Corticosteroids, while providing rapid remission and ongoing control of symptoms of autoimmune blistering diseases (AIBD), have numerous potentially serious acute and long-term side effects. Evidence-based medicine has reevaluated the various types of corticosteroids and forms of corticosteroid delivery in AIBD to ascertain whether any advantages of specific delivery systems or regimens exist. Careful monitoring of patients and simple preventive measures are effective in minimizing the adverse outcomes associated with their use. This article outlines the current level of evidence for corticosteroid use in AIBDs, and discusses appropriate investigations and interventions to minimize or prevent the associated adverse effects.
Corticosteroids have been used in the management of autoimmune blistering diseases (AIBD) for more than 50 years, and are an essential component in the pharmacologic management of these conditions. While providing rapid remission and ongoing control of the symptoms of AIBD, they come with a variety of potentially serious acute and long-term side effects. The advent of immunomodulating and immunosuppressive therapies has complemented the use of corticosteroids but have not usurped its pivotal role. The advent of evidence-based medicine (EBM) has reevaluated the various types of corticosteroids and forms of corticosteroid delivery in AIBD to ascertain whether any advantages of specific delivery systems or regimens exist. With rare diseases such as those that comprise AIBD, large randomized controlled trials are difficult to coordinate and accomplish, meaning a paucity of high-level evidence exists as to the best methods of corticosteroid use in these conditions. Experience and evidence from cross-discipline use of corticosteroids shows that careful monitoring of patients and simple preventive measures are effective in minimizing the adverse outcomes associated with their use. This article attempts to outline the current level of evidence for corticosteroid use in a variety of AIBDs, and discusses appropriate investigations and interventions to minimize or prevent the associated adverse effects.
Pharmacology of corticosteroids
Corticosteroids are based around the cyclopentano-penanthrane nucleus, a conjoined series of three 6-carbon rings and one 5-carbon ring, a base structure shared by cholesterol and sex hormones. All corticosteroids exhibit a double bond between carbon atoms 4 and 5, as well as two ketone groups, attached to carbon atoms 3 and 20, which distinguish them from other cholesterol-based compounds. Different corticosteroids differ by their differing functional groups attached to the core ring structure as well as the oxidation state of the carbon atoms comprising the rings. General additions that increase corticosteroid potency include the insertion of a double bond between carbon atoms 1 and 2 (as in prednisone); the fluorination of carbon atoms 6 or 9 (as in clobetasol or dexamethasone); and the addition of a hydroxyl group at carbon atom 11 (as in clobetasol).
Corticosteroids act through binding to glucocorticoid-specific receptors and altering transcription factors as well as diffusing through the cell membrane and acting directly on the cell nucleus. Inflammatory inhibition is mainly achieved through the interaction with and inhibition of nuclear factor κB transcription factor, suppressing the production of chemokines and cytokines. Suppressed mediators include cyclooxygenases (COX), interleukins (IL) 1 through 6, tumor necrosis factor (TNF)-α, and macrophage colony stimulating factor. Although all of the exact mechanisms controlling the plethora of side effects of corticosteroids have not yet been elucidated, it is believed the majority of them are controlled through cyclic adenosine monophosphate–mediated pathways. The end result is cytokine suppression, eosinopenia, lymphopenia, and monocytopenia. Neutrophilia is also observed. However, this is thought to be indirectly attributable to the decreased ability of neutrophils to migrate to the sites of inflammation due to cytokine suppression; neutrophil apoptosis is delayed as a result, contributing further to neutrophilia.
Regarding the pharmacokinetics of corticosteroids, when prednisone is consumed orally it must be reduced enzymatically in the liver to prednisolone (the active product); this is done through reduction of a ketone group by the enzyme 11β-hydroxysteroidiesterase. Consequently, patients with hepatic dysfunction may have impaired conversion of prednisone to active prednisolone. In these circumstances, administration of prednisolone would be more beneficial than prednisone in achieving the desired serum concentrations necessary for treatment. In patients with otherwise normal hepatic function, prednisone and prednisolone are drugs of equivalency. A table of steroid equivalencies for those drugs used in AIBDs is presented in Table 1 . With regard to conversion rates, serum concentrations for systemic steroids are roughly consistent. Measurements of equivalency for topical steroids have a much wider range than systemic steroids because, dependent on the site of measurement in the skin of the active ingredient, concentrations differ. The measurements presented in Table 1 are taken from studies wherein concentrations were measured in the dermis or at the dermoepidermal junction—the site of activity of disease and immune suppression. Consequently, concentrations in the epidermis would be much higher for topical steroids.
| Steroid Used | Converting To: | ||||||
|---|---|---|---|---|---|---|---|
| Prednisone/Prednisolone a | Oral Dexamethasone | Intravenous Dexamethasone | Intravenous Hydrocortisone | Topical Betamethasone Valerate (0.1%) b | Topical Clobetasol Propionate (0.05%) b | ||
| Converting from: | Prednisone/prednisolone a | Multiply by 1 mg/kg/d | Multiply by 0.12 mg/kg/d | Multiply by 0.196 mg/kg/d | Multiply by 16 mg/kg/d | Multiply by 0.48 mg/kg/d | Multiply by 360 mg/kg/d |
| Oral dexamethasone | Divide by 0.12 mg/kg/d | Multiply by 1 mg/kg/d | Multiply by 0.61 mg/kg/d | Multiply by 133 mg/kg/d | |||
| Intravenous dexamethasone | Divide by 0.196 mg/kg/d | Divide by 0.61 mg/kg/d | Multiply by 1 mg/kg/d | ||||
| Intravenous hydrocortisone | Divide by 16 mg/kg/d | Divide by 133.3 mg/kg/d | Multiply by 1 mg/kg/d | ||||
| Topical betamethasone valerate (0.1%) b | Divide by 0.48 mg/kg/d | Multiply by 1 mg/kg/d | |||||
| Topical clobetasol propionate (0.05%) b | Divide by 360 mg/kg/d | Multiply by 1 mg/kg/d | |||||
a Prednisone and prednisolone are assumed to be equivalent.
Responsiveness of AIBD to corticosteroids
Pemphigus Vulgaris/Pemphigus Foliaceus
Steroids have been used as the cornerstone of pemphigus management for more than 50 years. The different types of corticosteroids used in pemphigus include oral prednisone/prednisolone as a continuous dosage for remission or maintenance therapy, and dexamethasone as used in oral pulsed dosage for remission and topical application for local or mucosal disease. Table 2 presents the current recommendations and levels of evidence available for corticosteroid use in AIBD. A recent systematic review and meta-analysis examined a randomized controlled trial (RCT) of 22 participants comparing low-dose (45–60 mg/d) with high-dose (120–180 mg/d) oral prednisolone in a cohort of newly diagnosed pemphigus vulgaris (PV) and pemphigus foliaceus (PF) patients. Although the low number of participants made the study underpowered, no significant difference in the time to disease control was demonstrated. All patients achieved remission in a time ranging from 5 to 42 days for the high-dose steroids and 7 to 42 days for the low-dose steroids. Rates of remission as recorded over a 5-year period were also not statistically significant ( P = .30).
| Type of Corticosteroid | Recommendations and Level of Evidence | ||||
|---|---|---|---|---|---|
| Pemphigus | Bullous Pemphigoid | Mucous Membrane Pemphigoid | Linear IgA Dermatoses | Epidermolysis Bullosa Acquisita | |
| Prednisone/prednisolone (oral) | A (2–3) Basic pillar of therapy. Optimal regimen (high dose vs low dose) unknown with current evidence | C (1) Can be used if topical unfeasible (evidence of deleterious effect compared with topicals in severe disease) | C (3) | I (3) | C (3) Associated with increased mortality and adverse effects |
| Dexamethasone (intravenous pulsed) | C (2–2) No evidence supporting its use over oral corticosteroids. Experts recommend use in recalcitrant disease | N/A | N/A | N/A | C (3) Use in intractable or severe disease |
| Dexamethasone (Mouthwash) | N/A | N/A | B (3) | N/A | N/A |
| Clobetasol propionate (0.05%) | C (3) Localized or mild disease | A (1) Recommended for severe disease over systemic corticosteroids based on 12-mo mortality rates | C (3) | I (3) | N/A |
| Betamethasone (topical) | C (3) | N/A | I (3) | I (3) | N/A |
| Key to Recommendations and Level of Evidence |
|---|
|
Regarding pulsed corticosteroid use, an RCT of 22 participants compared the efficacy of adjuvant pulsed oral dexamethasone (300 mg/d for 3 consecutive days, monthly) versus placebo in newly diagnosed patients concurrently treated with prednisolone and azathioprine. Although the small number of patients in the cohort contributed to the poor power of the study, no significant differences in the rates of remission or relapse were identified. Of importance, the rates of adverse outcomes or side effects were significantly higher among the pulsed-corticosteroid cohort when compared with the continuous-dosage cohort ( P <.01). It must be noted, however, that the patients enrolled in this particular study did not have severe or refractory disease, and that pulsed corticosteroids may have a useful role in those particular subgroups of patients. At present no double-blinded placebo-controlled RCTs are available that evaluate pulsed corticosteroids in severe or refractory pemphigus, so the evidence supporting this stems from expert recommendation. As the power of the study by Mentink and colleagues was low, there is no evidence supporting the use of one intervention (dexamethasone or the control regimen) over the other. The study also commented that pulsed dexamethasone was associated with higher rates of corticosteroid-associated adverse effects. These findings again highlight the importance of a dynamic corticosteroid regimen individualized for each patient depending on their individual disease severity, treatment response, and degree of adverse effects from therapy.
Topical corticosteroid use in PV and PF has been documented in several case reports, and expert recommendations state that it may be useful in localized or mild disease. No controlled trials exist to formally evaluate its efficacy, but strong corticosteroids such as betamethasone or clobetasol are typically used. For mucosal lesions, topical clobetasol propionate is typically used in mild disease, although mostly as an adjunct to systemic treatment.
Bullous Pemphigoid
Corticosteroids, both oral and topical, are used widely in the management of bullous pemphigoid (BP), with topical preparations of high-potency steroids (such as clobetasol propionate) being used for mild to moderate disease and systemic corticosteroids used for more severe disease. As BP is a disease of the elderly, mortality of those diagnosed with BP is relatively high, and despite the introduction of corticosteroids and other immunosuppressive and immunomodulating agents has not improved since the 1950s. Debate is ongoing as to whether this is indicative of the underlying comorbidities inherent in the patient population and if the role of treatment actually improves mortality rates. Recent research by Parker and MacKelfresh indicates that as the natural history of the disease is usually self limiting and the majority of patients succumb to causes unrelated to their BP, adverse effects primarily from systemic corticosteroids may actually increase the risk of mortality.
A recent Cochrane systematic review and meta-analysis examined an RCT of 26 participants comparing high-dose (1.25 mg/kg) and low-dose (0.75 mg/kg) oral prednisolone in patients with newly diagnosed BP. Fifty-one percent of patients in the low-dose cohort patients achieved remission by day 21 compared with 64% of high-dose cohort patients. Power was limited by the small sample size of the study, and no significant difference between time to remission or overall mortality was revealed. A second study comparing oral prednisolone with methylprednisolone comprised 57 participants, monitored for 10 days. No significant difference in rates of remission or decrease in the number of bullous lesions was seen between the two treatment groups. Self-reported pruritus scores were found to be significantly more improved in the methylprednisolone cohort than in the prednisolone cohort. Examination of the methodology of the study shows that randomization and blinding were adequate, although the degree of allocation concealment is questionable, thus querying the reliability of this result.
The 2002 RCT by Joly and colleagues comparing topical clobetasol propionate (0.05%) with oral prednisone demonstrated a significant advantage of topical clobetasol propionate (0.05%, 40 g/d) over oral prednisone (1 mg/kg/d) in individuals with severe BP (defined as more than 10 new blisters per day) in regard of overall mortality within 1 year of initiation of treatment. The significance of this finding increased when multiple regression analysis took into account age and functional status. Of importance, this study also had adequate power to detect a decrease in the 1-year mortality rate in both severe and moderate disease groups. This result lends credence to the suggestion that in severe BP, systemic corticosteroids may have a deleterious effect on mortality rates when compared with topical high-potency corticosteroids. A follow-on study with 309 participants found that lower doses of clobetasol propionate (0.05%, 10–30 g/d) had noninferior mortality rates than the standard regimen of 40 g/d in both severe and moderate disease. When adjusted for age and functional status, the investigators concluded that the lower doses were more beneficial to patients with both moderate and severe disease, with lower rates of mortality or life-threatening adverse effects (including sepsis and diabetes mellitus) than the original 2002 study. Although the evidence may suggest that twice-daily topical corticosteroids more beneficial than oral dosing, the practicalities of application by elderly patients with multiple comorbidities is a significant barrier to the implementation of these recommendations.
Mucous Membrane Pemphigoid
Therapies for AIBD that involve mucous membranes are targeted at topical applications as well as the consideration of systemic corticosteroids in severe disease.
There is a paucity of evidence from RCTs regarding treatments for mucous membrane pemphigoid (MMP), cicatricial pemphigoid (CP), and other subtypes of AIBD that contain mucous membrane involvement. Expert recommendations cite topical therapies such as clobetasol propionate, betamethasone valerate, and dexamethasone mouthwashes. A Cochrane review confirmed that the only RCT evidence related to MMP regarded the treatment of ocular involvement with dapsone or cyclophosphamide, dependent on disease severity. There were no RCTs of steroid use in either MMP or epidermolysis bullosa acquisita (EBA). Furthermore, to date no reliable evidence sources (such as RCTs) have been found to further elucidate the efficacy of these topical treatments in these conditions.
Linear IgA Disease
Steroid use in linear IgA disease can be separated into topical and systemic regimens. While potent topical steroids such as clobetasol propionate 0.05% has been recommended for mild disease, it can also have a role in symptom control while the offending stimulant is removed in drug-induced disease. No RCTs have been identified to date regarding the efficacy of corticosteroids in linear IgA disease, and expert recommendation quotes dapsone as a first-line agent, with other immunosuppressive and immunomodulating agents such as mycophenolate mofetil (MMF) also having reports of successful treatment. In this regard, systemic corticosteroids are only considered a useful adjunctive treatment in the setting of other therapies, and to this end evidence of its usefulness is lacking.
Epidermolysis Bullosa Acquisita
EBA is a recalcitrant AIBD in which treatment is known to be difficult. A recent Cochrane review found no RCTs of treatment modalities in EBA, although a handful of nonrandomized studies were found involving a wide variety of immunosuppressive and immunomodulating therapies. Due to the adverse outcomes of the high-dose steroids needed to successfully control EBA, other management strategies such as intravenous immunoglobulins (IVIG) and anti-CD20 monoclonal antibodies (rituximab) have come to the fore as the mainstay of treatment in EBA. While prednisone/prednisolone, 0.5 to 1.0 mg/kg/d is still included in the initial treatment regimen for EBA, recalcitrant or severe disease management concentrates on other immunomodulating therapies such as cyclosporine, plasmapheresis, and colchicine for maintenance therapy. Ishii and colleagues state that pulsed corticosteroids may also be useful in severe disease, although these recommendations have not been borne out in randomized trials. Again, the rarity of the conditions comprising AIBD makes such evidence difficult to compile.
Pemphigoid Gestationis
Although there are no RCTs available assessing the effect of corticosteroids in this condition, as prednisone is relatively safe during the later stages of pregnancy and during breastfeeding as compared with many other systemic immunosuppressants, oral corticosteroids such as prednisone tend to be used.
Related posts:
Autoimmune Blistering Diseases Part II—Diagnosis and Management
Minimizing Complications in Autoimmune Blistering Diseases
Pemphigoid Gestationis: Current Management
Management of Linear IgA Disease
Management of Autoimmune Bullous Diseases in France: A Nationwide Network of 30 Centers
Treatment of Chronic Bullous Disease of Childhood
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