A number of studies in different therapeutic areas have assessed the clinical efficacy of RCI before and after treatment or compared RCI with placebo or other common therapies. These are described below and summarized in Table 1.
IS, also known as West syndrome, refers to a unique epilepsy syndrome of early infancy (<2 years of age) in which patients present with a distinct seizure type [5,6,7]. Untreated IS is associated with developmental delay, autism, mental retardation, and an 11% mortality rate by age 2 years [5,6,7,8]. In a study of 244 infants aged 0–18 months, a delay in time to diagnosis following initial presentation was associated with cognitive abnormalities (median time to diagnosis, 18 vs. 6 days; p < 0.001) and motor abnormalities (median time to diagnosis, 17.5 vs. 6 days; p < 0.001) . Outcomes may therefore be improved by early recognition of IS and immediate, effective treatment [6, 8, 10].
Compared with prednisone and conventional antiepileptic drugs, RCI may be more efficacious for the treatment of IS. RCI has orphan drug designation in the USA for treatment of IS . In a US randomized controlled trial of 29 infants (median age, 6 months), 86.6% of infants treated with RCI (150 U/m2/day) and 28.6% of infants treated with prednisone (2 mg/kg/day) (p = 0.002) had cessation of spasms and resolution of hypsarrhythmia after 2 weeks of therapy . The most frequently reported adverse events in RCI-treated infants were irritability and voracious appetite.
More recently, a US study of 230 infants at 22 centers participating in the National Infantile Spasms Consortium reported that 55% of infants receiving RCI as initial treatment responded to therapy, compared with 39% for oral corticosteroids, 36% for vigabatrin, and 9% for other therapies (p < 0.001) .
The 2004 IS guideline of the American Academy of Neurology and Child Neurology Society recommends ACTH for short-term control of IS, supported by strong (level B) evidence . Although the guideline refers to ACTH, RCI is the only form of ACTH approved for use in the USA, as noted previously. Based on three studies of RCI [14,15,16] and one study of synthetic ACTH [14,15,16], the 2012 guideline update recommends that low-dose ACTH be considered as an alternative to high-dose ACTH for treatment of IS (level B evidence) .
Multiple Sclerosis Relapses
MS is a complex and chronic demyelinating autoimmune neurological disorder. It is most frequently diagnosed between 20 and 40 years of age and is a leading cause of disability in this age group . Acute relapses in MS may present with severe symptoms. To decrease inflammation and hasten recovery, a short course of corticosteroids (high-dose intravenous [IV] or oral) is often prescribed. However, if a patient does not respond or presents with breakthrough disease, ACTH, IV immunoglobulin (IVIG), or plasma exchange (plasmapheresis; PMP) may be required . In the USA, RCI was first approved for treatment of MS exacerbations in 1978 and is currently indicated for treatment of acute exacerbations of MS in adults [1, 19]. Intravenous immunoglobulin and PMP are not FDA-approved therapies for relapses in MS.
The efficacy of RCI compared with placebo or other common therapies for the treatment of MS relapses has been evaluated. A large randomized, controlled, double-blind, multicenter trial found that RCI was superior to placebo for reducing the duration of relapse . In a small study comparing routes of administration, intramuscular and subcutaneous administration of a 5-day course of RCI produced a comparable decrease in symptoms .
Both the National Multiple Sclerosis Society and the American Academy of Neurology have noted that alternative treatment options are needed for patients who experience MS relapse but do not respond to, cannot tolerate, or do not wish to take steroids [22, 23]. Thus, for patients needing an alternative treatment, RCI may provide an option.
Proteinuria in Nephrotic Syndrome
Nephrotic syndrome is a constellation of renal and extrarenal signs and symptoms that includes edema, proteinuria, hypoalbuminemia, lipiduria, hyperlipidemia, and hypercoagulability. It is caused by several systemic diseases and by primary insult to the kidney. Primary renal causes of nephrotic syndrome include minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, immunoglobulin A (IgA) nephropathy, and membranoproliferative glomerulonephritis, and nephrotic syndrome may occur secondary to systemic diseases such as diabetes and systemic amyloidosis [24,25,26]. In patients with resistant glomerular disease, RCI is a treatment option, along with conventional therapy. It is indicated for inducing diuresis or remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type and in nephrotic syndrome due to lupus erythematosus .
Several studies have shown that RCI reduces proteinuria in several subtypes of treatment-resistant nephrotic syndrome: idiopathic membranous nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranoproliferative glomerulonephritis, lupus nephritis, and IgA nephropathy [27,28,29,30,31].
RA is an autoimmune disease that leads to progressive destruction of the joints and associated cartilage . It is associated with several comorbidities, including cardiovascular and pulmonary manifestations, skeletal disorders, cognitive effects, infection, and malignancies .
RCI is an FDA-approved adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) and for use in “selected cases who may require low-dose maintenance therapy” . It has been shown to be effective in combination with methotrexate in terms of clinical response, inducing remission and slowing structural changes, with few serious adverse events observed [34, 35]. In an open-label study, 10 patients with early RA and at least six tender and swollen joints were treated with methotrexate plus RCI either weekly (n = 5) or biweekly (n = 5) . An improved Clinical Disease Activity Index (CDAI) score was observed in eight patients. In the five patients who received RCI biweekly, both clinical and structural improvements were seen. A second open-label study of RA patients with an inadequate response to two or more biologic agents with different modes of action (N = 6) found that treatment with RCI for 12 weeks led to reductions in tender and swollen joint counts and improvements in Disease Activity Score for RA (DAS28), Patient Global Visual Analogue Scale (VAS), and Physician Global VAS in all patients .
Dermatomyositis and Polymyositis
DM and PM are autoimmune connective tissue diseases that are characterized by chronic inflammation of proximal skeletal muscles. DM also affects the skin and may affect the joints, esophagus, heart, and lungs. Patients with DM or PM typically present with slowly progressive weakness and reduced endurance in the muscles of the neck, shoulders, and pelvis [36,37,38].
Patients with DM or PM may experience clinical benefit from RCI therapy. In a case series study, five patients experiencing a disease exacerbation who had either failed or experienced adverse effects with conventional treatment were treated with RCI once or twice weekly for 12 weeks . All patients showed improvement in manual muscle testing scores at 12 weeks, and no patients experienced significant adverse events. In an open-label uncontrolled study of RCI (80 U twice weekly for 6 months), 10 of 11 patients (91%) experienced improvement in myositis as defined by the International Myositis Assessment and Clinical Studies Group (IMACS) . In addition, RCI was found to be generally safe, well tolerated, and steroid sparing.
Other than corticosteroids, RCI is the only FDA-approved drug for the treatment of DM/PM. It is indicated for use during an exacerbation or as maintenance therapy in selected cases .
Systemic Lupus Erythematosus
SLE is a systemic illness characterized by immune hyperactivity and the production of antinuclear, anticytoplasmic, and antiphospholipid antibodies. Patients typically present with fatigue, malaise, fever, arthralgia, myalgia, headache, loss of appetite, weight loss, and rash. The disease may progress to multiple end-organ involvement, resulting in photosensitivity, arthritis, and serositis as well as renal, neurological, and other disorders [41,42,43]. During the course of the disease, intermittent acute relapses or flares may result in tissue damage. RCI is indicated during an exacerbation or as maintenance therapy in selected cases of SLE .
In a single-arm, uncontrolled, open-label study of 10 female patients with moderate-to-severe SLE who were receiving conventional therapy and experiencing a disease flare, adjunctive RCI treatment for 10 days, with an optional five additional days, led to reduction in disease activity and to improvement in functional status, quality of life, and erythrocyte sedimentation rate at 28 days . No treatment-related serious or unexpected adverse events were observed. In an 8-week randomized controlled trial of RCI for the treatment of persistently active SLE, 38 participants received RCI 80 U every other day (n = 13), RCI 40 U daily (n = 13), or placebo (n = 12) . Disease activity was reduced in the RCI groups compared with placebo, including statistically significant decreases in the Hybrid SLE Disease Activity Index and the British Isles Lupus Assessment Group index in both treatment groups at 8 weeks and in tender swollen joint count in the 80 U RCI group at 8 weeks.
Sarcoidosis is a chronic inflammatory granulomatous disease that primarily affects the lungs (90% of affected patients have pulmonary involvement), although other organs such as the skin and eyes may be involved [46,47,48]. The disease follows a variable natural course, ranging from asymptomatic to a progressive disease that may be life threatening [48, 49]. Patients may be asymptomatic or have signs and symptoms such as cough, fever, weight loss, chest pain, painful ankle swelling, painful red nodules on the shins, eye pain, and blurred vision . Treatment is generally reserved for symptomatic disease. RCI is an FDA-approved treatment for symptomatic sarcoidosis .
RCI was reported to be effective for symptomatic sarcoidosis as early as the 1950s. A case series study of patients receiving RCI (n = 4) or cortisone (n = 1) reported that treatment with RCI led to improvements in lung function and regression of skin, peripheral lymph node, parotid gland, and eye lesions . In a recent retrospective chart review of patients with advanced sarcoidosis, 27 of 29 patients who received RCI (alone or in combination with steroids) for 6 months or longer experienced an improvement in their disease and 11 experienced objective improvement in the health of one or more affected organs. In addition, 17 of 19 patients receiving concomitant prednisone were able to reduce their prednisone dose by more than 50% . Further evaluation of RCI therapy for symptomatic sarcoidosis is warranted, and prospective studies are underway.