1. Approach to patients with Vasculitis
Dr. Müge Bıçakçıgil Kalaycı

2. Vasculitides is a group of disorders characterized by inflammation of vessel walls.
The unique feature of this group is multi-organ involvement.

3. Inflamed blood vessels are liable to occlude or rupture or develop a thrombus.
Depending on the size, distribution, and severity of the affected vessels, vasculitis can result in clinical syndromes
vary in severity from a minor self-limited rash to a life-threatening multisystem disorder.

4. Classification of the Primary Vasculitides:..
Classification of the Primary Vasculitides:
Large-artery vasculitis
Giant cell arteritis
Takayasu arteritis
Medium-vessel vasculitis
Polyarteritis nodosa
Kawasaki disease
Primary central nervous system disease
Buerger disease
Small-vessel vasculitis
ANCA-associated small-vessel vasculitis
Granulomatosis with polyangiitis (formerly Wegener granulomatosis)
Microscopic polyangiitis
Churg-Strauss syndrome
Drug-induced ANCA-associated vasculitis
Behçet disease
Hypersensitivity vasculitis
Urticarial vasculitis

5. the general and specific clinical clues
vasculitis is one of the great diagnostic challenges.
often begins with nonspecific symptoms and signs
develop slowly over weeks or months
the general and specific clinical clues ↓
suspect vasculitis

6. Establishing the diagnosis of vasculitis requires confirmation by;
laboratory tests,
usually a biopsy of an involved artery
but sometimes an angiogram or
a serologic test.

7. Because of the rich vasculature, the skin is prone to be frequently affected in vasculitis.
Cutaneous involvement in vasculitides may be primary or reflector of a fatal systemic disease or evidence of association with some other systemic disorder.

8. Sometimes it may be necessary to assess a patient's extent of organ involvement in several steps through clinical and laboratory examinations.
Hence a systematic approach is required for diagnosis and management of these multi-system disorders.

9. When to suspect vasculitis?

10. However, certain cutaneous features like ;
The cutaneous and systemic features of vasculitides are not pathognomonic of these conditions in most of the cases.
However, certain cutaneous features like ;
palpable purpura,
punched-out ulcers,
livedo reticularis,
subcutaneous nodules

11. certain systemic features like;
abdominal angina,
glomerulonephritis,
recurrent sinusitis,
pneumonitis,
peripheral neuropathy may point to a vasculitic etiology.

12. have sole cutaneous involvement.
In some entities, cutaneous involvement predominates; in others, systemic.
Henoch-Schönlein purpura (HSP),
Cutaneous PAN (c-PAN)
have sole cutaneous involvement.

13. Temporal arteritis (TA) and Takayasu's disease (TD) develop cutaneous lesions only rarely.
However, the majority of the vasculitic disorders, including
Microscopic polyangiitis (MPA),
Hypersensitivity vasculitis,
Wegener's granulomatosis (WG),
Churg-Strauss syndrome (CSS) and
Classic polyarteritis nodosa (PAN) show combined features.

14. Collagen vascular disorders,
some infections and
malignancies may present with vasculitic skin lesions as initial manifestation.
Hence, ruling out an underlying disorder is mandatory in all cases.

15. Cutaneous involvement Palpable purpura
Thrombocytopenic purpura- random distribution and mucosal involvement
Vasculitic palpable purpura-
is the hallmark cutaneous sign of this group of disorders
common in dependent body parts, over trauma-prone sites and under tight clothing, sparing the flexures.

16. Cutaneous involvement Palpable purpura
In cryoglobulinemic vasculitis (CV), skin lesions are predominantly acral and in 10-30% cases cold enhancement of the purpuric lesions is observed.

17. Cutaneous involvement Subcutaneous nodules
often indicate involvement of larger vessels with systemic involvement.
Recurrent episodes of tender, red nodules, mainly over calves, without any systemic features is suggestive of nodular vasculitis
Erythema nodosum-like lesions may be seen in Takayasu's arteritis and Behçet’s disease.

19. Cutaneous involvement livedo reticularis
livedo reticularis (LR), which may ulcerate, is the predominant cutaneous feature in c-PAN
observed in SLE and classic PAN.

20. Cutaneous involvement Ulcers
Ulcers in the peri-anal location are also common in WG.
Ischemic ulcers are seen with arterial involvement in their distribution like scalp ulceration in temporal arteritis.

21. Cutaneous involvement Raynaud's phenomenon
Raynaud's phenomenon and peripheral cyanosis are common in CV (20-50%).
Pale, cold extremities are seen in giant cell arteritis in association with asymmetric peripheral pulses.
Digital gangrene is common in conditions with involvement of the larger vessels like classic PAN.

22.   Mucosal involvement
Persistent oral and nasal mucosal ulcers are common in WG.
Hyperplastic gingivitis with petechiae (strawberry gingival hyperplasia), is a pathognomonic feature of WG

23. Mucosal involvement
Nasal polyps, persistent for years are seen in CSS.
Recurrent pansinusitis of long duration may be the presenting feature of WG before other organ involvements are evident.

24. Septal perforation and saddle-nose deformity, though rare, is strongly suggestive of WG.

25. Mucosal involvement
Cheilitis (dry, fissured lips) and strawberry tongue in association with a desquamating rash is suggestive of Kawasaki disease.
A swollen, cyanotic, cold, tender tongue, which later becomes atrophic, may result due to ischemia in TA.

26.   Systemic involvement
  Organ involvement may be present even in the absence of overt clinical features.
The extent and severity of systemic involvement determines the prognosis of the disease.
Moreover, the diagnostic and therapeutic approach to the patient is dependent on this.

27. Gastrointestinal symptoms like abdominal angina, hematemesis, melena, bloody diarrhea and intestinal obstruction are more common with small vessel vasculitis like CSVV, HSP.
Presentation with an acute abdomen is quite common (50-85%) in HSP and about one-third of these cases present with gastrointestinal hemorrhage

28. Renal involvement is variable;
Membrano-proliferative glomerulonephritis (MPGN) is typical of CV
Marked renal involvement is a feature of classic PAN; reno-vascular hypertension and renal failure are important diagnostic clues to this disorder.

29. A pulmonary-renal syndrome (crescentic, necrotizing glomerulonnephritis, pulmonary hemorrhage + circulating antineutrophil cytoplasmic antibody [ANCA]) is seen in WG, CSS and most commonly in MPA.
Renal involvement in CSS is comparatively uncommon and less severe than WG and MPA.

30. Asthma is the central feature of CSS which is not usual in WG.
Almost always it precedes other systemic manifestations and unlike atopic individuals, there is a late onset, at a mean age of 35 years
Lungs and spleen are usually spared in classic PAN.
A granulomatous myocarditis is characteristic of CSS and not found in other disorders in this group.

31. Arthralgia / arthritis are frequently associated with CSVV, HSP, CV, UV, MPA and PAN.
Peripheral neuropathy and mononeuritis multiplex involving mainly lower limbs is seen at highest frequency in CSS but is also common in CV, c-PAN, classic PAN and vasculitis associated with rheumatoid arthritis

32. mononeuritis multiplex
The most characteristic nervous system manifestation of vasculitis is mononeuritis multiplex
which is defined as a distinctive peripheral neuropathy in which named peripheral nerves are infarcted one at a time.
The nerve infarctions result from vasculitis of the vessels of the vasa nervorum, causing ischemia of a nerve.

33. mononeuritis multiplex
Clinically, the two features that characterize this neuropathy are the asynchrony and asymmetry of the symptoms and findings.
the onset of mononeuritis multiplex is strikingly memorable:
The patient often recalls the day that his or her foot drop or wrist drop began..

34. mononeuritis multiplex
the lesions are usually asymmetric.
The right hand may demonstrate a median nerve infarct while the left hand has an ulnar nerve lesion

35. Orchitis is a feature of classic PAN, more frequently seen in hepatitis B infection associated cases.
Sensory neural hearing loss- WG
Clinical presentations indicative of the type of the vasculitis.

36. Looking for treatable etiology

37. Looking for treatable etiology
evaluation of a patient with suspected vasculitis includes intensive search to find out any treatable underlying cause.
Infections (15-20%), inflammatory disorders (15-20%), drugs (10-15%) and malignancies (2-5%) are known precipitating factors for vasculitis.

38. Looking for treatable etiology
Approximately 5-7% cases of classic PAN are associated with hepatitis B virus infection.
approximately 20% patients with cutaneous vasculitis show a positive serology for HCV

39. Diagnostic approach

40. Diagnostic approach  
Thorough history and physical examination of patients help in initial clinical diagnosis.
Laboratory tests are required for
confirmation of the clinical diagnosis,
screening for underlying organ involvement and
to assess the risk factors, prognosis or response to treatment.

41. Role of histopathological examination

42. Histopathological examination
Skin, being the most accessible organ, is most frequently sampled for this purpose.
Though sensitive, skin biopsy may not be specific or sufficient to establish diagnosis of PAN, WG and CSS

43. In these disorders, as and when appropriate,
sural nerve biopsy (in presence of abnormal nerve conduction velocity),
open lung biopsy,
percutaneous kidney biopsy (in presence of persistent, abnormal urinary sediment) or
testicular biopsy may be indicated.

44. Nasal tissue biopsy, though easier to perform, has a far lower potential as diagnostic help than lung biopsy in cases with WG
Histopathological study of skin biopsy is confirmatory, while DIF(direct immunefloresein ) study is additive to this and helps to categorize the vasculitis.

45. Histologic Clues to Diagnosis of Vasculitic Disorders
Findings
Possible Diagnoses
Predominantly non-necrotizing granulomatous inflammatory infiltrate with lymphocytes, macrophages, and multinucleated giant cells
Giant cell arteritis
Primary angiitis of the CNS (certain types)
Takayasu's arteritis
Fibrinoid vascular necrosis of the vessel wall with a mixed infiltrate consisting of various combinations of leukocytes and lymphocytes
Churg-Strauss syndrome
Immune complex–associated vasculitis
Microscopic polyangiitis Polyarteritis nodosa RA
Wegener's granulomatosis
Granulomatous infiltrate of small and medium-sized vessels with varying degrees of necrosis
Table 1

46. IgA deposits*
Henoch-Schönlein purpura
Scant or complete absence of immunoglobulins and complement deposition in the vessel walls
Churg-Strauss syndrome
Microscopic polyangiitis
Wegener's granulomatosis

47. Screening for underlying organ involvement and other laboratory tests

48. This involves laboratory tests like routine hemogram, ESR, urinalysis, throat swab for culture and C-reactive protein (CRP).
Leukopenia or thrombocytopenia is almost never seen in primary vasculitic disorders and the presence of these may be indicative of underlying conditions like SLE, malignancy or it may be drug-induced

49. Marked eosinophilia (>1000/mL) is a feature of CSS and helps in differentiation from WG.
Urinalysis may reveal proteinuria, hematuria or presence of casts indicative of renal involvement.

50. An abnormal liver function test may be indicative of underlying viral hepatitis (B or C).
Estimation of cryoglobulin levels is an important parameter, as in addition to HCV, it may be indicative of associated hepatitis C infection.

51. Common Laboratory Tests in Vasculitis.
Laboratory Finding and Associated Disease
Hematocrit
Low in many forms
Erythrocyte sedimentation rate
Usually high, especially in giant cell arteritis
Creatinine
Elevated by renal forms of vasculitis
Urinalysis
Often abnormal, red blood cell casts caused by vasculitis of the glomeruli
Liver function tests
Abnormal in hepatitis B- or C-associated polyarteritis
Serum cryoglobulins
Present in cryoglobulinemia
Complement levels
Low in SLE, cryoglobulinemia
Immunoelectrophoresis
Monoclonal gammopathies common in hepatitis C–related vasculitis
Antineutrophil cytoplasmic
Positive in granulomatosis with polyangiitis,a microscopic polyangiitis,
Antibodies
Churg-Strauss syndrome

52. Role of ANCA

53. Role of ANCA
Estimation of ANCA in patients with clinical features suggestive of WG / CSS / MPA is recommended
as this may postpone the immediate need of invasive lungs / kidney biopsy and help in early diagnosis.
However, this test is not absolutely sensitive or specific.
Hence confirmation of diagnosis requires a biopsy of the involved organ.

54. C-ANCA is reasonably specific for WG (75-80%) and MPA (25-30%).
This is detected in only 10-15% cases of CSS.

55. P-ANCA is less specific, detected in MPA (50-60%), CSS (55-60%), WG (10-15%) and some other conditions like drug-induced vasculitis, rheumatoid arthritis (30-70%), SLE (20-30%), ulcerative colitis (50-70%), Crohn's disease (20-40%) and different hepatic disorders.
If C-ANCA and P-ANCA coexist in a patient, drug-induced vasculitis should be suspected.

56. role of ANCA is in screening for these disorders and should be asked for only when highly suggestive clinical features like pulmonary hemorrhage, recurrent sinusitis orbital mass or glomerulonephritis are present.
Estimation of ANCA level is also helpful in disease monitoring.
ANCA is almost always negative in Takayasu's disease, temporal arteritis and Kawasaki disease.

57. Serology for HIV, hepatitis B and C viruses,
immunological tests like rheumatoid factor (RA factor), antinuclear antibody (ANA) and anti ds-DNA are helpful screening tests for associated disorders

58. Endoscopy may be of diagnostic help in cases of HSP with gastrointestinal symptoms as presenting features.
Coin-like petechiae, hemorrhagic erosions, skip hyperemia and ecchymosis are the lesions suggestive of vasculitis.

59. In patients with palpable purpura and poorly localized colicky abdominal pain, CT scan / ultrasonography may be helpful to assess the extent of gastrointestinal involvement.
The hallmark findings in CT scan are focal areas of bowel thickening, mesenteric edema, nonspecific lymphadenopathy and vascular engorgement

60. Angiograms—
performed conventionally with CT or with MR—are especially helpful in supporting or establishing the diagnosis of
Takayasu arteritis, polyarteritis nodosa, and primary central nervous system vasculitis.

61. Treatment
make sure that the intensity of treatment fits the severity of vasculitis.
Although most forms of vasculitis require aggressive treatment to prevent morbidity and mortality, some do not.
Minor vasculitis limited to the skin and caused by drug reactions requires no therapy other than stopping the offending drug.

62. In contrast, rapid and intensive therapy is required;
Treatment
In contrast, rapid and intensive therapy is required;
to prevent blindness from developing in giant cell arteritis or
renal failure from complicating granulomatosis with polyangiitis (formerly Wegener granulomatosis).
Pulmoner hemorrage
Mononeuroitis multiplex

63. Large vessel vasculitis
GCA+ visual loss
who have experienced transient visual loss for a few hours should be admitted and given high-dose intravenous methylprednisolone (eg, 1000 mg/day) for 3–5 days
Visual loss of more than 1 day duration is almost always permanent.
GCA without visual loss
Prednisone (40–60 mg/day) should be given to any patient in whom GCA is strongly suspected.
Then the patient should be referred for a temporal artery biopsy.
low-dose aspirin (ie, 80–100 mg/day).
Takayasu arteritis
Prednisone (1 mg/kg/day) + low-dose aspirin

64. ANCA associated vasculitis
The management should be stratified according to whether the patient has severe or limited disease.
Severe disease (defined as an immediate threat to either the function of a vital organ or to the patient’s life) requires treatment with either rituximab or cyclophosphamide and high doses of glucocorticoids.

65. for remission induction in ANCA ass. Vasculitis;
Treatment
for remission induction in ANCA ass. Vasculitis;
combination of cyclophosphamide
(2 mg/kg/d for those with normal renal function) and
glucocorticoids (1 mg/kg/d of prednisone, perhaps preceded by a 3-day intravenous “pulse” of methylprednisolone).

66. To avoid the side effects of long-term cyclophosphamide therapy,
Treatment
To avoid the side effects of long-term cyclophosphamide therapy,
shorter courses (eg, 3–6 months) of induction treatment with cyclophosphamide are now used followed by longer-term treatment for the maintenance of remission with either azathioprine (up to 2 mg/kg/d) or methotrexate.

67. limited disease - are not severe.
Treatment
limited disease - are not severe.
nasosinus disease, arthritis,
nodular pulmonary lesions,
cutaneous findings
may respond to the combination of methotrexate (up to 25 mg/wk) and glucocorticoids

68. Treatment
Another important principle of treatment is to limit the toxicity of therapy.
long-term prednisone→ osteoporosis
high-dose prednisone + immunosuppressive drugs →prophylaxis against Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia should be started