CUTANEOUS MANIFESTATIONS OF HEPATITIS B and C VIRUS INFECTIONS

1. CUTANEOUS MANIFESTATIONS OF HEPATITIS B and C VIRUS INFECTIONS Marie-Sylvie DOUTRE Bordeaux (France)

2. Various dermatologic disorders are associated with viral hepatitis infections, sometimes revealing these infections.

3. Several cutaneous manifestations are associated with hepatitis C virus infection

4. The relation between HCV infection and some cutaneous manifestations is now clearly demonstrated • So, there are several arguments for the part of HVC in mixed cryoglobulinemia HCV RNA sequences are concentrated in the cryoprecipitate and detected in cutaneous lesions Agnello Arthritis Rheum 1997

5. Dermatologic findings includeinfiltrated purpura,livedo reticularis, legs ulcers, sometimes associated with arthritis, neuropathy, nephropathy…

6. The efficacy of alpha interferonin about 50% of patient is also an argument for the role of HCV in mixed cryoglobulinemia Sometimes, there are conflicting responses to treatment for liver and cryoglobulinemia

7. The association HCV-cryoglobulinemia is frequent : anti-HCV antibodies are detected in about 85% of cryoglobulinemia However, a clear relationship between HCV infection and cryoglobulinemia has not been etablished with - HCV genotypes - viral load - genetic factors

8. There are rare case-reports of cutaneous vasculitis without cryoglobulinemia

9. HCV infection has also reported in case reports or small series of polyarteritis nodosa Cacoub J Rheumatol 2001

10. It’s the same for porphyria cutanea tarda

11. High prevalence of HCV markers (50 to 90%) have been reported in sporadic PCT from Italy, Spain and France. Lower rates, but significant higher than in the corresponding general population, have been reported in other countries

12. Recently, an increased frequency of hemochromatosis gene mutations (C282Y, H63D) has been detected in patients with sporadic PCT, suggesting a synergistic action of genetic factors with extrinsec factors Egger Dig Dis Sci 2002

13. For other dermatosis, some studies indicate a relationship, some others do not. • So, the link between oral Lichen Planus and HCV infection is always contreversial Lodi Br J Dermatol 2004

14. It’s the same for pruritus There are aspecific lesions such as xerosis, excoriations, prurigo

15. Several factors contribute to the pruritus - cholestasis - direct effect of HVC - treatments (interferon, ribavirin) Fisher J Am Acad Dermatol 1994 Cribier Acta Dermatol Venereol 1998

16. A lymphocytic sialadenitis does occur in patients with HCV infection This is often associated with xerostomia but it is not associated with xerophtalmia or with anti SSA antibodies Ramos- Casals Medicine 2005

17. Anecdotal dermatologicdisorders have been reported in HCV infected patients • Urticaria • Erythema nodosum • Erythema multiform • Necrolytic acral erythema Abdallah J Am Acad Dermatol 2005

18. Dermatological manifestions are also observed during acute and/or chronic phase of HBV infection PARSONS Int J Dermatol 1996 PYRSOPOULOUS Curr Gastroenterol Rep 2001

19. URTICARIA during the pre-icteric phase of HBV infection, association with fatigue, headache, arthralgia DIENSTAG Ann Med Int 1978

20. There is a lymphocytic or leucocytoclastic vasculitis HBs antigen deposits are observed in the small vessels NEUMANN Br J Dermatol 1981

21. Chronic urticaria is rarely associated with HBV infection DOUTRE Presse Med 1987

22. CUTANEOUS VASCULITIS

23. cutaneous vasculitis can be associated with arthralgia, renal or neurological manifestations • vasculitis can occur during acute or chronic phase of HBV infection SERGENT Medicine 1976

24. The role of HBV in mixed cryoglobulinemia is contreversial • HBV markers are observed in high proportions of patients with type II or III cryoglobulins LEVO N Engl J Med 1977 • HBs antigen is present in the cryoprecipitate However, HBV DNA is rarely demonstrated in these patients CACOUB Arthritis Rheum 1992

25. POLYARTERITIS NODOSA In the seventies, the prevalence was estimated to be 30 to 40 %, at present, about 7 % Mouthon Pathol Biol 1999 Trepo Autoimmun 2001

26. the cutaneous manifestations are similar • some manifestations are more common in HBV related PAN : abdominal signs, renal failure, arterial hypertension, orchitis

27. mortality is not different in two types of PAN Guillevin J Int Med 1989 • treatment is different with short course of steroid therapy, plasma exchanges and anti viral drugs Guillevin J Rheumatol 1989

28. GIANOTTI-CROSTI syndrome The role of HBV infection was discovered in the seventies GIANOTTI Br J Dermatol 1970 The eruption is associated with an anicteric hepatitis CAPUTO J Am Acad Dermatol 1992

29. in fact, many different virus can be associated with this eruption (EBV, HBC, CMV, adenovirus, HHV-6...) CHUH Pediatr Dermatol 2002 TERASAKI Dermatology 2003

30. LICHEN PLANUS The link between L.P. and chronic hepatitis has been etablished. REBORA Int J Dermatol 1984 The frequency of HBV markers is between 4 to 40 % but the replication of HBV was not demonstrated

31. At present, the link between L.P. and HBV infection is difficult to etablish >> all studies were published when serological detection of HVC was not available

32. PORPHYRIA CUTANEA TARDA HBV markers are frequently associated with PCT but • HBs antigen was present in only few cases ROCCHI Liver 1986 VALLS J Dermatol 1986 • the series were published before the serological tests for HCV are available

33. OTHER TYPES OF CUTANEOUS ERUPTION ARE OBSERVED • photolocalized eruption KAYAKAWA Br J Dermatol 1996 • papular purpuric gloves and socks GUIBAL Lancet 1996

34. Some cutaneous manifestations can appear during the treatment of viral infection Cutaneous reactions represent 5 to 17 % of side effects observed in patients receiving Interferon, «classic» alpha INF or peg-interferon, alone or in combination with ribavirin DALEKOS Eur J Gastroenterol Hepatol 1998

35. Hair loss, itching, xerosis and eczematous lesions are the most frequent adverse cutaneous manifestations Sookoian Arch Dermatol 1999 Manjon-Haces Acta Derm Venereol 2001 Kerl Br J Dermatol 2003

36. Most patients showed clinical improvement with symptomatic treatment. However, some patients abandoned nterferon because of these side-effects Dereure Br J Dermatol 2002

37. Induction or exacerbation of psoriasis, lupus, lichen, vitiligo, autoimmune bullous dermatosis has been also described Georgetson Am J Gastroenterol 1993 Doutre Gastroenterol Clin Biol 1996

38. Cutaneous and systemic sarcoidosis have been reportedRamos-Casals Medicine 2005

39. Others cutaneous side-effects are also reported here and there Straightening of hair Bessis Br J Dermatol 2002 Lanigan Br J Dermatol 2003 Meyerson’s phenomenom Krischer J Am Acad Dermatol 1999 Girard Br J Dermatol 2005 Skin and cutaneous hyperpigmentation Willems Br J Dermatol 2003

40. Local reactions are also observed such as erythema, induration

41. Much less frequently, necrosis is observed, no dependent on the site of injection or the dose The exact mechanisms remain unknown

42. The extension of HB vaccination has led to the appearance of dermatologic side effects The tolerance of HB vaccine is generally good. However, some dermatologic manifestations have been observed in children and adults. MAC MAHON Am J Med 1992 AUBIN Rev Fr Allergol 1994

43. urticaria and angiooedema BARBAUD Br J Dermatol 1998 • lichen planus Numerous observations in the literature since the first case reported in 1990 by CIACCIO and REBORA

44. systemic and cutaneous leucocytoclastic vasculitisSome thirty cases in the literature • polyarteritis nodosa DE FAYSER Clin Exp Rheumatol 2000 BOURGEAIS Ann Dermatol Venereol 2003 • systemic lupus erythematosus TUDELA Nephron 1992 MAMOUX Arch Pediatr 1994 GUISERIX Nephron 1996 FINIELZ Nephrol Dial Transplant 1998

45. Other manifestations are observed more rarely • Generalized granuloma annulare WOLF Eur J Dermatol 1998 • Erythema multiform WAKEEL Br J Dermatol 1992 LOCHE Clin Exp Dermatol 2000 • Erythema nodosum DI GIUSTO Lancet 1986 GOOLSBY N Engl J Med 1989

46. cutaneous lupus erythematosus and buccal aphtosis GREZARD Ann Dermatol Venereol 1996 • pityriasis rosea like-eruption DE KEYSER Clin Exp Rheumatol 2000 • Gianotti-Crosti syndrome HANG Hautartz 2002

47. For these adverse reactions, it is still debated whether there is a causal association or a simple coincidence. "Sequence is not consequence" CALES Gastroenterol Clin Biol 2001

48. Reactions are also described at the injection site. They are usually transient, erythema, itching, oedema. COSNES Contact dermatitis 1990 KAABER Contactdermatitis 1992 SKOWRON Contactdermatitis 1997 Sometimes, painful erythematosus nodules apparead, due to aluminium

49. Other local reactions are observed • localized lichenoid reaction due to thiomersal STAURIANEAS Dermatology 2002 • lipoatrophy VILETTE Ann Dermatol Venereol 1997 • necrobiotic granuloma AJITHKUMAR Clin Exp Dermatol 1998

50. Considering the very low proportion of affected patients in comparaison with all subjects immunized (in France, 27 millions in 1998), an individual predisposition seems very likely. Vaccination with HBV is effective and safe