Urticarial vasculitis diagnostic challenge in 2 cases Ahmed Yehia, MD immunolgy

Urticarial vasculitis diagnostic challenge in 2 cases Ahmed Yehia, MD Immunology, rheumatology and allergy
How to approach a case of itching and urticaria and how to interprete skin biopsy

1. Ahmed Yehia, MD Internal Medicine Immunology (Allergy & Rheumatology) Beni-Suef Each itch will itch

2. Personal history N.S.S., 38 years old female patient, borne and living in El- Fashn , married 19 years ago with 5 offspring, the youngest is 2 years old, with no special habits of medical importance.

3. Complaint Red itchy & burning skin lesions

4. Present history Then they heal with no residual pigmentation . The lesions lasted from a few hours up to more than 2 - 3 days . The condition started 16 years ago by recurrent attacks of red swollen raised sometimes itchy & burning skin lesions, migratory appearing anywhere in the body.

5. No obvious precipitating factors were identified but frequency increases in summer.

6. She was on antihistaminics for long periods with fair response and “on and off” course.

7. 15 days prior to her presentation to us, she developed right wrist arthralgia.

8. Past history Negative.

9. Family history Irrelevant

10. So, we have local skin disease. Pruritus Skin lesion Local skin disease Normal skin except itch consequences Systemic disease

11. Clinical examination

12. General examination

13. Head, neck, heart, lung and abdomen Examination findings are unremarkable.

14. Musculoskeletal examination Normal except tender right wrist joint with no swelling or LOM.

15. Mucocutaneous examination At time of examination, there were wheals over the extremities .

16. Urticaria, how to approach? Acute Chronic 6 weeks

17. Dermographism

18. So, our patient was diagnosed as chronic spontaneous urticaria (CSU).

19. Investigations

20. 12.5 g/dl Hgb 334 PLT 6.3 TLC NAD significant Urine 25 ESR 6.4 S. Uric acid

21. Negative ANA 94.2 mg/dl C3 20.6 mg/dl C4 Negative HCV Ab, HBsAg Negative RF 0.94 TSH 112 IU/ml ( up to 100 ) Serum total IgE

22. Summary

23. What is the differential diagnosis?

24. Chronic Urticaria??? Against With Arthralgia Urticarial rash Rash persistence > 24 hours Burning sensation Itchiness Poor response to H1# blokers

25. Mostly not Chronic Spontaneous Urticaria

26. SLE??? Against With ANA - ve Hair falling ESR, C3, C4 : normal Arthralgias No other criteria Urticarial skin rash

27. Mostly not SLE

28. Cryoglobulinemia??? Against With Rash increases in summer Arthralgias ESR, C3, C4 : normal Urticarial skin rash HCV Ab – ve CBC: normal

29. Mostly not Cryoglobulinemia.

30. What is next?

31. Indications of skin biopsy in chronic urticaria P ersistence of individual lesion > 24 hours. P ain, burning or tenderness. P etechiae or purpura. P ostinflammatory p igmentation after wheal resolution. P oor response to antihistaminics . P yrexia or other systemic manifestations e.g. arthritis.

32. So, we took a skin biopsy from a fresh lesion.

33. Skin biopsy report Intact skin with related upper dermal mild perivascular inflammatory infiltrate by lymphocytes, plasma cells and eosinophils . No evidence of specific granulomas . No evidence of atypia or malignancy.

34. Pathology Picture is suggestive of Urticarial vasculitis

35. CU Urticarial vasculitis -- + P ain and burning + + P ruritus < 24 hours > 24 hours P ersistence - + P ostinflamatory pigmentation - + P etichae or palpable p urpura - + P resence of systemic manifestations Is it too late? Could we have detected it earlier?

36. Extracut . affection Complement deficiency Skin Vasculitis Urticaria C l assification --- --- --- ++ CSU Urticarial vasculitis, is it the end of the diagnostic journey?!

37. Extracutaneos affection Complement deficiency Skin Vasculitis Urticaria C l assification --- --- --- ++ CSU +/- --- + ++ NUV Urticarial vasculitis, is it the end of the diagnostic journey?!

38. Extracut . affection Complement deficiency Skin Vasculitis Urticaria C l assification --- --- --- ++ CSU +/- --- + ++ NUV ++ +++ ++ ++ HUV Urticarial vasculitis, is it the end of the diagnostic journey?!

39. Extracut . affection Complement deficiency Skin Vasculitis Urticaria C l assification --- --- --- ++ CSU +/- --- + ++ NUV ++ +++ ++ ++ HUV ++++ +++ ++++ ++ HUVS UV represents a continuum of disease, ranging from urticaria with minimal vasculitis, to life- or organ-threatening systemic vasculitis with minimal urticaria.

40. Assess for a c ause for UV especially HUV

41. Assess for a c omplication for UV especially HUV

42. Does differentiation matter a lot?

43. Urticaria treatment guidelines No systemic GCs except in severe exacerbation.

44. Urticaria treatment guidelines No systemic steroids except in exacerbation.

45. UV treatment Often difficult to treat & therapy is based upon case reports & small series. Systemic GCs are the mainstay of therapy. Antihistamines are used to manage pruritus. GCs with dapsone, colchicine or HCQ are initial therapy for mild to moderate UV.

46. For refractory symptoms or organ- or life-threatening manifestations Based on limited data, along with our experience, we use the following agents in order of preference:

47. For refractory symptoms or organ- or life-threatening manifestations We rarely use cyclophosphamide , given the potential toxicity & limited benefit.

48. For refractory symptoms or organ- or life-threatening manifestations As more evidence becomes available, these agents may become preferred.

49. Case 2 Personal history M.F.H., 47 years old male patient, borne & living in Beni-Suef, married since 2000 with 3 offspring, the youngest is 4 years old, smoker (40 pack-year) .

50. Red itchy skin lesions Complaint

51. Present history The condition started 3 years ago by recurrent attacks of red swollen raised, markedly itchy & burning skin lesions, migratory appearing allover the body including the face and the scalp.

52. No obvious precipitating factors (drugs, infections, foods…….) were identified.

53. Not to be missed

54. Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis) is vasculitis accompanied by urticaria and hypocomplementemia affecting small vessels (i.e., capillaries, venules, or arterioles), and it is often associated with anti-C1q antibodies ( Jennette et al, 2013 ). Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation are commonly present in HUV, and HUV has overlapping clinical and laboratory features with SLE, though it also occurs independently of SLE (  Venzor et al, 2002 ;  Kallenberg , 2008 ;  Grotz et al, 2009 ).

55. Mucocutaneous examination At time of examination, there were wheals over the extremities.

56. Mucocutaneous examination

57. What is next?

58. Indications of skin biopsy in chronic urticaria P oor response to antihistaminics . P ersistence of individual lesion > 24 hours. P etichae or purpura . P resence of systemic manifestations e.g. P yrexia, arthritis. P ostinflammatory p igmentation after wheal resolution.

59. Skin biopsy August

60. Erythema annulare centrifugum !! Annular, erythematous lesion Urticarial-like papule Enlarges centrifugally, then clears centrally.

61. Histopathology The superficial variant: an infiltrate of histiocytes, lymphocytes, &, rarely, eosinophils around vessels of the superficial vascular plexus. The infiltrate is well-demarcated, with fairly tight aggregate around vessels,"coat -sleeve" distribution. Cells may reach into the walls of the small vessels. Pseudovasculitis rather than a vasculitis as there is never any fibrin extravasation. The advancing edge, which is slightly raised, may also show edema in the papillary dermis. The central area of clearing may contain dermal melanophages .

62. So, we did skin rebiopsy

63. What is your diagnosis?

64. The hallmark of UV is Leucokytoclastic vasculitis

65. The hallmark of UV Leucokytoclastic vasculitis CSU UV

66. Could we have vasculitis without vasculitis??

67. Guitart , J. J. J. o. t. A. A. o. D. (2008). "“Lymphocytic vasculitis” is not urticarial vasculitis." 59(2): 353. A comment on the previous article

68. Histopathologically , UV is defined as a minimum of leukocytoclasia with vessel wall necrosis , with or without fibrinoid deposits, perivascular inflammation, or RBC extravasation. Although findings can be subtle & consist only of interstitial neutrophils or perivascular lymphocytes with extravasated erythrocytes (especially in older lesions), these findings alone do not fulfill the histologic criteria for the diagnosis of UV.

69. Leukocytoclasis & fibrinoid deposits are the most important aspects of LCV, as they represent direct signs of vessel damage. A continuum exists in the amount & type of vessel inflammation in UV, ranging from a sparse perivascular infiltrate with no leukocytoclasis to a dense infiltrate with frank leukocytoclasis and fibrin deposition in the most severe forms. These more severe findings, typically with a neutrophilic infiltrate, are seen in patients with HUVS.

70. Skin biopsy typically reveals a small-vessel LCV that involves post-capillary venules. However, it seems that non-specific findings, such as lymphocyte & eosinophil infiltrates are relatively common, when an ‘older’ lesion is biopsied.

71. Often, multiple biopsies are needed to establish diagnosis of LCV, preferably of a wheal < 12 h after eruption. This is, in author’s opinion, the reason why our patient’s skin biopsies were negative for vasculitis and, considering that she already fulfilled Schwarz criteria, we chose not to put her through a third biopsy.

72. A novel histopathological scoring system to distinguish UV from CSU Results:  The greatest differences between UV & CSU samples were observed for leukocytoclasia (present in 76% of UV vs. 3.9% of CSU samples; p < 0.0001), erythrocyte extravasation (present in 41.3% of UV vs. 2.0% of CSU samples; p < 0.0001), and fibrin deposits (present in 27.9% of UV vessels vs. 9.7% of CSU vessels; p < 0.0001). Based on these findings, we developed a diagnostic score, the urticarial vasculitis score (UVS), which correctly assigned 37 of 46 cases of UV and 49 of 51 cases of CSU to the previously established diagnosis. Puhl V, Bonnekoh H, Scheffel J, Hawro T, Weller K, von den Driesch P, Röwert -Huber HJ, Cardoso J, Gonçalo M, Maurer M, Krause K. Clin Transl Allergy. 2021

73. A novel histopathological scoring system to distinguish UV from CSU Conclusion:  Our results suggest that the UVS, a combined quantitative assessment of the three criteria leukocytoclasia , fibrin deposits and extravasated erythrocytes, distinguishes UV from CSU in skin histopathology. The UVS, if validated in larger patient samples, may help to improve the diagnostic approach to UV. Puhl V, Bonnekoh H, Scheffel J, Hawro T, Weller K, von den Driesch P, Röwert -Huber HJ, Cardoso J, Gonçalo M, Maurer M, Krause K. Clin Transl Allergy. 2021

74. Timing of the skin biopsy is critical. Thus, it is strongly recommended that the lesion be less than 48 hours old. Ting, T. V. J. P. C. (2014). "Diagnosis and management of cutaneous vasculitis in children." 61(2): 321-346.

75. Our patient Dependent on high dose steroid. So, we add cyclosporine A He may have resistant CSU or missed NUV.

76. To further complicate the diagnosis. In a study, wheals lasted < 24 hours in 57.4% of patients & pain or tenderness was reported by 8.6% of those affected. Extracutaneous features were present in 81%, hypocomplementemia in 11% & abnormalities of other laboratory parameters (e.g., elevated ESR, microscopic hematuria) in 76.6%.   Clinical Dermatology , Sixth Edition, 2016, Elsevier Inc.

77. IS HUV = SLE? UV is sometimes considered a clinical feature that is part of another diagnosis,& sometimes as a primary diagnosis or syndrome.

78. UV etiopathogenesis (still undefined) I mmune complex–driven

79. UV etiopathogenesis ( I mmune complex–driven)

80. Pathophysiology The pathophysiology of UV is believed to involve the deposition of immune complexes in vessel walls, complement activation & mast cell degranulation due to C3a and C5a with resultant urticaria.

81. Pathophysiology

82. HUVS ( McDuffie syndrome ( Defined as a severe subset of HUV, characterized by multiorgan involvement

83. Diagnostic criteria of HUVS Hypocomplementemic urticarial vasculitis syndrome (HUVS) is recognized as a specific autoimmune disorder However, these criteria lack specificity, & a diagnosis of HUVS should not be made without a skin biopsy.

84. Hypocomplementemic urticarial vasculitis Patients with UV and hypocomplementemia who do not meet diagnostic criteria for HUVS. (HUVS)

85. EPIDEMIOLOGY The precise prevalence of UV is unknown due to its rarity. The incidence in the US population has been found to be 0.5/100,000 person-years. A Swedish study estimated an annual HUV incidence rate per million inhabitants of 0.7 (95% CI, 0.4- 1.1) with a point prevalence on December 31, 2015, of 9.5/million.

86. EPIDEMIOLOGY Although the proportion between observed cases ofHUV & NUV may depend on setting, for example, dermatology, allergology & rheumatology, according to most published case series, NUV is more common than HUV.

87. EPIDEMIOLOGY

88. Epidemiology  The peak reported incidence is in the fourth decade . The prevalence of UV in patients with chronic urticaria varies from 5% to 20%. NUV S everity S ystem involvement

89. EPIDEMIOLOGY Women are more frequently affected especially in the fourth decade. Only rare reports in children have been reported in the literature with UV being diagnosed in approximately 1% of children with vasculitis.

90. HUVS ( McDuffie syndrome ( main differential diagnoses

91. D.D.: A, Bullous pemphigoid. B, LCV. C, Lupus erythematosus tumidus. D, Wells syndrome. E,Erythema multiforme. F, Maculopapular cutaneous mastocytosis.

92. Dermatology Rheumatology & Immunology

93. Key messages Timing of the skin biopsy is critical. UV is a clinico pathologic entity consisting of urticaria & evidence of LCV on skin biopsy. To biopsy or not ( Biopsy is the gold standard in vasculitis diagnosis.) Some dermatology for the rheumatologists And some rheumatology for the dermatologists.

94. Urticarial Vasculitis

95. Consider UV and don’t forget. UV Dermatologists Rheumatologists

96. Consider the 6 P. Although none is diagnostic. 6 P Pain & tenderness, burning Persistence >24 h Purpura or Petichae Postinflam . Pigment Pyrexia or systemic S or Ss Poor response to H1# UV Biopsy LCV 3 C C lassification C ause C omplications

97. Don’t let the pathology or lab test guide you blindly.

98. You are the leader. You are a physician. Use your clinical sense & tools.

99. Finally Each itch Will itch BUT Differs much.

100. THANK YOU جزاكم الله خيرا

101. Typical laboratory findings in HUVS ● ESR acceleration ● Hypocomplementemia with low C1q, C3, C4 ● C1q antibodies ● ANA without anti-double-stranded DNA

102. Prognosis UV is a benign & self-limited disease for the majority of patients, although symptoms can last for decades in some individuals.

103. Diascopy of urticarial vasculitis skin lesion