NEWPORT BEACH, CALIF. (FRONTLINE MEDICAL NEWS) – Current treatment of autoimmune blistering diseases is not backed by evidence-based medicine and solid randomized, controlled trials, according to David T. Woodley, MD.

“These are rare diseases; there’s no consensus on the treatment of choice,” Dr. Woodley said at the annual meeting of the Pacific Dermatologic Association.

Dr. Woodley , professor of dermatology at the University of Southern California, Los Angeles, limited his discussion to pemphigus vulgaris (PV), pemphigus foliaceus (PF), and bullous pemphigoid (BP). The histologic hallmark of PV and PF is acantholysis. “Because these are intraepidermal blistering diseases, you don’t see the blister very often; maybe you’ll have a few intact loose sacklike blisters, but you mostly see erosions and crusting,” he said. “PV often only begins with mouth lesions.”

Work-up for a suspected autoimmune blistering disease includes a physical exam, histology, direct and indirect immunofluorescence, and serologic tests. The diagnosis should be based on the target autoantigen in the skin. PV and PF can appear identical on direct immunofluorescence, even though the blister cleavage plane is very high in PF and usually just above the basal keratinocytes in PV. “PF can have an intercellular keratinocyte cell surface staining pattern throughout the full epidermis or sometimes only the upper epidermal layers,” Dr. Woodley said.

At an international meeting on pemphigus in 2015, Dr. Woodley and his associates presented results from an ongoing study that is following 44 pemphigus patients at Keck Hospital of USC (a private university health care system) and 40 patients at Los Angeles County and USC Medical Center (a public safety net health care system). “The question we asked was, When the same doctors treat patients with a serious complicated disease requiring lots of details and follow-up at two very different health care systems, were there any differences in the outcomes of these patients?”

They found that the rates of clinical and immunologic remission were identical at both hospitals. However, at the county hospital, there was a higher incidence of relapses (59% vs. 30%). In addition, complications between the county and private hospitals differed in terms of hyperglycemia (38% vs. 11%, respectively), infections (79% vs. 37%), deaths (1 vs. none), medication dosage nonadherence (68% vs. 22%), and inappropriate discontinuation of one or more medications (68% vs. 15%). “Current research goals are to determine what factors cause medication compliance and noncompliance,” he said.

Dr. Woodley noted that one autoimmune blistering disease can evolveinto another because of the phenomenon of epitope spreading. “The concept is that inflammation from one autoimmune blistering disease creates skin injury and reveals new neoautoantigens that get recognized by the patient’s immune system,” he said.

For example, a patient who had PF and high-titer autoantibodies to desmoglein 1 after a couple of years began to have blisters and erosions in her mouth, which is not supposed to happen in PF. Immunologic testing of this patient showed that in addition to antibodies against desmoglein 1, she began making high-titer autoantibodies against desmoglein 3 and had transformed into PV.

Bullous pemphigoid is another well-characterized autoimmune bullous disease that usually occurs in elderly patients. The blister is beneath the epidermis at the dermal-epidermal junction. These patients may have oral involvement. BP is characterized by tense subepidermal bullae on inflammatory bases. Histology reveals epidermal-dermal separation, many eosinophils and mast cells, and sometimes many polymorphonuclear leukocytes. “Many of these patients have very high IgE antibodies as well as IgG,” he said.

Features of BP include IgG and C3 deposits at the dermal-epidermal junction by direct immunofluorescence and by indirect immunofluorescence. “On salt-split human skin substrate, these antibodies bind to the epidermal roof of the separation and not to the dermal floor,” Dr. Woodley said. “You can send off the patient’s serum for ELISA [enzyme-linked immunosorbent assay] testing to detect autoantibodies against the BP230 antigen and the BP180 antigen to confirm the diagnosis. Autoantibodies to the BP180 antigen often correlate with the patient’s disease activity. The sensitivity of indirect immunofluorescence and ELISA are both above 95%.”

BP can present with urticarial plaques and pruritus and without blisters. Also, recent research has demonstrated that BP can present with just pruritus and no skin lesions. “So that’s something to keep in mind in refractory pruritus patients,” he said.

The incidence of BP seems to be increasing, from an estimated 7 cases per million in 1995 to 43 cases per million in 2008, Dr. Woodley said. “It may be that it is associated with some drugs like loop diuretics and spironolactone, but the precise reason is not known,” he said. “If your patient has dementia or Parkinson’s disease, he or she has a fourfold increased chance that they will have BP, because the BP180 and BP230 antigens are also in neuronal cells. Parkinson’s patients are known to make antibodies to the BP180 antigen, but not to the NC16A domain of the BP180 antigen. The development of BP in a Parkinson’s patient occurs when he or she begins to also make autoantibodies against the NC16A domain.”

The standard of treatment for autoimmune blistering diseases is prednisone 0.7-2 mg/kg. Nonsteroidal immunosuppressive agents are also helpful, including methotrexate, azathioprine, cyclophosphamide, and mycophenolate mofetil. Emerging evidence suggests that rituximab is the drug of choice for PV and PF, and should be the first-line therapy. Rituximab is a chimeric monoclonal antibody that targets CD20–positive B lymphocytes. “It removes cells that are ready to transform into autoantibody-producing short-lived plasma cells,” Dr. Woodley said. “The depletion lasts 6-12 months.”

Another new development in BP is the use of omalizumab, a monoclonal antibody to IgE. “Omalizumab inhibits the IgE antibody binding to the BP180,” Dr. Woodley said.

“It’s thought that the BP180 antigen is released from basal keratinocytes into the high papillary dermis. In BP patients, there are numerous mast cells at that location. IgE binds to the mast cells, which have IgE receptors on their surface, and in the presence of the BP180 antigen, forms dimers on the mast cells, and causes them to release inflammatory cytokines, some of which recruit eosinophils. This is likely why BP is such an inflammatory disorder. You cannot follow the IgE levels; you have to follow the eosinophils. The IgE is still high, but it’s nullified and inactive.”

Other biologics that have been successfully used in PV, PF, and BP include tumor necrosis factor–alpha inhibitors and rituximab (Rituxan). Common dosing for rituximab is 325 mg/m2 per week for 4 weeks. Infusion reactions are the most common side effect, he said, but other reported adverse reactions include infections, transient hypogammaglobulinemia, neutropenia, deep vein thrombosis, and pulmonary embolism. “The incidence of side effects seems to be going down, because we are now premedicating patients with antihistamines and IV hydrocortisone before giving them rituximab,” Dr. Woodley noted.

The development of progressive multifocal leukoencephalopathy has also been reported with the use of rituximab. “This is exceedingly rare with rituximab but has been described, and this is what keeps doctors who use this drug awake at night,” he said.

Elderly patients with mild BP sometimes can get by without using immunosuppressive agents to manage their disease. One option is potent topical steroids plus niacinamide 0.5-2 g after each meal as an anti-inflammatory B vitamin. “Doxycycline 100 mg b.i.d. also works to inhibit neutrophils,” he said. “Antihistamines can also be helpful, and some French dermatologists have found total body clobetasol to be useful.”

Dr. Woodley disclosed that he holds patents on human recombinant type VII collagen. He is also a consultant for Shire Pharmaceuticals and a speaker for Biofusion.


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