Calista D, Morri M. Department of Dermatology, M. Bufalini Hospital, Cesena, Italy. 

 In May 1996, as part of his routine antihepatitis B (hepB) vaccination plan, a 28-year-old HbsAg-negative man, hospital worker, received his first dose (20 microg) of a recombinant vaccine (EngerixB-B, Smith Kline and Beecham, Belgium), administered via deltoid injection. The patient was otherwise healthy and taking no medication.

Thirty days after the 2nd booster dose, several pruritic, polygonal, purple, papules appeared on the volar aspect of the patient’s wrists. New lesions gradually spread to the arms and trunk (Fig. 1).

The clinical diagnosis of lichen planus (LP) was confirmed by histology, which revealed hyperorthokeratosis, hypergranulosis, vacuolar degeneration of the basal layer cells and a dense, band-like lymphocytic infiltrate in the superficial dermis.

The disease started to heal after treatment with topical clobetasol propionate 0.05% and sun exposure during the following summer.

Five days after the 3rd booster dose, in November 1996, the dermatosis relapsed on the forearms, trunk, and legs. On that occasion, routine laboratory tests, including a complete blood count, blood chemistry and liver function tests, were within normal limits.

Screening serologic tests for autoantibodies including antinuclear antibodies, antidouble-stranded DNA, anti-SS-A, anti-SS-B and anti-Sm were all negative.

As a result of the inadequate levels of antihepatitis B antibodies, less than 10 IU/l in May 1998, in a high-risk patient who was frequently exposed to blood and its products, an additional booster dose was performed.

Three days later a new recurrence of disseminated lichen planusoccurred.

The patient was successfully treated with prednisone 1 mg/kg/day for 2 weeks. There was no recurrence the following year.

HCV and lichen planus

Alfredo Rebora1*1 Clinica Dermatologica dell’Università, University of Genoa, Italy

Dear Editor,

Mahboobi et al. should be commended for providing a clear and exhaustive review of the literature on the intriguing topic of the association of HCV infection with Lichen Planus [1]. It is somewhat surprising, however, especially for a dermatologist such as myself, to read that the histopathology of LP is nonspecific, but for cutaneous LP the specificity is out of question. Actually, the reference that Mahboobi et al. cite for this point concerns oral LP, and most of their statements refer to the oral form of LP. The point is not immaterial, as it was the striking similarity of microscopic LP features with those of the liver affected by HCV-related active hepatitis that should suggest that a connection between the two conditions does exist. In both conditions, a T-cell infiltrate impinges on the cells of the epithelial structure that are in direct contact with the corium: keratinocytes of the basal layer of the epidermis in LP and hepatocytes of the murallium of the hepatic lobe in active hepatitis. Also in both conditions, T-cells induce apoptosis of the epitheliocytes, disorganize the epithelium, and in some instances destroy it (erosive forms). Some time ago, when I described the first cases of a severe hepatic disease in patients with erosive LP [2], I was amazed not only by the striking similarity, but also by the fact that nobody had noticed it before. Certainly, not all the observations and epidemiological studies concur on the relationship between LP and HCV infection, and the geographical explanation may not be completely convincing. In addition to the explanation provided by Mahoobi et al. the possibility that OLP diagnoses might not always be correct cannot be overruled given the nonspecificity of OLP histopathology. Another epidemiological observation that cannot be neglected suggests a strict connection between LP and HCV infection. Specifically, this perspective has to do with a disease that is certainly HCV related: porphyria Cutanea Tarda (PCT). All arguments that have been made for the LP-HCV connection have been made for PCT as well. Yet, the explanation that is universally accepted is the geographical one: PCT is prevalent in the regions in which HCV infection is prevalent, and nobody contests that HCV is the major etiologic factor of PCT. Even the combination of the three diseases has been reported [3]. Certainly, HCV is not the sole cause of LP.

In my view, LP is a cell-mediated immune reaction to various agents, including viruses, the most important of which are hepatotropic. In fact, LP is a relatively rare but well-recognized reaction to HBV vaccination [4].

The real problem may simply be that most studies are retrospective, which makes it difficult to establish whether HCV exposure occurs prior to or after the onset of LP. The occurrence of LP reactions after HBV vaccination irrespective of the type of vaccine used, however, strongly suggests that LP occurs after the infection. I agree with the authors that no definite conclusion can be reached at this point and also with their statement that “screening of LP patients with ELISA is cost-effective only with the presence of other risk factors”. The safety of patients and of oral specialists deserves attention in hyperendemic countries, and LP, regardless of the site affected, provides an invaluable clue in this regard

References

1. Mahboobi N, Agha-Hosseini F, Lankarani K. Hepatitis C Virus and Lichen Planus: The Real Association. Hepat Mon. 2010;10(3):161–4.

2. Rebora A. Lichen planus and the liver. Lancet. 1981;2(8250):805–6.

3. Mouly F, Pawlotsky JM, Schaeffer A, Benkhraba F, Roujeau JC, Revuz J, Bagot M. Association of porphyria cutanea tarda and lichen planus in a patient with chronic hepatitis C virus infection. Br J Dermatol. 1995;132(1):158–9.

4. Drago F, Rebora A. Cutaneous immunologic reactions to hepatitis B virus vaccine. Ann Intern Med. 2002;136(10):780;author reply -1.

Il 42% aveva uno o più membri della famiglia  che presentavano disfunzione della tiroide, malattie autoimmuni o  entrambe.
Non è stato trovato ipo- o ipertiroidismo nei soggetti esaminati. 

Int J Dermatol 2011, 50: 175

Study shows link between autoimmune thyroiditis and pediatric vitiligo  Uncu, S. et al.

A Turkish study to assess the incidence of thyroid dysfunction and autoimmune thyroiditis was conducted in 50 children with vitiligo and 50 controls (mean ages 9.5 and 8.6 years, respectively).

Data collected included the onset, duration, disease activity, presence or absence of thyroid disorders, autoimmune disease, poliosis and mucosal vitiligo.

Several thyroid-related parameters, including free thyroxine, T3, T4, thyroid-stimulating hormone (TSH) and antibodies to thyroperoxidase and thyroglobulin, were measured.

Vulgaris-type vitiligo was common and was found in 56% of patients; 42% had one or more family members with thyroid dysfunction, autoimmune disease or both.

No overt hypo- or hyperthyroidism was found.

A significant association between autoimmune disease and both gender and disease duration was found

(P = 0.046 and P = 0.07, respectively), but no association was seen between the other factors.

Children with vitiligo should be screened annually for thyroid function and antithyroxine antibodies

Cutis. 2006 Jan;77(1 Suppl):11-6.

Pharmacologic doses of nicotinamide in the treatment of inflammatory skin conditions: a review.

Niren NM.

Various skin disorders with an inflammatory component often have been treated with steroids and/or oral antibiotics. However, long-term use of these agents has drawbacks

As a result, alternative oral treatments, such as nicotinamide, have been investigated. During the past 50 years, many clinical reports have identified nicotinamide as a beneficial agent in the treatment of a variety of inflammatory skin disorders;

what’s more, its exceptional safety profile at pharmacologic doses makes it a potentially ideal long-term oral therapy for patients with inflammatory skin diseases.

A recent large study evaluating nicotinamide for the treatment of acne or rosacea has confirmed the potential benefits of oral nicotinamide as an alternative approach to managing inflammatory lesions associated with acne vulgaris and acne rosacea.

This article reviews the substantial number of reports published over the past 50 years that document the clinical utility and safety of oral and topical formulations of nicotinamide for the treatment of a variety of inflammatory skin conditions.

La nicotinamide (vitamina B3) risulta efficace nel ridurre la immunosoppressione  UV indotta. Sembra esercitare i suoi effetti protettivi  intervenendo nei meccanismi energetici cellulari. 

Photochem Photobiol. 2010 Jul-Aug;86(4):942-8.

Nicotinamide prevents ultraviolet radiation-induced cellular energy loss.

Park J, Halliday GM, Surjana D, Damian DL. 

UV radiation is carcinogenic by causing mutations in the skin and also by suppressing cutaneous antitumor immunity.

We previously found nicotinamide (vitamin B3) to be highly effective at reducing UV-induced immunosuppression in human volunteers, with microarray studies on in vivo irradiated human skin suggesting that nicotinamide normalizes subsets of apoptosis, immune function and energy metabolism-related genes that are downregulated by UV exposure.

Using human adult low calcium temperature keratinocytes, we further investigated nicotinamide’s effects on cellular energy metabolism. We found that nicotinamide prevented UV-induced cellular ATP loss and protected against UV-induced glycolytic blockade.

To determine whether nicotinamide alters the effects of UV-induced oxidative stress posttranslationally, we also measured UV-induced reactive oxygen species (ROS). Nicotinamide had no effect on ROS formation, and at the low UV doses used in these studies, equivalent to ambient daily sun exposure, there was no evidence of apoptosis.

Hence, nicotinamide appears to exert its UV protective effects on the skin via its role in cellular energy pathways.

Pediatrics. 2009 May;123(5):e808-14.

Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity.

Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS.

The goals were to determine the prevalence of community-acquired methicillin-resistant Staphylococcus aureus colonization in patients with atopic dermatitis and to determine whether suppression of S aureus growth with sodium hypochlorite (bleach) baths and intranasal mupirocin treatment improves eczema severity.

METHODS: A randomized, investigator-blinded, placebo-controlled study was conducted with 31 patients, 6 months to 17 years of age, with moderate to severe atopic dermatitis and clinical signs of secondary bacterial infections.

All patients received orally administered cephalexin for 14 days and were assigned randomly to receive intranasal mupirocin ointment treatment and sodium hypochlorite (bleach) baths (treatment arm) or intranasal petrolatum ointment treatment and plain water baths (placebo arm) for 3 months. The primary outcome measure was the Eczema Area and Severity Index score.

RESULTS: The prevalence of community-acquired methicillin-resistant S aureus in our study (7.4% of our S aureus-positive skin cultures and 4% of our S aureus-positive nasal cultures) was much lower than that in the general population with cultures at Children’s Memorial Hospital (75%-85%).

Patients in the group that received both the dilute bleach baths and intranasal mupirocin treatment showed significantly greater mean reductions from baseline in Eczema Area and Severity Index scores, compared with the placebo group, at the 1-month and 3-month visits.

The mean Eczema Area and Severity Index scores for the head and neck did not decrease for patients in the treatment group, whereas scores for other body sites (submerged in the dilute bleach baths) decreased at 1 and 3 months, in comparison with placebo-treated patients.

CONCLUSIONS: Chronic use of dilute bleach baths with intermittent intranasal application of mupirocin ointment decreased the clinical severity of atopic dermatitis in patients with clinical signs of secondary bacterial infections.

Patients with atopic dermatitis do not seem to have increased susceptibility to infection or colonization with resistant strains of S aureus.

Am J Clin Dermatol. 2010;11(2):123-9.

Dexamethasone-cyclophosphamide pulse therapy in pemphigus: a review of 72 cases.

Zivanovic D, Medenica L, Tanasilovic S, Vesic S, Skiljevic D, Tomovic M, Nikolic MM.

BACKGROUND: Autoimmune pemphigus is a group of severe blistering diseases. Although corticosteroids have dramatically altered the prognosis of pemphigus, morbidity and mortality resulting from the adverse effects of systemic corticosteroids remain high. Dexamethasone-cyclophosphamide pulse (DCP) therapy was introduced to diminish the adverse effects of prolonged conventional daily dose regimens.

OBJECTIVE: To report our experience with the use of the DCP regimen in patients with autoimmune pemphigus.

METHODS: In the period 1998-2002, 72 patients with various forms of autoimmune pemphigus treated with DCP therapy were included, of whom 36 patients were previously treated with conventional corticosteroid therapy, and 36 were newly diagnosed patients.

RESULTS: Of the 72 patients, 43 completed treatment, while 13 patients did not respond adequately to the treatment and continued with the conventional daily regimen, nine patients were lost to follow-up, and seven patients died. Two of these deaths were probably a consequence of DCP therapy.

CONCLUSION: DCP regimen is a beneficial treatment for patients with pemphigus, sparing the adverse effects of conventional regimens.

Br J Dermatol. 2010 Apr;162(4):790-7.

Pulsed intravenous cyclophosphamide and methylprednisolone therapy in refractory pemphigus.

Saha M, Powell AM, Bhogal B, Black MM, Groves RW.

BACKGROUND: Pemphigus is a rare autoimmune blistering disorder. The mainstay of current treatment is high-dose oral corticosteroid therapy in combination with a steroid-sparing agent. Adjuvant therapy is important for disease control and to reduce the iatrogenic effects of oral prednisolone. Pulsed therapy with intravenous methylprednisolone and cyclophosphamide (PPC) has been shown to be an effective treatment but there are currently few data on its use in patients who have failed to respond to conventional immunosuppression.

OBJECTIVES: To report the clinical and immunological responses of 21 patients with pemphigus refractory to prednisolone and azathioprine or mycophenolate mofetil treated in our department with a standard protocol of monthly PPC.

METHODS: Patients with pemphigus were identified who had undergone PPC therapy during the period between 1997 and 2006. Initial clinical severity and response to treatment was assessed. In addition, change in intercellular antibody titres and desmoglein 1 and 3 antibodies to PPC therapy was also recorded.

RESULTS: Of the 21 patients treated, seven had an excellent response, two a good response, five a moderate response, six a minimal response and one patient had no clinical response. Four patients achieved complete clinical remission and the number of pulses for these patients varied between 11 and 22. We observed significant reductions in indirect immunofluorescence titres for normal human skin substrate (P = 0.0078) and antidesmoglein 1 and 3 autoantibody levels (P = 0.007 and P = 0.0085, respectively) from pre-PPC therapy to 1 year after the last pulse. All patients were able to reduce their prednisolone dose from a pre-pulsing median dose of 40-10 mg at the last pulse with a median dose reduction of 66% (P < 0.001). The most common adverse effect was transient lymphopenia (12 patients); nonlife-threatening sepsis (seven patients) and premature ovarian failure (two patients) also occurred.

CONCLUSIONS: PPC can be an effective treatment for refractory pemphigus but its adverse effects should be considered prior to therapy and closely monitored in patients on treatment.

Il prednisone per os con ciclofosfamide risulta il trattamento più efficace per il pemfigo volgare.

Am J Clin Dermatol. 2007;8(2):85-92.

Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris.

Olszewska M, Kolacinska-Strasz Z, Sulej J, Labecka H, Cwikla J, Natorska U, Blaszczyk M.

BACKGROUND: Pemphigus vulgaris is a potentially life-threatening, autoimmune bullous disease of the skin and mucous membranes. Most commonly, the disease is treated with prednisone in combination with an immunosuppressant agent, frequently referred to as adjuvant drug. However, there is no consensus regarding the first-choice adjuvant drug for the treatment of pemphigus vulgaris or the recommended dosage.

OBJECTIVE: To evaluate the efficacy and safety of prednisone as monotherapy and in combination with the three most popular adjuvant agents – azathioprine, cyclosporine (ciclosporin), and cyclophosphamide – in the treatment of pemphigus vulgaris.

METHODS: This was a retrospective study with a follow-up of 7-21 years. The study was conducted in an academic hospital with an outpatient division for patients with bullous diseases. A total of 101 patients with moderate-to-severe mucocutaneous pemphigus vulgaris were included in the study. For assessment of disease severity a ‘pemphigus score,’ based on the percentage of involved skin or oral mucous membranes, was developed.

At treatment initiation the average pemphigus score was comparable in all treated groups of patients. Four treatment regimens were evaluated: oral prednisone at an initial dose of 100mg (1.1-1.5 mg/kg) per day as monotherapy, and prednisone combined with adjuvant drugs, i.e. oral azathioprine at a dose of 100mg (1.1-1.5 mg/kg) per day; cyclosporine (ciclosporin) at a dose of 2.5-3 mg/kg/day; or cyclophosphamide at a dose of 100mg (1.1-1.5 mg/kg) per day.

The main outcome measures were average time to clinical remission, average time to immunologic remission (non-detectable circulating pemphigus vulgaris antibodies), proportion of patients who remained free of clinical relapse within 5 years after discontinuation of therapy, time from treatment discontinuation until first relapse, and incidence of adverse effects.

RESULTS: The average (+/- SD) time to clinical remission was 7.2 +/- 13.1 months in patients who received prednisone monotherapy, 6.8 +/- 10.5 months in patients receiving additional azathioprine, 8.1 +/- 11.8 months in the cyclosporine group, and 4.9 +/- 6.9 months (which was significantly shorter than all other treatment groups, p < 0.05) in patients receiving cyclophosphamide. The average (+/- SD) times to immunologic remission were 33 +/- 27 months, 28 +/- 24 months, 30 +/- 21 months, and 23 +/- 17 months for prednisone monotherapy, azathioprine, cyclosporine, and cyclophosphamide, respectively.

The proportions of patients who remained free of clinical relapse within 5 years after discontinuation of therapy were 55%, 50%, 43%, and 69% for prednisone monotherapy, azathioprine, cyclosporine, and cyclophosphamide, respectively.

In patents who experienced relapse, the average (+/- SD) time from treatment discontinuation to clinical relapse was 10.50 +/- 6.86 months in patients receiving prednisone monotherapy, 16.40 +/- 17.36 months in the azathioprine group, 12.44 +/- 6.48 months in the cyclosporine group, and 21.16 +/- 20.13 months in the cyclophosphamide group. The safety profiles of all treatment regimens were comparable.

CONCLUSION: Oral prednisone with cyclophosphamide is the most effective treatment for pemphigus vulgaris. All therapy regimens had a similar safety profile. In our opinion, cyclophosphamide at a dose of 1.1-1.5 mg/kg/day should be the adjuvant drug of choice in the treatment of moderate-to-severe pemphigus vulgaris.

Curr Drug Discov Technol. 2009 Dec;6(4):270-80.

Current treatment of autoimmune blistering diseases

Kasperkiewicz M, Schmidt E.

Autoimmune bullous diseases are a heterogeneous group of disorders that can be subdivided according to the level of split formation in the intraepidermal blistering pemphigus diseases and subepidermal bullous disorders, latter including pemphigoid diseases, epidermolysis bullosa acquisita, and dermatitis herpetiformis.

In the majority of autoimmune bullous disorders, disease activity can be sufficiently controlled by systemic corticosteroids in combination with further immunosuppressants/immunomodulants such as dapsone, doxycycline, methotrexate, azathioprine, or mycophenolate mofetil.

In contrast, in pemphigus, mucous membrane pemphigoid, and epidermolysis bullosa acquisita, treatment is challenging and only in a minority of patients, conventional immunosuppressive therapy induces clinical remission.

Since only a few years ago, only cyclophosphamide and high-dose intravenous immunoglobulin were available as potent second-line therapies.

Meanwhile, immunoadsorption and the monoclonal anti-CD20 antibody rituximab have been established as further therapeutic options.

Here, both conventional therapies and novel treatment regimens for autoimmune blistering diseases are discussed.