tacrolimus and Pemphigus

Inflammatory mucosal disorders are treated conventionally with potent or superpotent topical corticosteroids. For more than 20 years, topical cyclosporine has been used in the management of oral mucous membrane affections. Recently other topically applied calcineurin inhibitors, namely tacrolimus and pimecrolimus, expanded the armamentarium for the treatment of inflammatory mucosal diseases. This chapter places its main emphasis on the efficacy and safety of topical calcineurin inhibitors in the management of different oral and genital conditions, including anogenital lichen sclerosus (LS), oral and genital lichen planus, plasma cell balanitis and vulvitis, mucous membrane pemphigoid and pemphigus vulgaris, all conditions having usually a protracted course, requiring long-lasting treatment. There is current evidence for the effectiveness of both pimecrolimus and tacrolimus in the topical treatment of inflammatory oral mucosal diseases and genital dermatoses, especially oral lichen planus and genital LS.

Topics: Administration, Topical; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Balanitis; Calcineurin Inhibitors; Carcinogens; Female; Genital Diseases, Female; Humans; Lichen Planus; Lichen Planus, Oral; Lichen Sclerosus et Atrophicus; Male; Mucositis; Paraneoplastic Syndromes; Pemphigoid, Benign Mucous Membrane; Pemphigus; Tacrolimus; Vulvitis

Treatment modalities in pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are many and varied, although level 1 evidence supporting their use is limited. To date, only 2 systematic reviews exist to support the use of different treatment modalities to control this group of conditions. Overall, within the literature, the quality of trials comparing treatment modalities is poor. Cohort sizes are small, methodologies are varied, and standardized outcome measurements are lacking. The authors aim to present a comprehensive view of the level 1 evidence that exists for common treatment modalities used in PV and PF.

Topics: Azathioprine; Cyclophosphamide; Cyclosporine; Dapsone; Dermatologic Agents; Epidermal Growth Factor; Evidence-Based Medicine; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Medicine, Chinese Traditional; Mycophenolic Acid; Pemphigus; Pentoxifylline; Plasmapheresis; Randomized Controlled Trials as Topic; Sulfasalazine; Tacrolimus

Paraneoplastic pemphigus (PNP) or paraneoplastic autoimmune multiorgan syndrome (PAMS) is a life-threatening autoimmune blistering disease commonly associated with lymphoproliferative neoplasms. This article focuses on current management strategies in PNP/PAMS, and reported instances of their treatment successes and failures. Due to the rarity of the condition and the high rates of treatment failure, no randomized control trials exist to guide the evidence-based treatment of this condition; all evidence to date on the efficacy of therapeutic modalities has been gained from individual case reports, small case series, and expert recommendations.

Topics: Adrenal Cortex Hormones; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Autoimmune Diseases; Azathioprine; Cyclophosphamide; Cyclosporine; Dermatologic Agents; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Multiple Organ Failure; Mycophenolic Acid; Paraneoplastic Syndromes; Pemphigus; Plasmapheresis; Rituximab; Tacrolimus

Pemphigus is an autoimmune skin disease that can present in a variety of forms and can be a challenging disease to manage and treat. An overview of the different forms of pemphigus and diagnostics are discussed including pemphigus foliaceus (PF), pemphigus erythematosus (PE), panepidermal pustular pemphigus (PPP), pemphigus vulgaris (PV) and paraneoplastic pemphigus (PNP). Emphasis on therapy is presented. Included are the most current commonly used therapeutics (glucocorticoids, azathioprine, chlorambucil and tetracycline and niacinamide); current alternative therapeutics (cyclosporin and tacrolimus and mycophenolate mofetil) and additional alternative therapeutics (cyclophosphamide, chrysotherapy, dapsone, sulfasalazine and intravenous immunoglobulin (IVIG) therapy).

Topics: Animals; Antirheumatic Agents; Azathioprine; Chlorambucil; Cyclophosphamide; Cyclosporine; Dapsone; Dog Diseases; Dogs; Glucocorticoids; Immunoglobulins, Intravenous; Mycophenolic Acid; Niacinamide; Organogold Compounds; Pemphigus; Sulfasalazine; Tacrolimus; Tetracycline

Introduction: To investigate the therapeutic efficacy of tacrolimus compared with azathioprine in the treatment of pemphigus vulgaris.. About 23 patients received prednisolone and azathioprine, and 23 patients prednisolone and tacrolimus for 6 months. Pemphigus activity scores, the time that new bulla formation stopped, the time corticosteroid was tapered, cumulative steroid dosage and medication side effects were analyzed.. In the control group, the new bulla formation was ceased after a mean ± SD of 11.8 ± 4.7 days, and steroid tapering was done after a mean ± SD of 28.3 ± 5.45 days. Of the 23 patients receiving prednisolone and tacrolimus, the new bulla formation was ceased after a mean ± SD of 12.9 ± 5.26 days, and steroid tapering was done after a mean ± SD of 28.2 ± 5.39 days. About 8.6% of patients did not reach remission in each group. In patients receiving azathioprine, life-threatening side effects were seen in 1 (4.7%), moderate side effects in 2 (9.5%) and mild side effects in 1 (4.7%). In patients receiving tacrolimus, moderate side effect was seen in 1 (5%) and mild in 1 (5%).. Tacrolimus effects are comparable to azathioprine as pemphigus vulgaris adjuvant treatment, also it has less severe side effects. Trial registration No. IRCT2012073010450N1 available at www.IRCT.ir.

Topics: Adult; Aged; Azathioprine; Drug Therapy, Combination; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Pemphigus; Prednisolone; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Pemphigus vulgaris (PV) is a chronic, bullous disorder that is usually characterized by the presence of bulla and erosion on the skin and mucosa. Many studies on PV focus on the use of topical non-steroid agents. One of these agents is pimecrolimus; its efficacy is established in some inflammatory and autoimmune disorders such as oral and genital lichen planus.. This was a double-blind study that was performed in 11 patients with confirmed diagnosis of PV. Patients under treatment with systemic steroid and azathioprine who had bilateral symmetrical oral lesions were selected and right- or left-sided lesions of those identified were randomized to be treated either by pimecrolimus 1% cream or placebo. The largest diameter of lesions was measured at the baseline and every 15 days for two times. Epithelization Index (EI) was calculated and data were analyzed with a program for statistical analysis.. Overall, 11 patients (62 cutaneous lesions; 31 lesions in the pimecrolimus group and 31 lesions in the placebo group) with cutaneous lesions of the pemphigus vulgaris were included in this study. At the end of day 15, there was significant difference regarding EI between the pimecrolimus and placebo groups. In addition, EI was significantly different at the end of study (day 30) in favor of pimecrolimus group (P = 0.000).. Pimecrolimus can be used as an effective and safe adjunctive treatment for cutaneous lesions of pemphigus vulgaris.

Topics: Adult; Aged; Calcineurin Inhibitors; Double-Blind Method; Female; Humans; Male; Middle Aged; Pemphigus; Tacrolimus

Glucocorticoids are the first-line treatment for Pemphigus vulgaris (PV), but its serious side effects can be life-threatening for PV patients. Tacrolimus (FK506) has been reported to have an adjuvant treatment effect against PV. However, the mechanism underlying the inhibitory effect of FK506 on PV-IgG-induced acantholysis is unclear.. The objective of this study was to explore the effect of FK506 on desmoglein (Dsg) expression and cell adhesion in an immortalized human keratinocyte cell line (HaCaT cells) stimulated with PV sera.. A cell culture model of PV was established by stimulating HaCaT cells with 5% PV sera with or without FK506 and clobetasol propionate (CP) treatment. The effects of PV sera on intercellular junctions and protein levels of p38 mitogen-activated protein kinase (p38MAPK), heat shock protein 27 (HSP27), and Dsg were assayed using western blot analysis, immunofluorescence staining, and a keratinocyte dissociation assay.. PV sera-induced downregulation of Dsg3 was observed in HaCaT cells and was blocked by FK506 and/or CP. Immunofluorescence staining revealed that linear deposits of Dsg3 on the surface of HaCaT cells in the PV sera group disappeared and were replaced by granular and agglomerated fluorescent particles on the cell surface; however, this effect was reversed by FK506 and/or CP treatment. Furthermore, cell dissociation assays showed that FK506 alone or in combination with CP increased cell adhesion in HaCaT cells and ameliorated loss of cell adhesion induced by PV sera. Additionally, FK506 noticeably decreased the PV serum-induced phosphorylation of HSP 27, but had no effect on p38MAPK phosphorylation.. FK506 reverses PV-IgG induced-Dsg depletion and desmosomal dissociation in HaCaT cells, and this effect may be obtained by inhibiting HSP27 phosphorylation.

Topics: Autoantibodies; Desmoglein 3; HaCaT Cells; HSP27 Heat-Shock Proteins; Humans; Immunoglobulin G; Keratinocytes; Pemphigus; Phosphorylation; Tacrolimus

Topics: Adrenal Cortex Hormones; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; COVID-19; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Lichen Planus; Male; Middle Aged; Pemphigus; Psoriasis; SARS-CoV-2; Tacrolimus

Topics: Female; Humans; Middle Aged; Pemphigus; Pemphigus, Benign Familial; Tacrolimus

A 76-year-old woman presented with a pruritic photodistributed rash and dysphagia. Serum anti-nuclear antibody was positive (titre 1/1280) and skin and muscle biopsies confirmed a diagnosis of dermatomyositis. She was treated with oral prednisolone (5-50 mg/day), mometasone furoate 0.1% ointment and lotion, and tacrolimus 0.03% ointment. Four years later she presented with multiple painful scaly erosions on the face, scalp and trunk. Histopathology and direct and indirect immunofluorescence confirmed a diagnosis of pemphigus vulgaris. Repeated malignancy screens were negative. She was treated with methotrexate (10 mg/week) and prednisolone (50 mg/day slowly tapered to 5 mg/day), with good control of both diseases.

Topics: Aged; Anti-Inflammatory Agents; Antibodies, Antinuclear; Dermatomyositis; Female; Humans; Methotrexate; Mometasone Furoate; Pemphigus; Prednisolone; Pregnadienediols; Tacrolimus

Pemphigus vulgaris (PV) is an auto-immune blistering skin disease characterized by flaccid blisters and painful erosions of mucous membranes and skin. Suprabasal blister formation results from a loss of epidermal cohesion induced by auto-antibodies against the desmosomal protein desmoglein 3. Treatment of PV currently consists of systemic glucocorticosteroids and adjuvant immunosuppressive drugs such as azathioprine, mycophenolate mofetil, cyclophosphamide or dapsone. Due to the low incidence of PV, there are insufficient data to conclude which treatment is the most effective and safest. Thus far, systemic tacrolimus (FK506, Prograf) has not yet been reported as adjuvant medication for PV. Here, we describe the successful use of systemic tacrolimus in 2 patients with recalcitrant PV of the oral mucosa. Tacrolimus was well tolerated, and clinical improvement allowed tapering of corticosteroids. Thus, oral tacrolimus may be a therapeutic alternative for patients with recalcitrant PV.

Topics: Adrenal Cortex Hormones; Aged; Autoantibodies; Azathioprine; Cyclophosphamide; Dapsone; Dermatologic Agents; Desmoglein 3; Female; Humans; Immunosuppressive Agents; Middle Aged; Mouth Mucosa; Mycophenolic Acid; Pemphigus; Tacrolimus; Treatment Outcome

Pemphigus vulgaris (PV) is an autoimmune bullous disease caused by immunoglobulin G (IgG) autoantibodies against desmoglein 3 (Dsg3). We have generated an active disease mouse model for PV by adoptive transfer of Dsg3(-/-) lymphocytes. In this study, we investigated the benefits and limitations of this model as a tool to evaluate various immunosuppressive therapeutic strategies. We used the following three measurements to evaluate the effects of the drugs during the time course: Dsg3 enzyme-linked immunosorbent assay scores that represent the level of production of anti-Dsg3 IgG, body weight loss that reflects the severity of oral erosions and PV score that reflects the extent of skin lesions. We examined various immunosuppressive agents currently used to treat patients with PV model mice in preventive protocol. Cyclophosphamide almost completely suppressed the production of anti-Dsg3 IgG, development of body weight loss and the appearance of the PV phenotype in contrast with the control group without the drug. Azathioprine, cyclosporin A and tacrolimus hydrate also showed suppressive effects to various degrees. However, methylprednisolone and dexamethasone failed to show significant effects in contrast to the findings reported in humans. Knowing the advantages and limitations of this model will provide an important foundation for the future evaluation and development of novel therapeutic strategies.

Topics: Animals; Azathioprine; Body Weight; Cyclophosphamide; Cyclosporine; Desmoglein 3; Dexamethasone; Disease Models, Animal; Disease Progression; Female; Immunoglobulin G; Immunosuppressive Agents; Male; Methylprednisolone; Mice; Mice, Inbred C57BL; Mice, Knockout; Pemphigus; Phenotype; Tacrolimus

Cutaneous plasmacytosis is a rare condition affecting middle-aged individuals, characterized by multiple red-brown papules and plaques over the trunk. It has been reported mainly in Japan. The condition is accompanied by polyclonal hypergammaglobulinemia and superficial lymphadenopathy. Lung or retroperitoneal involvement occurs rarely. In the present study, 3 consecutive cases of cutaneous plasmacytosis were observed histologically to have abundant infiltration of IgG4-bearing plasma cells. All 3 were associated with superficial lymphadenopathy, one with interstitial lung involvement showing ground-glass opacity on computed tomography and the others with bone marrow plasmacytosis, showing histologic evidence of more IgG4-positive plasma cells. All 3 had polyclonal hypergammaglobulinemia, one had high serum concentration of IgG4, and all had elevated serum IL-6. The ratios of IgG4+ to IgG+ plasma cells were assessed using skin biopsy specimens with pemphigus (n = 7), discoid lupus erythematosus (n = 5), and morphea (n = 2) (mean ratios, 19%, 0%, and 0%, respectively); we noted the proportion of IgG4-positive plasma cells in cutaneous plasmacytosis (mean, 48%). IgG4-related sclerosing disease is a newly recognized systemic disorder characterized by lymphoplasmacytic infiltration and fibrosis and by a high serum IgG4 level and increased IgG4-positive plasma cells in the tissues. Skin manifestations of this disorder have not been described. Although cutaneous plasmacytosis could be a chronic allergic hypersensitivity reaction, our findings raise the possibility of a relationship in pathogenesis between cutaneous plasmacytosis and IgG4-related sclerosing disease.

Topics: Anti-Inflammatory Agents; Biopsy; Case-Control Studies; Cell Count; Dermatologic Surgical Procedures; Diagnosis, Differential; Fibrosis; Follow-Up Studies; Humans; Hypergammaglobulinemia; Immunoglobulin G; Immunohistochemistry; Immunosuppressive Agents; Inflammation; Interleukin-6; Japan; Lung; Lung Diseases, Interstitial; Lymphatic Diseases; Male; Middle Aged; Ointment Bases; Pemphigus; Plasma Cells; Prednisolone; Radiography; Sclerosis; Skin; Tacrolimus; Time Factors; Treatment Outcome

Topical 0.03% tacrolimus was used for treatment of a Korea Jindo dog diagnosed with pemphigus erythematosus. The dog was slowly improved following application of tacrolimus but did not achieve complete remission until end of this study. No adverse effects on clinical or laboratory parameters were noted during the topical tacrolimus therapy period.

Topics: Administration, Topical; Animals; Dog Diseases; Dogs; Female; Immunosuppressive Agents; Pemphigus; Skin; Tacrolimus

Topics: Administration, Cutaneous; Aged; Anti-Inflammatory Agents; Clobetasol; Female; Humans; Immunosuppressive Agents; Ointments; Pemphigus; Tacrolimus; Treatment Outcome

Topics: Absorption; Administration, Topical; Female; Humans; Immunosuppressive Agents; Middle Aged; Pemphigus; Tacrolimus

We report a case of pemphigus vulgaris in which a recalcitrant area of erosion on the cheek cleared only when topical tacrolimus was used in addition to a regime of systemic therapy consisting of cyclophosphamide and prednisolone. Clinical improvement occurred within 10 days of applying topical tacrolimus with healing of erosions and reduction in pain and burning sensations. Topical tacrolimus may inhibit local activation of T lymphocytes through altered expression of cytokines such as interleukin-1, -4 and -5, tumour necrosis factor-alpha and interferon-gamma. Some of these cytokines may also contribute directly to increasing keratinocyte fragility in the aetiology of pemphigus vulgaris erosions. This case illustrates that topical tacrolimus may be a useful adjunct in the management of patients with pemphigus vulgaris.

Topics: Administration, Cutaneous; Aged; Female; Humans; Immunosuppressive Agents; Pemphigus; Tacrolimus

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Diagnosis, Differential; Forehead; Humans; Immunosuppressive Agents; Male; Pemphigus; Scalp; Tacrolimus

Topics: Female; Humans; Immunosuppressive Agents; Middle Aged; Paraneoplastic Syndromes; Pemphigus; Recurrence; Stomatitis; Tacrolimus

Topics: Administration, Topical; Aged; Eye Diseases; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Pemphigoid, Benign Mucous Membrane; Pemphigus; Tacrolimus