resulting from inflammation and subsequent occlusion of ocular and extra cranial arteries, respectively. More recently, however, GCA has been recognized to also affect limb arteries and the aorta with a high prevalence.

8 GCA (Horton’s disease)
It is believed to be an old disease evidenced by a stone relief from ancient Egypt In the grave of Pa-Aton-Ern-Hebs, built during the Amarna period (around 1350 AD) very likely depicts a blind harp player suffering from GCA. Ali Ibn Isa an ophthalmologist in Baghdad (940–1010 BC), recommended removal of the temporal artery not only to treat headaches, but also inflammation of the scalp muscles associated with blindness. the first official case was published in 1932 by Horton. In their report an individual with blindness, tongue necrosis and jaw claudication is described.

9 GCA Inflammation of the vessel wall is characterized by infiltration of T-cells and macrophages, presence of multinucleated giant cells, granulomatous lesions, intimal hyperplasia and destruction of elastic fibers. Dendritic cells (DCs), similar to skin-residing Langerhans cells, have been implicated in providing initial signals that break the immune protection of arterial walls. T cells are functionally selected as well, and belong to either the T helper (Th ) 1 or the Th 17 lineage. CD4+ T cells producing IFN-gama have been identified as key regulators in the vascular lesions of GCA

10 GCA why old age? Self tolerance is an active process within the immune system. Immunosenescence refers to the changes that occur in the immune system in the elderly population With advanced aging fine tuning within the immune system is lost which results in a defect in clearing antigens that lead to self damage and a chronic inflammatory state called inflamm-aging. Cytokines, such as IL-6, TNF-α, and IL-1β, are suspected to have an important role in sustaining chronic inflammation. With advanced age spontaneous production of cytokines leads to a pro-inflammatory environment in which tissues are constantly ‘primed’ by cytokines. Remodeling of the blood vessel wall might also play a role in the pathogenesis of GCA.

11 Feature of GCA Clinical consequences of vascular insufficiency include headaches, scalp tenderness, claudication of the masseter muscles, and vision loss due to ischemia in the visual pathway. The headaches are often intense, throbbing, and sharp in character, and are combined with temporal tenderness. On physical examination, the temporal vessels are thickened, with nodules and absence of pulses. Other arteries of the scalp can be involved. Vision loss is one of the reasons that GCA is considered a prime ophthalmic emergency. Occlusion in branches of the ophthalmic artery results in ischemic optic neuropathy that causes sudden and pain-free blindness. Amaurosis fugax can precede complete vision loss. Patients with blindness in one eye are at high risk to suffer additional visual loss in the other eye.

12 Criteria of GCA Age ≥50 years at disease onset
New onset of localized headache Temporal artery tenderness or decreased temporal artery pulse ESR ≥50 mm/hour Biopsy: necrotising arteriitis; mononuclear cell infiltrates or a granulomatous process with multinucleated giant cells Presence of ≥3/5: sensitivity of 93% and specificity of 91% for distinguishing GCA from other primary vasculitis syndromes

13 Treatment of GCA The golden standard for treatment of GCA is corticosteroids. Patients respond explicitly well, with prompt and substantial improvement of symptoms within 24–48 hours. Initial doses of 60 mg of prednisone (or approx. 1 mg per kg body weight) have been found to be effective in almost all patients. Once patients are stabilized on high doses of corticosteroids, daily prednisone doses should be tapered. A reduction of 10–20% every 2 weeks has proven to be a clinically useful guidance. Corticosteroids can be discontinued in most patients after approximately 2 years of therapy. There is evidence that the disease process does not enter remission but continues with smoldering activity

14 Treatment of GCA Although results of clinical trials have been controversial, a well-designed clinical study with a large cohort of patients could not demonstrate any advantage for MTX/corticosteroid combination therapy compared with corticosteroids alone. From a retrospective study of 143 patients with GCA, aspirin and warfarin were associated with a decrease in the incidence of acute ischemic events. Anti TNF are not efficacious in GCA. Many case series showed that tocilizumab improves clinical outcome in steroid dependent or refractory patients.

15 Takayasu’s Arteritis (TKA)
TKA is a systemic arteritis that predominantly manifests in the aorta and its major branches. It is also known as pulseless disease or occlusive thromboaortopathy. The typical patient is a female of Asian or South American origin presenting with vascular insufficiency and generalized inflammation in the second or third decades of life. Arterial stenosis, occlusion, and aneurysms lead to various signs and symptoms such as extremity pain, claudication, light-headedness, bruits, absent or diminished pulses and loss of blood pressure. Although TA may present with acute events such as visual loss or stroke, it may also cause non-specific constitutional features such as fever, malaise, anorexia, and weight loss.

16 TKA In 1830, Yamamoto reported the first case of TA.
In 1908, Mikito Takayasu was the first to describe peculiar optic fundus abnormalities with coronal anastomosis, which 40 years later were interpreted as neovascularization and anastomosis secondary to ischemia caused by theocclusion of cervical vessels. In 1951, Shimizu and Sano described a cohort of 31 cases and made the connection between pulselessness, coronal anastomosis of retinal vessels, and carotid abnormalities and called it pulseless disease.

17 Classification Criteria for TAK
Age at disease onset < 40 years Claudication of extremities Decreased brachial artery pulse BP difference >10 mm Hg Bruit over subclavian arteries or aorta Arteriogram abnormality For purposes of classification, a patient shall be said to have Takayasu’s arteritis if at least 3 of these 6 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 90.5% and a specificity of 97.8%. BP = blood pressure (systolic; difference between arms).

18 Histopathology Microscopically, the vasculitis may be divided into an acute florid inflammatory phase and a healed fibrotic phase. In the acute phase a vasa vasoritis is seen in the adventitia. The media is infiltrated by lymphocytes and occasional giant cells with neovascularisation. Mucopolysaccharides, smooth muscle cells, and fibroblasts thicken the intima. In the chronic phase there is fibrosis with destruction of elastic tissue. Infection has been considered to play a role in the pathogenesis of Takayasu arteritis. Tuberculosis has been particularly implicated in view of the high prevalence of infection, past or present, in affected patients

19 Investigation TAK Acute phase reactants are non-specific
Angiography is the gold standard, but CT angiography, MRA, US and PET all can be used in assessing stenotic lesions and aid in early diagnosis. MRI, US and PET can also be used for disease activity monitoring.

20 Investigation TAK

21 Treatment of TAK Oral corticosteroids are started at 1 mg/kg daily or divided twice daily and tapered over weeks to months as symptoms subside. Steroid sparing agents such as azathioprine, MTX and CYC are frequently used. Anti-TNF and anti-IL-6 have been successful in treating refractory or steroid dependent disease. Bypass graft surgery is the procedure with the best long-term patency rate. Percutaneous balloon angioplasty can provide good outcomes for short lesions. Angioplasty and stenting have been used to treat recurrent stenosis.

22 Medium Vessel Vasculitis
Polyarteritis nodosa (PAN) Kawasaki’s disease

23 Kawasaki’s Disease  is an acute febrile vasculitic syndrome of early childhood that, although it has a good prognosis with treatment, can lead to death from coronary artery aneurysm in a very small percentage of patients. Treatment includes: aspirin and IVIG. Steroids, anti-TNF’s and cyclophosphamide can be used in resistant cases Long term follow with serial echo is recommended.

24 PAN First described in 1866 by Kussmaul and Maier.
It is a systemic necrotizing vasculitis that predominantly affects medium-sized arteries, and is primary in most patients but is the consequence of viral infections, mainly hepatitis B virus (HBV), in some. Many similarities between PAN and Microscopic polyangitis made it difficult to differentiate between the 2 disorders till a strong association with ANCA was found in MPA. In addition to the tendency to involve arterioles, venules, and capillaries.

25 PAN and Hepatitis B Infection
A link has been found between hepatitis B infection (HBV) and PAN. HBV can cause endothelial injury to the blood vessel wall leading to inflammation. The development of PAN is usually in the first 6 months of HBV contraction. The activity of HBV-PAN does not parallel that of the hepatitis. HBV previously caused up to 30% of PAN now with the widespread use of vaccination it accounts to only 8% of all PAN patients. HCV and HIV has also been described to cause PAN.

26 PAN Pathology Vascular lesions in medium-sized muscular arteries occur mainly at bifurcations and branch points. Inflammation may start in the vessel intima and progress to include the entire arterial wall, destroying the internal and external elastic lamina, resulting in fibrinoid necrosis.  Aneurysms develop in the weakened vessel, carrying a subsequent risk for rupture and hemorrhage. Thrombi may develop at the site of the lesions. As lesions progress, proliferation of the intima or media may result in obstruction and subsequent tissue ischemia or infarction.

27 PAN Pathology PAN is divided into subacute, acute, and chronic stages.
In the subacute stage, infiltration of mononuclear cells becomes more prominent, while in the acute stage, polymorphonuclear neutrophils infiltrate all layers of the vessel wall. In the chronic stage, fibrinoid necrosis of the vessels causes thrombosis and tissue infarction. Aneurysmal dilatations of the involved arteries. Kidney lesions show predominant arteritis without glomerulonephritis; however, in patients with severe HTN, glomerulosclerosis may be superimposed with glomerulonephritis. Pulmonary arteries are not involved, and bronchial artery involvement is uncommon.

28 PAN Angiography should be considered if clinically involved tissue is inaccessible. Conventional angiography is preferred. CT angiography or MRA are not as sensitive for smaller abnormalities but can reveal larger aneurysms and stenoses. Positive findings include aneurysms and stenoses of medium-sized vessels. Aneurysms are most commonly found in the kidney, liver, and mesenteric arteries, and their presence is associated with more severe and extensive disease. Angiography has a higher yield in cases with evidence of intra-abdominal involvement, including clinical symptoms or signs and laboratory abnormalities of liver or renal function. NCS is important to detect MNP.

29 Classification Criteria of PAN
Weight loss Livedo reticularis Testicular pain or tenderness Myalgias, weakness or leg tenderness Mononeuropathy or polyneuropathy Diastolic BP >90 mm Hg Elevated BUN or creatinine Hepatitis B virus Arteriographic abnormality Biopsy of small or medium-sized artery containing PMN For classification purposes, a patient shall be said to have polyarteritis nodosa if at least 3 of these 10 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 82.2% and a specificicy of 86.6%.

30 Treatment of PAN Corticosteroids are the cornerstone of treatment.
The addition of CYC is the standard of care for patients with idiopathic PAN. In contrast, for hepatitis B–related PAN, treatment consists of schemes that include corticosteroids with antiviral agents and plasmapheresis. Cyclophosphamide is not routinely recommended in hepatitis B–related PAN as the use of steroids with cyclophosphamide in these patients has been demonstrated to enhance viral replication. Antiviral drugs used include vidarabine or interferon alpha-2b.

31 Small Vessel Vasculitis
Microscopic polyangiitis (MPA) Granulomatosis with polyangiitis (Wegener’s) (GPA) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Immune complex SVV Anti–glomerular basement membrane (anti-GBM) disease Cryoglobulinemic vasculitis (CV) IgA vasculitis (Henoch-Schonlein) (IgAV)

32 MPA One of the AAV Necrotizing vasculitis, with few or no immune deposits, affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. A very important cause of pulmonary renal syndrome

33 History In 1923, Friedrich Wohlwill described 2 patients who seemed to have a novel form of this disease, characterized by the presence of GN and nongranulomatous inflammation of the small-caliber blood vessels. This ‘‘microscopic form of periarteritis nodosa’’ was gradually recognized as a new entity, distinct from classic polyarteritis nodosa. In 1953, Pearl Zeek noted that this disease was pathologically similar to hypersensitivity vasculitis, preferentially involving the arterioles and venules of the visceral organs (including the lung) but often sparing the medium-caliber blood vessels. In 1950, Wainwright and Davson used the phrase microscopic polyarteritis to describe this phenotype. In 1985, Caroline Savage and colleagues defined microscopic polyarteritis as a small-vessel vasculitis associated with focal segmental glomerulonephritis and hemoptysis.

34 MPA an Entity between PAN and WG!
The discovery of this new form of vasculitis has led to reclassification of many patients. In 1980’s were ANCA was discovered with its 2 different patterns perinuclear (P-ANCA) and cytoplasmic C-ANCA, this entity became a member of AAV. It is most common in southern Europe with an incidence of 93/1’000’000 in Sweden compared to 2.6/1’000’000 in Germany. VS

35 GPA Peter McBride first described the condition in 1897 in a BMJ article entitled "Photographs of a case of rapid destruction of the nose and face".  Heinz Karl Ernst Klinger (born 1907) would add information on the anatomical pathology. but the full picture was presented by Friedrich Wegener (1907–1990), a German pathologist , in two reports in 1936 and 1939. It was recently changed to granulomatosis with polyangiitis GPA Its hallmark features include necrotizing granulomatous inflammation and pauci-immune vasculitis in small- and medium-sized blood vessels

36 GPA Affects both the upper and lower airways (in 90% of cases) causing significant inflammation and destruction. It is a recognized cause of Otitis media, sinusitis, oral ulcers, periorbital swelling and saddle nose. It also causes subglotic stenosis, lung nodules, infiltrates and an important cause of DAH.

37 Classification Criteria
Nasal or oral inflammation - Development of painful or painless oral ulcers or purulent or bloody nasal discharge Abnormal chest radiography findings - Chest radiograph showing nodules, fixed infiltrates, or cavities Urinary sediment - Microhematuria (>5 red blood cells [RBCs] per high-power field [HPF]) or RBC casts in urine sediment Granulomatous inflammation on biopsy - Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole) For the purposes of classification, a patient is said to have WG if at least 2 of these 4 criteria are present. The presence of any 2 or more criteria yields a sensitivity of 88.2% and a specificity of 92%

38 Subtypes Limited is a mild form with no life-threatening manifestations, and findings are usually confined to the respiratory system. Severe is a more generalized disease with serious organ involvement. Granulomatous form involves the upper and lower airways with a relapsing remitting course. Vasculitic type is usually life-threatening but when treated adequately has a better long term outcome.

39 Churg-Strauss Syndrome (CSS)
CSS or EPGA has 3 phases  Allergic rhinitis and asthma Eosinophilic infiltrative disease, such as eosinophilic pneumonia or gastroenteritis Systemic medium- and small-vessel vasculitis with granulomatous inflammation. The vasculitic phase usually develops within 3 years of the onset of asthma, although it may be delayed for several decades. The most prominent symptoms and signs are those related to pulmonary, cardiac, dermatologic, renal, and peripheral nerve involvement. Mononeuritis multiplex is a major clinical finding.

40 EPGA The first description of CSS was made by Churg and Strauss in 1951 on 13 patients (11 autopsied) under the title “allergic granulomatosis, allergic angiitis, and periarteritis nodosa.” Churg and Strauss emphasized the findings common to all cases: history of asthma; blood and tissue eosinophilia; necrotizing vasculitis; and a granulomatous response to eosinophilic necrosis

41 Classification Criteria of EPGA
Asthma Eosinophilia >10% Neuropathy, mono or poly Pulmonary infiltrates, non-fixed Paranasal sinus abnormality Extravascular eosinophils For classification purposes, a patient shall be said to have Churg-Strauss syndrome (CSS) if at least 4 of these 6 criteria are positive. The presence of any 4 or more of the 6 criteria yields a sensitivity of 85% and a specificity of 99.7%.

42 EPGA In the prodromal phase; biopsy of any involved organ will reveal heavy eosinophilic infiltrates are the rule, but vasculitis is very rare The classic histologic hallmarks of the vasculitic phase are An eosinophil rich necrotizing vasculitis involving primarily small arteries, arterioles, venules, and veins Necrotizing granulomas centered on necrotic eosinophils

43 Treatment of AAV Induction:
Pulse steroids, cyclophosphamide, rituximab and plasma exchange Maintenance: Steroids, azathioprine, MTX and rituximab Cotrimixazole full dose twice a day, has been shown to reduce staph Aureus carrier which is a cause of relapse. This is the only reason to wake me up anytime

44 Relapsing Polychondritis
It is a rare autoimmune disorder in which the cartilaginous tissues are the primary targets of destruction but the immune damage can spread to involve noncartilaginous tissues like the kidney, blood vessels, and so forth. It can be associated with other autoimmune diseases. Treatment includes; steroids and MTX or azathioprine.

45 Cryoglobulinemic Vasculitis
Cryoglobulins are single or mixed immunoglobulins that undergo reversible precipitation at low temperatures.  A combination of hepatitis C, high RF and purpura is typical of cryoglobulinemia. GN, acrocyanosis, arthritis, peripheral neuropathy , retinal hemorrhage, severe RP with digital ulceration, livedo reticularis, and arterial thrombosis are other of many features. An idiopathic form also exists. Immune complex mediated leading to consumption of complements. Treatment includes: steroids, azathioprine, CYC, rituximab and plasma exchange are the mainstay treatment. In HCV-related INF and ribavirin are indicated.

46 Preparation The blood specimen must be obtained in warm tubes (37°C) in the absence of anticoagulants. Allow the blood sample to clot before removal of serum with centrifugation (at 37°C). The period required for the serum sample to incubate (at 4°C) depends on the type of cryoglobulin present, as follows: Type I tends to precipitate within the first 24 hours (at concentrations >5 mg/mL). Type III cryoglobulins may require 7 days to precipitate a small sample (< 1 mg/mL). Repeat centrifugation to determine cryocrit (volume of precipitate as a percentage of original serum volume).

47 Isolated CNS Vasculitis
Isolated central nervous system (CNS) vasculitis is a rare and complicated disorder. Patients typically present with nonspecific neurologic symptoms such as headache and encephalopathy, and have variable progression and severity of the disease. Challenges to definitive diagnosis include the limitations of currently available diagnostic modalities with high likelihood of false-positive or false-negative findings. Imaging, serologic, and cerebrospinal fluid (CSF) evaluation, and even angiography can fail to establish the diagnosis.  The gold standard for the diagnosis of PACNS is histopathology. Sampling of the leptomeninges as well as the underlying cortex increases the diagnostic yield. Treatment includes steroids and CYC

48 Vasculitis Mimickers Are disorders that have similar presentations to systemic vasculitides. Many of these do not need any medical therapy. The challenge is more in large vessel vasculitis when biopsy is not possible. Infectious mimickers can worsen with immunosuppression.

49 Mimickers


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