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In general, the quality of published data concerning the therapy for bullous conditions is limited, and there are few controlled therapeutic trials. The majority of data is confined to case reports and small case series with short follow-up periods in which cases of variable severity are included. For this reason the effectiveness of most treatments other than systemic steroids is uncertain and little objective information is available to judge the relative effectiveness of treatments other than steroids. Drugs are often used in combination, particularly adjuvant drugs given concurrently with steroids, and dosing schedules vary widely.

The treatment of immunobullous diseases consists of three phases:

  1. Control: period of intense therapy given to suppress disease activity until no new lesions appear. The duration of this phase is weeks.
  2. Consolidation: Drugs and doses are maintained until complete clearance of lesions.
  3. Maintenance: Medications can be gradually tapered aiming for the lowest dose that prevents new lesions from appearing.

Relapse may occur at any time, resulting in renewed disease control effort. (z).

The main focus of treatment has been medications with potent anti-inflammatory properties (corticosteroids) as well as medications that reduce antibody production.

The drugs used for treating immunobullous disorders can be classified into rapid and slow acting (see Table below), topical and systemic, or immunosuppressant and anti-inflammatory.

Pemphigus Vulgaris

Pemphigus is a particularly difficult disease to treat. Anti-desmoglein antibodies are produced in all forms of pemphigus. These antibodies bind to adhesion molecules on the epithelial cell surface, which leads to separation of keratinocytes from each other and to blister formation. The exact mechanism by which this occurs is uncertain but likely involves inflammatory pathways triggered by binding of antibodies to the adhesion molecules. Therefore, therapy is intended to reduce the production of pathogenic antibodies and to inhibit the other pathways involved in the disease process (aa). It is unclear at this time, whether drug therapy’s effect on reducing autoantibody synthesis is more or less significant than the effect of decreasing the inflammatory response

A recent analysis of therapeutic approach identified the following patterns and opportunities for improving care:

  • Early expert evaluation: as “the long delay from onset of symptoms to expert evaluation is quite striking”. In PV, similarly to other autoimmune diseases, if the process is not promptly and appropriately controlled, the disease becomes more resistant, making the condition more difficult to treat.
  • Confirmation of the clinical diagnosis: by tissue biopsy specimen for histopathologic and both indirect and direct immunofluorescence examination.
  • Although still under evaluation, consideration of early adjuvant immunosuppression in moderate and severe cases: e.g. azathioprine or mycophenolate mofetil
  • Review of the length of adjuvant immunosuppressant use: The vast majority (82%) of experts use adjuvant immunosuppressants for 2 years or less (bb).

Pediatric pemphigus vulgaris maybe more refractory to treatment than the adult form. (aa)

Corticosteroids

Systemic corticosteroids are the best established therapy for the management of PV. If used in high enough doses, they rapidly control of disease activity is achieved in almost all patients, resulting in decreased mortality (o, e).

Initial Therapy

Initial therapy is determined by the extent and rate of the progression of lesions. Localized, slowly progressive disease can be treated with intralesional injections of corticosteroids (triamcinolone acetonide, 10 to 20 mg/ml) or topical application of high-potency corticosteroids (o). New lesions that continue to appear in a limited number may be controlled with low-dose systemic corticosteroids (b).

If the disease fails to respond to the above measures, or is extensive or progressing rapidly when first seen, then it is generally treated with high-doses of systemic steroids (prednisolone, prednisone, methylprednisolone, dexamethasone), orally or by IV. The doses required will vary depending on the activity and severity of the disease and can range from 1 to 2 mg/kg/day of prednisone equivalents, often in split daily doses initially.

Formally, when no alternate therapeutic approaches were available, doses over 250 mg/day of prednisone were sometimes required to control the disease. Now that alternates approaches are available, if the disease remains active despite high doses of corticosteroids (e.g., 90 to 120 mg/day of prednisone equivalent), one of the following approaches could be considered for rapid control (o):

  • Use of an immunosuppressant (added to the glucocorticoids).
  • If the disease is unresponsive or particularly severe, IVIG or plasmapheresis may be used.
  • The use of corticosteroids and immunosuppressives prior to IVIG or plasmapheresis may help to prevent rebound phenomena that may otherwise occur (o) due to an increase in level of pemphigus antibodies.
  • Intravenous immunoglobulin (IVIg), usually given at a dosage of 400 mg/kg/day for 5 days or in higher doses for 3 days. The procedure may need to be repeated every 4 weeks for several cycles. It is very expensive. The use of IVIg for the treatment of skin diseases has recently been reviewed.
  • Plasmapheresis, normally performed three times a week, involves removal of 1 to 2 L of plasma per procedure. This procedure is being replaced by IVIg, which can reduce circulating levels of pemphigus antibodies almost as rapidly and may be safer.
  • Pulse therapy with megadoses of intravenous methylprednisolone, given at a dosage of 1 g/day for 5 days.
  • (The TNF-a inhibitors such especially Rituximab are currently being investigated for efficacy in the treatment of Pemphigus Vulgaris).

No comparative studies have yet evaluated the relative effectiveness of these procedures (o). Once disease activity is controlled, the patient is maintained on the type and dose of medications required to establish control until approximately 80% of lesions are healed. Therapy should not be tapered while new lesions are appearing. (b)

Maintenance Therapy

Once most lesions have healed, the dose and type of medication that controlled disease activity are gradually tapered to reduce the risk of side effects. This is important since most patients who die today with pemphigus die due to complications of therapy (e). The rate of dose reduction is an art, determined by clinical response and disease activity. (o).

Systemic steroids are the mainstay of therapy, but longer-term treatment and higher doses often causes significant side effects: therefore consider:

  • Screening and risk assessment of possible side effects e.g. diabetes, glaucoma, osteoporosis, hypertension, GI bleeding, hyperlipidemia, tuberculosis is required prior to and during treatment.
  • The use of adjuvant therapies, which may help reduce the steroid dose, limit side effects and still control disease (o).
  • Adjuvant therapies include various immunosuppressive drugs (see below) and anti-inflammatory drugs such as gold, dapsone, and antibiotics such as tetracycline and minocycline.
  • It is recommended to give concomitant calcium and vitamin D (non-activated) supplements to all patients on corticosteroids
  • It is recommended to give bisphosphonates to all patients (e.g. most male and post-menopausal) on long term steroids, unless contra-indicated (e.g. premenopausal women anticipating pregnancy in the future) – see section on management later.

A recent study of prescribing practices from academic and tertiary care centers

indicated that initial steroid dose ranged from 1 – 1.5mg/kg/d (q).

Long-term dosing approaches varied as follows:

  • 37% of physicians polled stated that their goal is to eliminate corticosteroids completely; 11% had a goal of an alternate daily prednisone dose of 5 mg;
  • 26% were comfortable with a dose of 5 mg/d; and 26% were satisfied with 10 mg/d.

Immunosuppressants: (as adjuvant medications)

Depending upon the response and or tolerance of medication, adjuvant (immunosuppressive) therapy may be substituted or added to corticosteroid therapy, in an attempt to spare or reduce prednisone dose and its associated complications (i). Very few controlled studies of adjuvants have been done, so that their effectiveness remains uncertain, as does their relative safety.

In a recent review of prescribing practices (q) Azathioprine was the most frequently used adjuvant immunosuppressant, then Mycophenolate mofetil (CellCept®), cyclophosphamide, and cyclosporine in that order. Forty-six percent of respondents in that review reported they maintain steroid-sparing immunosuppressants in their patients for 6 months to 1 year, whereas 36% continue the immunosuppressants for 1 to 2 years, and 18% maintain this regimen indefinitely.

There are a number of clinical trials underway to better evaluate these adjuvant therapies (e).

Azathioprine

Azathioprine is a well-established choice as an adjuvant drug for the management of pemphigus (i). Typical dosage is 2.5 mg/kg/day. It is believed (but not proven) to have a steroid sparing effect, and may reduce mortality and increased remissions versus corticosteroids alone (c).

Azathioprine should be titrated to TPMT activity (i) (Azathioprine is best avoided in patients with very low TPMT levels (which exists in 1: 200-300 of the general population (d), and should be used at reduced doses, e.g. 0.5 mg kg-1, in those with low levels (~ 10%). This group is particularly at risk for bone marrow suppression and thus anemia, thrombocytopenia, and leucopenia (x). TPMT is an enzyme that converts azathioprine into its inactive metabolites Patients with high levels (~ 10%) are at risk of under-treatment using standard doses. Other side effects of this drug include abnormal liver function tests, nausea, hypersensitivity reactions and increased susceptibility to infection.

The dose should be titrated upwards according to clinical response and side-effects, and doses up to 3.5-4 mg kg-1 may be required. Monitoring includes a CBC and platelet count every 1-2 weeks with changes in dosage, and every 1-3 months thereafter

Mycophenolate mofetil

Mycophenolate mofetil is safe and effective for adjuvant treatment for pemphigus. MFM is an ethylester of mycophenolic acid which is metabolized to the active drug mycophenolic acid (MPA). MPA is a product of several Penicillium species. This immunomodulatory drug selectively inhibits inosine monophosphate dehydrogenase (IMPDH) in the denovo pathway of purine synthesis (cc).

Total daily doses of 2–3.5 g (depending on body weight) are typically given in two divided doses with glucocorticoids (i). It is believed to have a glucocorticoid-sparing effect. At usual doses, MMF is generally well tolerated. Compared to other immunosuppressants, such as methotrexate, azathioprine and cyclosporine, the relative lack of hepatonephrotoxicity with MMF offers an important therapeutic advantage.

The most common side-effects are gastrointestinal (i.e., nausea, diarrhea, abdominal cramps, constipation, vomiting and anorexia) and genitourinary (i.e., urgency, frequency, dysuria, hematuria and, occasionally, sterile pyuria). These occur in up to 36% and 40% of patients, respectively (dd). Also lymphopenia, anemia, thrombocytopenia, and increased risk of opportunistic infections.

Remission rates of about 70% in patients with pemphigus vulgaris and 45% in patients with pemphigus foliaceus, with a median time to achieve complete remission of nine months (range, 1-13 months) demonstrated at higher doses of about 35-45 mg/kg/day have been reported (ee).

Methotrexate:

Like most other therapies, there have been no controlled trials of Methotrexate in Pemphigus (e). Case series suggest 10-25mg/week usually in combination with prednisone may be helpful. Methotrexate may have a glucocorticoid-sparing effect. Recent studies have shown low-dose methotrexate (up to 15 mg weekly), as monotherapy or adjunctive therapy, to be efficacious in bullous pemphigoid (x) which should only be used if other more established therapies are exhausted. Side effects include hepatic fibrosis, cirrhosis, pulmonary infiltrates or fibrosis, nausea/vomiting, and lymph node swelling. Screening for hepatitis prior to initiation of therapy is recommended. Monitoring includes CBC, platelet count, AST, albumin, creatinine every 4-8 weeks (eee).

Cyclophosphamide:

Oral cyclophosphamide can be considered an alternative to azathioprine.

It is believed to have a glucocorticoid-sparing effect, and some cases of prolonged remission have been documented (i). The dose used is 1-3mg/kg/day.

Cyclophosphamide is a potent cytotoxic agent which can cause severe cytopenia and hemorrhagic cystitis (bladder inflammation). Because of these potential toxicities, the drug should be reserved for patients who don’t respond to other immunosuppressives.

Other side effects include neutropenia, alopecia, GI disturbances, raised transaminases, thrombocytopenia, and secondary infertility (i).

Recommended monitoring includes a CBC and platelet count every 1-2 weeks with changes in dosage, and every 1-3 months thereafter, with urinalysis and urine cytology every 6-12 months after cessation (eee).

Chlorambucil

Chlorambucil is an alkylating agent of the nitrogen mustard group of chemotherapeutics which works by binding DNA strands and preventing its replication.

Chlorambucil orally at 4 mg day and titrated upwards according to clinical response could be considered as an adjuvant drug if more established options cannot be used, but there are limited data to support its use (i). Side effects include myelosuppression and monitoring includes CBC and platelet count every 1-2 weeks with changes in dosage, and every 1-3 months thereafter (eee).

IVIG

IVIG treatment is still experimental, although it seems to be effective for the initial suppression of the condition in some patients. The actual degree and length of effectiveness and the optimum dosages and intervals are still being determined. There has been increasing use and interest in early use of IVIG, which has been reported in some patients to rapidly control active PV. IVIG selectively and rapidly decreases circulating pathogenic autoantibodies in PV when combined with other treatments, such as prednisone, and immunosuppressives (jj,ll), although more evaluation of such combinations is necessary). Adequate and frequent medical supervision of treatment is necessary (kk).

IVIg is given through an IV line, each cycle lasting up to 5 days, at a dose of 1 to 2 g/kg per cycle. Several cycles are usually required. Cost and availability of this agent limits its use.

Repeat courses can be considered as an adjuvant, maintenance agent in recalcitrant disease, where more conventional therapies have failed or cannot be used.

For autoimmune bullous disease the recommended guidelines for IVIg are as follows:

1) failure of conventional therapy; 2) significant adverse effects from conventional therapy; 3) contraindications, relative or absolute, to the use of high-dose long-term systemic therapy; 4) progressive disease despite conventional therapy; 5) uncontrolled, rapid debilitating disease (mm).

Plasmapheresis: is recommended for disease suppression in severe recalcitrant disease. Plasmapheresis is extracorporeal treatment which acts rapidly on disease activity by lowering the load of the causative auto-antibodies in the patient’s circulation. IVIG seems to work similarly but is safer. It should be used only in conjunction with other immunosuppression, since there can otherwise be rebound of autoantibody production. A variant therapy, immunoadsorption (IA) has been tried effectively in a case study as adjuvant therapy in pemphigus (nn).

Other Drugs

THE FOLLOWING DRUGS HAVE WEAKER EVIDENCE AND THEREFORE ARE NOT RECOMMENDED AS STANDARD THERAPYAT THIS TIME

Cyclosporine:

5mg/kg/day. This is one of the few drugs that has been studied in randomized trials, in which it did not show effectiveness, and is therefore not recommended as an adjuvant therapy on the basis of increased morbidity and mortality rates. The use of cyclosporine is limited by its toxicity, especially hypertension and dose-related loss of renal function. The loss of renal function with cyclosporine appears to be largely, but not entirely, reversible with discontinuation of the drug. Many medications may increase cyclosporine levels and thus increase the risk of nephrotoxicity. Therefore, cyclosporine treatment is primarily confined to patients with refractory disease (oo)

Anti-inflammatory agents

Anti-inflammatory agents such as dapsone, tetracyclines, and gold are used as they also may have a steroid sparing effect in mild to moderate disease (e), often in patients who are in maintenance phase but corticosteroid-dependent. Dapsone is a first-line treatment in dermatitis herpetiformis, linear IgA disease, and milder cases of pemphigus foliaceus:

Dapsone

Dapsone must be started after glucose-6-P-dehydrogenase screening and is administered as 7.5mg/kg/day, up to 200mg/day.

Gold:

Gold may also have a steroid sparing effect. It is not commonly used because of side effects (proteinuria, nephritic syndrome, dermatitis, urticaria etc. (e). It is administered as 50 mg IM injections of gold thiomalate or as the oral form auronafin.

Tetracycline antibiotics:

Tetracycline, doxycycline and minocycline have been used by some in glucocorticoid-dependent patients in the maintenance phase of therapy, often with niacinamide (nicotinamide). It is administered as tetracycline 2g/day and niacinamide 1.5g/day (in divided doses, or minocycline 100mg twice daily) and niacinamide 1.5g/day (in divided doses.

Cholinergic agonists:

These can affect desmosomal adhesion, and acetylcholine seems involved in the acantholysis of pemphigus (e). It may be beneficial for some patients, but there are no completed trials to date. Examples are pyridostigmine bromide and pilocarpine.

Desmoglein 3 Peptides: A phase I clinical trial was completed.

Biologic agents:

A variety of biological agents are being introduced in the management of pemphigus. The one with the most evidence suggestive of effectiveness is rituximab, as others have been used in too few patients to determine effectiveness (ff).

Rituximab

Rituximab, an anti-CD20 chimeric monoclonal antibody, is approved for use in non-Hodgkin lymphoma. It reduces circulating B cells and prevents their maturation into antibody-secreting plasma cells (o). 그러나, there is a case report of partial remission from recalcitrant, life-threatening pemphigus vulgaris after treatment with rituximab (anti-CD20 antibody) and IVIG (gg). In another recent study (hh) the efficacy of rituximab for severe pemphigus was demonstrated when it achieved 86% complete remission 3 months after receiving four weekly infusions.

Administered as 375mg/m2, infusions over 4 wks. Some patients treated with this regimen contracted severe infections, one of which was fatal (o). In summary, a single cycle of rituximab has shown to be effective in pemphigus. Because of its potential severe side effects, its use should be limited to the most refractory disease. (hh)

The following drugs have been used in few patients and studied infrequently at this time:

Infliximab

Infliximab a chimeric IgG1 monoclonal anti-TNFa antibody (ii). It is usually administered at a dose 5 mg/kg, frequently in combination usually with MTX).

This drug’s safety and efficacy in PV patients have not been established.

With infliximab (and etanercept – see later), caution should be exercised when considering the initiation of TNF inhibition in patients with an increased risk of infection (IDDM, CHF, renal insufficiency, debility, etc.) and should be avoided in those with active serious infections (e.g., sepsis, tuberculosis) or chronic and recurrent infections.

Patients starting infliximab (or any other TNF inhibitor) should have a PPD test and/or chest x-ray to check for underlying tuberculosis (TB). If there is underlying or inactive TB, anti-TB treatment should be added before starting infliximab.

Compared with etanercept, there is a higher risk of side effects with rituximab, including anaphylaxis, reactivation of tuberculosis, and the production of neutralizing autoantibodies.

Etanercept

Etanercept is a TNF-a inhibitor administered as 50 mg subcutaneous injection weekly. It is a chimeric fusion protein. It has not been approved for use in Pemphigus or Pemphigoid.

There are a number of side effects, including the development of autoantibodies in approximately 3% of patients, injection site reactions, and a concern about infections and autoimmune demyelination.

Adalimumab

Adalimumab is another TNF-a inhibitor, and a fully human monoclonal antibody that has shown beneficial effect in Pemphigus in some limited case studies. It is administered as 40 mg biweekly. Also reported is concomitant use with mycophenolate mofetil (e).

Topical therapy

PV is largely managed with systemic therapy but adjuvant topical therapy may be of additional benefit, although there are no controlled studies to confirm this.

  • Skin: Topical high potency steroid therapy may help reduce the requirement for systemic agents.
  • Intralesional injections have demonstrated efficacy.
  • There have been anecdotal reports concerning the treatment of pemphigus with topical tacrolimus as an adjunct. (e.g. 0.1% tacrolimus ointment twice daily for 3 to 4 weeks while continuing systemic immunosuppressive therapy, or 0.03% topical tacrolimus (applied twice daily) to the systemic regimen for ocular lesions) (pp).
  • Oral: For multiple oral erosions, ‘corticosteroid mouthwashes are practical, for example, soluble betamethasone sodium phosphate 0.5 mg tablet dissolved in 10 mL water may be used up to four times daily, holding the solution in the mouth for about 5 min. Isolated oral erosions could be treated with application of triamcinolone acetonide 0.1% in adhesive paste or clobetasol 0.05% gel. Topical cyclosporine (100 mg/ m1) in oral pemphigus has been described and may be of some benefit but is expensive (qq).
  • Intralesional therapy with an injectable corticosteroid may be useful for the management of discrete lesions.

Pemphigoid

There are similarities in the management of BP and Pemphigus Vulgaris in that systemic steroids are the mainstay of therapy. In patients with extensive disease, other immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and rarely cyclophosphamide, can be added as steroid-sparing agents. Unlike pemphigus however (rr),

  • Bullous Pemphigoid normally, but not invariably, responds to lower doses of systemic corticosteroids (alone or combined with other oral or topical agents), with most patients improving on prednisone at a dosage of 80 mg/day or less;
  • Topical corticosteroids (high potency) are commonly used for management of lesions.
  • In an open prospective study of 18 cases, low-dose methotrexate was shown to be effective for maintenance of clinical remission induced by initial short-term use of potent topical steroids;
  • Considering that the prognosis of untreated BP is better than that of pemphigus, side effects of treatment are of greater concern.
  • Two small studies of severe ocular mucous membrane pemphigoid suggest that this condition responds more favorably to treatment with cyclophosphamide combined with prednisone, whereas dapsone suppresses some cases of mild to moderate disease

General guidelines for therapy

Pemphigoid is a condition of the elderly who are more likely to be in poor health, much more susceptible to side effects, and may be taking multiple medications.

  • Avoid aggressive non-validated treatments
  • Objectives of treatment
    • control of itch and skin lesions
    • avoid serious side effects (mortality)
    • cost-effectiveness

Therapy algorithm (l)

  • For Localized BP: use potent topical steroids (validated). As elderly people have low tolerance for standard regimens of oral corticosteroids, a 2002 study (l) showed topical corticosteroid therapy is effective for both moderate and severe bullous pemphigoid (this would not be localized, so it is confusing to put this here) and is superior to oral corticosteroid therapy for extensive disease.
  • For Extensive BP:
    • potent topical steroids (validated)
    • higher doses of oral steroids (validated) e.g. 0.75 mg/kg prednisone
    • combined treatments (not validated)
    • topical/oral steroids plus systemic treatments e.g.
      • immunosuppresants : MTX, azathioprine, mycophenolate mofetil, cyclophosphamide, chlorambucil
      • other: tetracycline and nicotinamide
    • Routine use of immunosuppressive drugs has shown
      • no additional benefit (no improvement in disease control, no reduction in doses of steroids)
      • more severe complications
  • IVIG: potentially useful in reducing the doses of steroids used, but poor data

Pemphigoid Gestationis

The goals of treatment are to relieve pruritus and to suppress extensive blister formation, and to minimize the risk for the mother and fetus. The lowest effective dose of medication is used. Non-medical therapy includes tepid baths, compresses, and emollients. Topical therapies include antihistamines and topical or intralesional steroids, such as triamcinolone. In moderate to severe cases, systemic steroids remain the mainstay of therapy (typically prednisone 0.5 mg/kg/d). Limited experience with adjuvant or other immunosuppressive therapy exists (h).