minocycline and Pemphigus

The development of nonhormonal treatment of pemphigus vulgaris (PV) has been hampered by a lack of clear understanding of the mechanisms leading to keratinocyte (KC) detachment and death in pemphigus. In this study, we sought to identify changes in the vital mitochondrial functions in KCs treated with the sera from PV patients and healthy donors. PV sera significantly increased proton leakage from KCs, suggesting that PV IgGs increase production of reactive oxygen species. Indeed, measurement of intracellular reactive oxygen species production showed a drastic increase of cell staining in response to treatment by PV sera, which was confirmed by FACS analysis. Exposure of KCs to PV sera also caused dramatic changes in the mitochondrial membrane potential detected with the JC-1 dye. These changes can trigger the mitochondria-mediated intrinsic apoptosis. Although sera from different PV patients elicited unique patterns of mitochondrial damage, the mitochondria-protecting drugs nicotinamide (also called niacinamide), minocycline, and cyclosporine A exhibited a uniform protective effect. Their therapeutic activity was validated in the passive transfer model of PV in neonatal BALB/c mice. The highest efficacy of mitochondrial protection of the combination of these drugs found in mitochondrial assay was consistent with the ability of the same drug combination to abolish acantholysis in mouse skin. These findings provide a theoretical background for clinical reports of the efficacy of mitochondria-protecting drugs in PV patients. Pharmacological protection of mitochondria and/or compensation of an altered mitochondrial function may therefore become a novel approach to development of personalized nonhormonal therapies of patients with this potentially lethal autoimmune blistering disease.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Autoantibodies; Cell Line, Transformed; Cyclosporine; Enzyme Inhibitors; Female; Humans; Immunoglobulin G; Keratinocytes; Male; Mice; Mice, Inbred BALB C; Minocycline; Mitochondria; Niacinamide; Oxygen Consumption; Pemphigus; Reactive Oxygen Species; Vitamin B Complex

Topics: Glucocorticoids; Humans; Immunosuppressive Agents; Minocycline; Pemphigus; Prednisolone

Minocycline/tetracycline is clinically used for the treatment of bullous pemphigoid (BP), and its clinical benefits are superior to those of prednisolone when considering adverse events. Although the clinical benefits of minocycline/tetracycline are well known, its immunosuppressive mechanisms are still unclear. In this study, we investigated the immunomodulatory effects of traditional anti-BP drugs (minocycline, nicotinic acid amide, dexamethasone and cyclosporine) on CD163

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cells, Cultured; Chemokine CCL17; Chemokine CCL2; Chemokine CCL22; Chemokine CCL24; Chemokine CCL26; Chemokine CXCL10; Chemokines, CC; Dexamethasone; Female; Humans; Macrophages; Male; Middle Aged; Minocycline; Niacinamide; Pemphigoid, Bullous; Pemphigus; Protein Biosynthesis; Receptors, Cell Surface; Vitamin B Complex

Pemphigus vegetans is a rare variant of pemphigus vulgaris, accounting for 1-2% of all pemphigus diseases. Systemic corticosteroids are the therapy of first choice in combination with immunosuppressants as steroid-sparing agents.. To highlight the exceptional but successful use of minocycline/nicotinamide monotherapy in pemphigus vegetans.. A review of the literature to date about pemphigus vegetans with special emphasis on therapy was performed. Due to its rarity, multiple anecdotal reports without long-term follow-up are available and prospective controlled trials are lacking. Only one retrospective study from Tunisia includes 17 patients with pemphigus vegetans.. We present a 76-year-old woman with pemphigus vegetans achieving complete response to a minocycline/nicotinamide monotherapy at onset and at relapse of the disease. Treatment has been discontinued after repeated direct immunofluorescence (DIF) of previously affected normal skin and anti-desmoglein 3 antibodies had become negative. In addition, DIF of previously involved oral mucosa was negative. During long-term follow-up clinical remission has been maintained for more than 5 years. Up to now, negative results of serial performed indirect immunofluorescence and desmoglein ELISA testing also predict immunological remission.. In our patient and in a case with oesophageal involvement, published more than 20 years ago, clearly the benefit of minocycline/nicotinamide monotherapy was demonstrated. We propose to consider minocycline/nicotinamide as first-line monotherapy in pemphigus vegetans, especially in elderly patients with comorbidities and contraindications to standard therapy, as it avoids the toxicities of systemic corticosteroids and immunosuppressants.

Topics: Aged; Female; Humans; Minocycline; Niacinamide; Pemphigus

The twin goals of long-term disease control and minimizing toxicities related to immunosuppression necessitate efforts to find effective steroid-sparing agents in the management of patients with autoimmune bullous diseases. Pemphigus especially requires a long view, because the disease can persist throughout a patient's lifetime, yet few clinical trial reports exist to guide the practitioner.. We review the response of pemphigus patients to tetracycline, doxycycline, or minocycline plus niacinamide (TCN/NAM) as steroid-sparing therapy and to determine the effects of TCN/NAM on autoantibody levels during the long-term treatment of pemphigus.. This was a retrospective chart review in a private medical dermatology practice setting of all pemphigus patients treated between 1993 and 2013. Clinical responses to TCN/NAM therapy after initial high-dose steroid induction therapy and pemphigus antibody levels were recorded over the course of disease flares and treatment cycles along with any related side effects. Anti-desmoglein 1 and 3 titers were compared in a subset of patients over time, and a statistical analysis was performed to correlate the clinical response with antibody levels.. Fifty-one pemphigus patients (43 with pemphigus vulgaris, 7 with pemphigus foliaceous, and 1 with pemphigus erythematosus) received at least 3 months of TCN/NAM, and 16 patients with pemphigus vulgaris had 1 set of pemphigus antibody titers correlating to a baseline/flare and clinical remission. TCN/NAM was associated with disease control in 43 of 51 patients, with a duration of response ranging from 1 to 13 years (mean, 3.14 ± 2.97 years). Thirteen of 51 patients needed no additional treatment for complete disease control, while 33 of 51 needed intermittent topical clobetasol or short courses of oral steroids for long-term management. There were 5 nonresponders. Antidesmoglein titers trended lower in TCN/NAM responders, but only desmoglein 3 approached statistical significance (anti-desmoglein 1, P = .21; anti-desmoglein 3, P = .02).. This is a retrospective analysis from a single practice. A lack of serial autoantibody titers limited statistical analyses.. TCN/NAM may be useful as a steroid-sparing therapy for pemphigus.

Topics: Anti-Inflammatory Agents; Clobetasol; Doxycycline; Drug Therapy, Combination; Humans; Minocycline; Niacinamide; Pemphigus; Retrospective Studies; Tetracycline; Treatment Outcome

Topics: Aged; Anti-Bacterial Agents; Dermatitis Herpetiformis; Female; Humans; Minocycline; Niacinamide; Pemphigus

We report a patient with herpetiform pemphigus who was negative for autoantibodies to desmoglein (Dsg)1 or 3. He had erythemas with vesicles lining the margins on the trunk and extremities. Histopathology revealed intraepidermal blister with prominent eosinophil infiltration. Direct and indirect immunofluorescence demonstrated the presence of depositing and circulating immunoglobulin (Ig)G autoantibodies, but no IgA antibodies, to keratinocyte cell surface. Nonetheless, neither anti-Dsg1 nor Dsg3 antibodies were detected by enzyme-linked immunosorbent assay. Immunoblotting using human epidermal extracts also showed no reactivity with known intraepidermal or epidermal-dermal junctional substances. Immunoelectronmicroscopy revealed the reactivity on the portion of keratinocyte cell surface but not on the desmosomes. This case suggests that non-desmoglein antigen on keratinocyte cell surface can be targeted in some patients with this unusual variant of pemphigus.

Topics: Aged; Autoantibodies; Carcinoma, Squamous Cell; Dapsone; Desmoglein 1; Desmoglein 3; Desmosomes; Eosinophils; Esophageal Neoplasms; Humans; Immunoglobulin A; Immunoglobulin G; Keratinocytes; Male; Minocycline; Pemphigus; Prednisolone

Minocycline is another possible alternative therapy for pemphigus vulgaris. We successfully treated a Jewish patient with oral pemphigus vulgaris with with minocycline and nicotinamide. Minocycline may be a useful second-line drug for therapy- resistant cases of pemphigus vulgaris.

Topics: Adult; Drug Therapy, Combination; Female; Humans; Minocycline; Mouth Mucosa; Niacinamide; Pemphigus; Stomatitis; Treatment Outcome

Immunosuppressive medications typically used to treat the immunobullous disorders pemphigus vulgaris, pemphigus foliaceous, and bullous pemphigoid can have serious adverse effects. The tetracycline family of antibiotic drugs has been shown to be effective in the treatment of these conditions with a more favorable side effect profile. Minocycline hydrochloride use has been associated with various forms of hyperpigmentation, and its incidence is well reported in acne vulgaris and rheumatoid arthritis. We examined a series of 9 patients treated with minocycline for pemphigus or pemphigoid, most of whom have developed cutaneous hyperpigmentation.. Seven of 9 patients treated with minocycline, 50 mg daily (1 patient) or 100 mg twice daily (8 patients), for pemphigus vulgaris, pemphigus foliaceous, or bullous pemphigoid developed hyperpigmentation, which necessitated discontinuing therapy. Five of these patients had experienced notable clinical improvement of their immunobullous disease with minocycline therapy. The average duration of treatment was 8.2 months (range, 1-25 months). The second most common adverse effect in our group was oral candidiasis, which occurred in 2 patients.. We found a favorable response to minocycline therapy in 5 of 9 patients. However, 7 patients developed localized hyperpigmentation as early as 1 month after starting medication use. This incidence of minocycline-induced hyperpigmentation is significantly higher in immunobullous disease than in acne vulgaris or rheumatoid arthritis. This increased incidence may be related to an increase in pigment deposition complexed with collagen during the remodeling process, subclinical inflammation, or glucocorticosteroid-induced skin fragility. The hyperpigmentation process was reversible, as most of our patients had fading of their pigmentation after minocycline cessation.

Topics: Adult; Aged; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Hyperpigmentation; Male; Middle Aged; Minocycline; Pemphigoid, Bullous; Pemphigus; Skin

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis; Azathioprine; Calcium Channel Blockers; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Minocycline; Mycophenolic Acid; Nifedipine; Pemphigus; Penicillamine; Skin

Pemphigus is an autoimmune blistering disease with high mortality if untreated. The cases of 10 patients who had minocycline 100 mg daily added as adjuvant therapy are reported. Prior to the use of minocycline, all patients had active disease, nine were on prednisolone (10-40 mg) and five were on azathioprine (100-200 mg). The response was assessed on clinical improvement and reduction of immunosuppressive (IS) drugs. It was graded into four categories: major, minor, equivocal and no significant response. A major response was seen in four patients, minor in two, equivocal in one and no improvement in three patients. The prednisolone dose in the six responders was reduced to 0-6 mg (0 mg in three patients), with an average decrease of 21 mg. The average time to respond was 8 months. Of the six responders, three were on azathioprine, which was ceased in two patients and reduced by two-thirds in the other patient. No patient ceased minocycline because of side effects. In conclusion, minocycline 100 mg daily is a simple, safe and well tolerated treatment that should be tried in patients with pemphigus to reduce disease activity and/or the dose of potent IS agents.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Anti-Inflammatory Agents; Azathioprine; Drug Combinations; Humans; Immunosuppressive Agents; Middle Aged; Minocycline; Pemphigus; Prednisolone; Remission Induction; Retrospective Studies

Topics: Drug Therapy, Combination; Esophageal Diseases; Female; Humans; Middle Aged; Minocycline; Niacinamide; Pemphigus