What Is Acthar Gel and How Does It Work?

Acthar Gel (repository corticotropin injection) is a pituitary-derived medication with a surprisingly broad set of FDA-approved uses, ranging from infantile seizures to lupus flares to kidney disease. Unlike a typical steroid, it works partly by stimulating your body’s own hormone pathways and partly through direct effects on immune cells, which makes it pharmacologically unusual. It also carries one of the most contentious histories of any drug on the U.S. market, having been approved in 1952 under regulatory standards that look nothing like what the FDA demands today.

What Acthar Gel Actually Is

Acthar Gel is a naturally sourced mixture of adrenocorticotropic hormone (ACTH) analogs and other pituitary peptides, extracted from the whole porcine pituitary gland. It is not a single molecule or a synthetic copy of a hormone. The mixture is dissolved in a gelatin-based formulation designed to release slowly after subcutaneous or intramuscular injection, which gives it a longer duration of action than a single bolus of synthetic ACTH would provide.¹ That slow-release design is where the “repository” in the name comes from: the gelatin acts as a depot, parceling out the active compounds over hours rather than minutes.

Because it comes from an entire gland rather than being synthesized in a lab, Acthar Gel contains a complex and somewhat variable blend of peptides. This matters clinically because the drug’s effects do not track cleanly with what a simple dose of synthetic ACTH does, a distinction that researchers have spent the last decade trying to unpack.

How It Works, and Why It Is Not Just a Steroid

The most intuitive part of Acthar Gel’s mechanism is straightforward: ACTH tells the adrenal glands to produce cortisol and related steroid hormones. That is the classical pathway, and it accounts for some of the drug’s anti-inflammatory punch. But if that were the whole story, doctors could just prescribe prednisone or a synthetic ACTH analog like cosyntropin and call it a day. Research over the past decade suggests the picture is more complicated.

Acthar Gel activates a family of receptors called melanocortin receptors, of which there are five types. The adrenal glands respond mainly through one of these (MC2R), but the other four sit on immune cells, brain tissue, and skin cells. Lab studies have shown that Acthar Gel actually stimulates MC2R less powerfully than the others. Its activity at the MC1R, MC3R, and MC4R receptors was several-fold higher than at MC2R, and its effect on adrenal steroid output was weaker than that of synthetic ACTH.² In plain terms, the drug’s strongest interactions are with the receptors that do not involve cortisol production at all.

Those non-adrenal effects appear to be immunomodulatory. A narrative review of Acthar Gel’s immune effects concluded that the drug reduces B-cell proliferation and antibody production, inhibits T-cell proliferation, and decreases pro-inflammatory signaling from T cells and macrophages.³ Animal research in a mouse model of lupus showed that Acthar treatment significantly reduced specific types of splenic B cells and lowered circulating autoantibodies, including anti-double-stranded DNA antibodies, which are central to lupus pathology.⁴ This dual action, part steroid stimulation and part direct immune modulation, is what distinguishes Acthar Gel from both conventional corticosteroids and simple synthetic ACTH.

Infantile Spasms

The most firmly established use of Acthar Gel is in treating infantile spasms, a severe seizure disorder of early childhood. This is where the clinical evidence is strongest, and it is the one indication where Acthar Gel is widely regarded as a first-line therapy rather than a backup option.

A systematic literature review comparing Acthar Gel (as repository corticotropin injection) to synthetic ACTH analogs found that Acthar Gel had roughly eight times the odds of achieving complete cessation of spasms compared to tetracosactide, a synthetic form of ACTH. It also had about five times the odds of resolving hypsarrhythmia, the chaotic brain-wave pattern associated with infantile spasms. When compared to another corticotropin formulation (CCMC), the advantage was even larger, with roughly 17 times the odds of spasm cessation.⁵ In a clinical study of high-dose once-daily ACTH, about 70% of infants were spasm-free two weeks after starting treatment, and roughly half remained spasm-free at the three-month mark. All responders showed resolution of hypsarrhythmia on their brain-wave recordings.⁶

These numbers matter because infantile spasms are a neurological emergency. Without effective treatment, the seizure pattern causes lasting developmental damage. The speed of response and the rate of complete resolution give Acthar Gel a strong foothold in this particular niche, and most pediatric neurologists consider it a go-to treatment alongside vigabatrin.

Multiple Sclerosis Relapses

Acthar Gel carries an FDA-approved indication for acute exacerbations (relapses) of multiple sclerosis, and it is generally used when a patient has not responded adequately to high-dose intravenous corticosteroids, the standard first-line approach. A randomized, double-blind, placebo-controlled study tested Acthar Gel in exactly this population: MS patients whose relapses had not improved enough with steroids. At day 42, about 61% of patients in the Acthar Gel group showed meaningful improvement on a standard disability scale, compared to roughly 12% in the placebo group.⁷

An observational registry study looking at real-world outcomes reinforced these findings. Patients treated with Acthar Gel for MS relapses showed improvements on both the physical and psychological components of the MS Impact Scale at two and six months, along with a meaningful reduction in disability scores. About 63% of patients showed clinical improvement at two months, and improvements in work productivity and reductions in emergency department visits were also observed over the six-month follow-up.⁸ For MS patients stuck in a relapse that steroids have not resolved, this represents a meaningful alternative.

Nephrotic Syndrome and Kidney Disease

Nephrotic syndrome, a condition in which the kidneys leak large amounts of protein into the urine, is another approved indication. Different underlying kidney diseases cause nephrotic syndrome, and Acthar Gel’s effectiveness varies by type. A systematic review found a promising association between ACTH treatment and reduced proteinuria (protein in the urine), with the strongest evidence in membranous nephropathy and focal segmental glomerulosclerosis.⁹

A multicenter retrospective study broke down the response rates by kidney disease subtype. Patients with minimal change disease and membranous lupus nephritis achieved complete or partial remission universally in this small sample, while about 80% of patients with focal segmental glomerulosclerosis and roughly 73% of those with idiopathic membranous nephropathy achieved at least a clinical response.¹⁰ A separate pilot study in patients with idiopathic membranous nephropathy found that by 12 months, proteinuria had dropped significantly across the cohort, and about 65% of patients achieved at least a 50% decrease. Patients who received higher cumulative doses tended to have better outcomes.¹¹

These results are encouraging, but worth noting that the studies are mostly retrospective and involve relatively small numbers of patients. Nephrologists typically reach for Acthar Gel when standard immunosuppressive therapies have failed or are not tolerated, not as a first option.

Rheumatoid Arthritis, Lupus, and Inflammatory Myopathies

Acthar Gel is FDA-approved for use in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and dermatomyositis/polymyositis (DM/PM). It is approved specifically for SLE flares and as maintenance therapy.¹² In practice, it tends to be used in patients whose disease is not adequately controlled by other treatments.

A physician-reported chart analysis covering patients across all three conditions found high rates of improvement: 93% of RA patients, 89% of SLE patients, and 96% of DM/PM patients showed improved health status after starting Acthar Gel, according to their treating physicians. Beyond global improvement, common treatment goals that were met included reduced symptoms, better physical function, and decreased use of corticosteroids, which is itself a therapeutic win since long-term steroid use carries serious consequences.¹³

A real-world study focusing specifically on RA patients tracked outcomes over 12 months after starting Acthar Gel. Prescriptions for glucocorticoids, NSAIDs, and opioids all decreased, while disease-modifying therapy prescriptions remained stable, suggesting that Acthar Gel was displacing some of the more problematic pain and inflammation medications rather than adding to the pill burden. Disease activity scores dropped by a clinically meaningful amount, and few patients stopped treatment due to side effects.¹⁴ For patients with refractory autoimmune disease already cycling through biologics and immunosuppressants, the ability to reduce steroid and opioid use while maintaining disease control is a practical benefit that goes beyond what the disease-activity numbers alone convey.

Sarcoidosis and Eye Inflammation

Acthar Gel also has approved indications for symptomatic sarcoidosis and for certain types of eye inflammation. A literature review spanning all nine of its approved indications noted evidence of improved lung function and reduced corticosteroid use in symptomatic sarcoidosis, along with real-world effectiveness data in patients with uveitis and severe keratitis.¹⁵

The evidence for eye inflammation, however, is notably mixed. A prospective open-label study in sarcoidosis-related uveitis found that while some patients with moderate to severe disease did respond, a substantial proportion either failed treatment or could not tolerate it. Four of the nine enrolled patients discontinued before completing the 24-week course, primarily due to worsening eye inflammation.¹⁶ A separate small cohort study reached a similarly cautious conclusion: most patients failed to achieve adequate steroid-sparing control of their eye inflammation and experienced side effects while on therapy.¹⁷ These are small studies with limited statistical power, but the pattern across them does not suggest Acthar Gel is reliable for ocular sarcoidosis the way it appears to be for infantile spasms or MS relapses.

Side Effects to Know About

Because Acthar Gel stimulates cortisol production and has broad immune effects, its side effect profile overlaps substantially with what you would expect from corticosteroid therapy. The commonly reported adverse effects include:

Elevated blood pressure: fluid retention and hormonal effects can raise blood pressure, especially with extended use.
High blood sugar: cortisol drives glucose production, so people with diabetes or prediabetes need close monitoring.
Infection risk: suppressing immune function means the body is less able to fight infections.
Weight gain: a familiar consequence of cortisol elevation.
Bone density loss: prolonged exposure to elevated cortisol can weaken bones over time.

These effects were documented across multiple indications.¹⁸ That said, in several of the studies described above, few discontinuations were attributed specifically to side effects, and individual tolerability varies widely. Your doctor will typically monitor blood pressure, blood sugar, and signs of infection during treatment.

The Evidence Gap and Regulatory History

Acthar Gel’s regulatory story is unusual and worth understanding, because it shapes much of the controversy around the drug. It was first approved in 1952, long before the FDA required the kind of rigorous, large-scale randomized controlled trials that modern drugs must pass. A scoping review published in JAMA Internal Medicine characterized the clinical evidence supporting Acthar Gel’s approved indications as “weak,” attributing this partly to the fact that its approval predated modern review standards.¹⁹

This does not mean Acthar Gel is ineffective. It means that for most of its indications, the evidence base consists of small trials, retrospective chart reviews, case series, and observational registries rather than the large, randomized, placebo-controlled trials that a newly approved drug would need. The infantile spasms data and the MS relapse trial described earlier represent the strongest controlled evidence. For the rheumatologic and nephrologic indications, the data are real-world and often retrospective. The practical consequence is that clinicians prescribing Acthar Gel are making judgments based on a patchwork of evidence that would not meet the bar for a new drug approval today, even though the drug itself has decades of clinical use behind it.

This gap fuels a persistent debate. Critics argue that the evidence does not justify the drug’s cost. Supporters counter that newer, more rigorous studies (like the MS relapse trial) have been filling in the gaps, and that real-world outcomes data from thousands of patients provide meaningful signal. Where you land probably depends on how much weight you give to real-world evidence versus randomized trials, and how you feel about the cost question.

What Self-Injection Looks Like

Acthar Gel is given by injection, either subcutaneously or intramuscularly, which means most patients either visit a clinic or learn to inject at home. A common dosing regimen for rheumatologic conditions is 80 units twice per week, though the dose and frequency vary by indication and individual response.

A newer autoinjector device (called SelfJect) has changed the home-injection experience for many patients. In a cross-sectional survey of patients using the device, about 39% reported dexterity or visual problems, yet the average injection took only about three and a half minutes. Satisfaction rates were high: 91% of participants said they were satisfied or very satisfied with the device, 89% felt confident using it, and 87% said they were likely to stay on treatment with this delivery method.²⁰ For patients with chronic autoimmune diseases who may already be fatigued or dealing with joint stiffness, the ease of the injection matters more than it might seem. Difficulty with self-injection is a real barrier to medication adherence, and any device that removes friction can affect long-term outcomes.

How Acthar Gel Compares to Standard Corticosteroids

A question that comes up often, understandably, is why a doctor would prescribe Acthar Gel instead of prednisone or another conventional steroid. The two drug classes share anti-inflammatory effects, but there are meaningful differences. Conventional corticosteroids deliver the steroid hormone directly, flooding receptors throughout the body. Acthar Gel works upstream, prompting the adrenal glands to produce cortisol in a more physiologic pattern while simultaneously activating melanocortin receptors on immune cells. This dual pathway means Acthar Gel can dampen immune activity through mechanisms that steroids simply do not engage.

In practice, this distinction matters most for patients who have stopped responding to steroids, cannot tolerate them, or need to reduce their steroid dose because of accumulating side effects. Multiple studies have documented reductions in concomitant glucocorticoid prescriptions after Acthar Gel was added, suggesting it can help patients escape the steroid treadmill. Whether the immunomodulatory benefits truly outweigh the cost and complexity compared to steroids remains an active debate, and the answer likely depends on the individual patient’s disease severity and treatment history.

Nine Approved Indications, Uneven Evidence

Acthar Gel holds FDA approval for nine distinct indication categories, which makes it one of the more broadly approved drugs in the U.S. pharmacopeia. A narrative literature review covering all nine found that the evidence supports efficacy across the board, but the strength and quality of that evidence varies enormously.²¹ Infantile spasms and MS relapses sit at one end, with controlled trial data. Sarcoidosis uveitis sits at the other, with a handful of small studies that show inconsistent results. The rheumatologic and nephrologic indications fall in the middle, supported mainly by real-world data and retrospective analyses.

For patients and clinicians, this unevenness means the conversation about Acthar Gel should always be indication-specific. A parent whose infant has been diagnosed with infantile spasms is looking at a drug with strong evidence and first-line recommendation status. A patient with lupus nephritis is looking at a drug with encouraging but less rigorous data, typically considered after other immunosuppressants have been tried. And a patient with ocular sarcoidosis is looking at a drug where the early signal is genuinely uncertain. Lumping all nine indications together under a single verdict about whether Acthar Gel “works” misses the reality that the answer depends entirely on what it is being used for.