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A retrospective pilot study examining the use of Acthar gel in sarcoidosis patients

Open ArchivePublished:November 18, 2015DOI:https://doi.org/10.1016/j.rmed.2015.11.007

      Highlights

      • Acthar gel was tolerated in majority of treated patients.
      • In those patients who received more than 3 months of treatment, half had improvement in their disease.
      • In those patients who received more than 3 months of treatment, almost all had prednisone dose reduced.

      Abstract

      Introduction

      Acthar was reported as effective for the treatment of pulmonary sarcoidosis in the 1950s. Use of drug waned due to cost and toxicity compared to prednisone. Recent interest has reemerged as an alternative to high dose oral glucocorticoids.

      Methods

      Chart review was performed on all advanced sarcoidosis patients seen at two centers who received at least one dose of Acthar gel therapy with at least six months of posttreatment follow up. In all cases prior sarcoidosis therapy and indications for use along with clinical outcome were noted. All patients initially received 80 IU intramuscular or subcutaneous administration twice a week.

      Results

      A total of 47 patients were treated with Acthar gel therapy during the study period, and 18 (37%) discontinued drug within six months due to cost (four patients), death (two patients), or drug toxicity (eleven patients), or noncompliance (1 patient). Of the remaining 29 patients, eleven experienced objective improvement in one or more affected organs. All but two patients noted disease improvement or oral glucocorticoid reduction. Twenty-one patients were treated for more than six months (Median 274 days). Nineteen patients were on prednisone at time of starting Acthar gel: seventeen had their prednisone dosage reduced by more than fifty percent and one patient discontinued cyclophosphamide therapy.

      Conclusion

      In this group of advanced sarcoidosis patients, Acthar gel treatment for at least three months was associated with objective improvement in a third of patients. A third of patients were unable to take at least a three months of treatment.

      Keywords

      1. Introduction

      In the early 1950s corticotrophin (Acthar) was reported effective in treating sarcoidosis based on a limited number of case reports [
      • Miller M.A.
      • Bass H.E.
      Effect of Acthar-c (ACTH) in sarcoidosis.
      ,
      • Salomon A.
      • Appel B.
      • Collins S.F.
      • et al.
      Sarcoidosis: pulmonary and skin studies before and after ACTH and cortisone therapy.
      ]. This agent was the first drug approved for treatment of pulmonary sarcoidosis by the Food and Drug Administration (FDA) in the United States. With the subsequent approval of hydrocortisone and prednisone for the treatment of symptomatic sarcoidosis, the use of corticotrophin for sarcoidosis markedly diminished. This was due to several factors, including cost, convenience of an oral versus injected route of delivery, and local reactions at the site of injection. In addition, there was a question that Acthar may have been less effective, which may have related to incomplete information about dosing.
      Initially, the mechanism of action of corticotrophin was attributed solely to corticosteroid secretion by the adrenal glands. As an improved formulation of long acting corticotrophin (Acthar gel) became commercially available, investigators questioned whether corticotrophin had other endocrine and immune effects outside the adrenal axis. Physicians treating multiple sclerosis patients have noted stimulation of alternative melanocorticoreceptors (MCRs) [
      • Arnason B.G.
      • Berkovich R.
      • Catania A.
      • et al.
      Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis.
      ,
      • Berkovich R.
      • Agius M.A.
      Mechanisms of action of ACTH in the management of relapsing forms of multiple sclerosis.
      ] which appear to have direct anti-inflammatory activities [
      • Arnason B.G.
      • Berkovich R.
      • Catania A.
      • et al.
      Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis.
      ,
      • Gong R.
      The renaissance of corticotropin therapy in proteinuric nephropathies.
      ]. Studies suggested that Acthar gel may be as effective as high doses of glucocorticoids in various chronic inflammatory conditions [
      • Hladunewich M.A.
      • Cattran D.
      • Beck L.H.
      • et al.
      A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar(R) Gel) in nephrotic syndrome due to idiopathic membranous nephropathy.
      ,
      • Fiechtner J.
      • Montroy T.
      Treatment of moderately to severely active systemic lupus erythematosus with adrenocorticotropic hormone: a single-site, open-label trial.
      ].
      Approximately half of sarcoidosis patients require systemic therapy and between 20 and 80% of these patients will remain on treatment for more than two years [
      • Baughman R.P.
      • Judson M.A.
      • Teirstein A.
      • et al.
      Presenting characteristics as predictors of duration of treatment in sarcoidosis.
      ,
      • Gottlieb J.E.
      • Israel H.L.
      • Steiner R.M.
      • et al.
      Outcome in sarcoidosis. The relationship of relapse to corticosteroid therapy.
      ]. In general these patients requiring chronic therapy can be maintained on either low doses of prednisone or with anti-metabolites such as methotrexate or azathioprine [
      • Baughman R.P.
      • Nunes H.
      • Sweiss N.J.
      • et al.
      Established and experimental medical therapy of pulmonary sarcoidosis.
      ]. However, a small but significant proportion of these sarcoidosis patients will require increases in systemic disease medications five or more years beyond original diagnosis [
      • Baughman R.P.
      • Nagai S.
      • Balter M.
      • et al.
      Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.
      ]. This group of patients has been treated with different medications, including infliximab and rituximab [
      • Baughman R.P.
      • Nunes H.
      • Sweiss N.J.
      • et al.
      Established and experimental medical therapy of pulmonary sarcoidosis.
      ,
      • Baughman R.P.
      • Drent M.
      • Kavuru M.
      • et al.
      Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.
      ,
      • Sweiss N.J.
      • Lower E.E.
      • Mirsaeidi M.
      • et al.
      Rituximab in the treatment of refractory pulmonary sarcoidosis.
      ]. However, because these biologic agents are often associated with significant morbidity, the search for alternative options continues. Recently, we have begun prescribing Acthar gel for some cases of advanced sarcoidosis. Because the FDA originally approved Acthar (corticotropin) for sarcoidosis based on a limited number of case reports [
      • Miller M.A.
      • Bass H.E.
      Effect of Acthar-c (ACTH) in sarcoidosis.
      ,
      • Salomon A.
      • Appel B.
      • Collins S.F.
      • et al.
      Sarcoidosis: pulmonary and skin studies before and after ACTH and cortisone therapy.
      ], there is minimal information regarding the dosage, effectiveness, and toxicity of Acthar gel in treating chronic sarcoidosis. Because there is minimal information regarding the dosage, effectiveness, and toxicity of ACTHAR gel in treating sarcoidosis, we present our initial experience with this agent.

      2. Methods

      This retrospective chart review of patients treated with Acthar gel for sarcoidosis was performed at two institutions. Charts of patients prescribed Acthar gel by one of three physicians (JB, RPB, and EEL) were reviewed. Entry criteria included patients diagnosed with sarcoidosis based on standard criteria [
      • Hunninghake G.W.
      • Costabel U.
      • Ando M.
      • et al.
      ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders.
      ]. Patients were considered evaluable if they received at least one dose of Acthar gel with a minimum of three months follow-up available after Acthar gel was discontinued. All patients were receiving one or more systemic therapies for sarcoidosis at drug institution. Patients were on stable therapy for at least two months prior to institution of Acthar gel. No additional testing such as serum biomarkers was done systematically to assess for disease activity. Acthar gel was prescribed because patients were classified as having an incomplete response to their current therapy because of progressive symptomatic disease despite immunosuppressive therapy and/or excessive toxicity with current treatment. In all cases, the patient and/or clinician did not want to institute or increase the dose of prednisone because of current or past toxicity with glucocorticoids. While glucocorticoid toxicity was the usual reason for seeking an alternative agent, in one case a patient also wished to stop cyclophosphamide therapy because of nausea and fatigue with cyclophosohamide therapy. The decision to initiate Acthar gel was made by the treating physician with patient input. The use of opiates and benzodiazepines was not excluded during the study. The medical records of the patients were reviewed for adverse events while taking Acthar gel. The patients were informed that Acthar gel had been approved for sarcoidosis. Patients were informed about the potential toxicity of Acthar gel, including the fact that it may increase the glucocorticoid toxicity they had experienced with prednisone. The protocol to review the clinical outcome of treating patients with Acthar gel was approved by the University of Cincinnati (UC) Institutional Review Board and the University of Alabama Institutional Review Board, and it is listed on ClinicalTrials.gov (NCT02356445).
      For each patient, the age, sex, and self-reported race were noted. Organ system involvement was determined using standard criteria proposed by Judson et al. [
      • Judson M.A.
      • Baughman R.P.
      • Teirstein A.S.
      • et al.
      Defining organ involvement in sarcoidosis: the ACCESS proposed instrument.
      ]. All patients were treated for symptomatic disease in one or more organ. The target organ for which treatment was prescribed was noted, and all other organ involvement was also noted. Each organ was assessed by appropriate testing, such as liver function testing, skin lesion assessment, or neurologic examination. Pulmonary status was assessed using patient reported dyspnea. Pulmonary function testing and chest imaging were performed at the discretion of the treating physician, PET scanning was not routinely used to assess disease activity. Current and past systemic sarcoidosis treatments were recorded. Prednisone doses at Acthar gel institution and during therapy were recorded.
      Patients were defined as “improved” when clinically significant improvement was noted in the target organ. This improvement could include reduced inflammation by chest imaging or PET scanning, greater than 10% improvement in forced vital capacity, greater than 50% reduction of skin lesion(s), or greater than 50% reduction in central nervous system lesion on magnetic resonance imaging. The radiologic imaging and skin lesion comparisons were performed in a non blinded fashion. Additionally, improvement could include a greater than 50% reduction in the use of topical glucocorticoids for ocular disease, or normalization and/or reduction by 50% of abnormal liver function tests or serum calcium to the upper limit of normal. “Stable” was defined by no clinically significant change in the target organ, but reduction in dosage of glucocorticoids. “Relapsed” was defined as worsening of target organ when prednisone dosage was reduced and patient had to be maintained on the initial or a higher dosage of glucocorticoids.
      All patients were scheduled to receive at least three months of Acthar gel therapy. At one institution, the University of Cincinnati, therapy was continued for patients who were tolerating the drug and demonstrating possible drug benefit at three months. For patients receiving less than 3 months of treatment, clinical outcomes were evaluated at Acthar initiation, at discontinuation, and six months after therapy discontinuation. Those patients receiving therapy three months or more were evaluated at drug institution, after three months of treatment, and at long term follow up as of January 1, 2015. The reason(s) for discontinuation of therapy within three months were assigned to four categories: death, cost, serious adverse event (SAE), or noncompliance. For patients who received the full three months of treatment, organ responses and initial and post treatment prednisone and other concurrent sarcoidosis drug doses were compared.
      After six months of therapy or January 1, 2015, the clinical status was recorded for those patients who received more than three months of Acthar gel. Information collected included target organ response, adverse side effects along with pre and post prednisone average daily doses, and other concurrent treatments.

      3. Results

      A total of 47 sarcoidosis patients were identified who received Acthar gel for at least one treatment with at least six months of follow-up available. At the time of institution of drug, the median age was 51, with a range of 20–70 years. Thirty of the patients were women and twenty-eight were Caucasians and nineteen self-declared African Americans. The outcomes of these patients are summarized in Fig. 1. Within three months of the drug institution, 18 (38%) patients discontinued drug due to various issues: death (2 patients), cost (4 patients), SAEs including anxiety/agitation (3 patients), cryptococcal infection (2 patients), peripheral edema (2 patients), and one patient each for pain at injection site, weakness, worsening disease, allergic reaction to injection, and noncompliance. The two patients who died (one with neurosarcoidosis and other with advanced pulmonary disease) had not received Acthar gel for more than six weeks when they developed complications of their sarcoidosis. The neurosarcoidosis patient had progressive neurologic symptoms despite high dose oral prednisone while the other patient developed pneumonia. The two deaths were felt to be due to progression of the underlying sarcoidosis with respiratory infections as the terminal events. In both cases, the deaths were not felt to be related to Acthar gel therapy. The remaining 29 patients received at least three months of therapy. Eleven (38%) patients experienced objective improvement in one or more organs, and 16 (55%) remained stable. Only two (7%) patients had relapsed after six months of treatment.
      Figure thumbnail gr1
      Fig. 1The overall clinical results of 47 patients treated with Acthar gel. Patients were separated into those who received less than three months of treatment versus those who were treated for three months or longer. * Of three not reducing prednisone, one stopped cyclophosphamide, other two were not treated with prednisone.
      Table 1 summarizes the primary indication for treatment commencement. Response to treatment was based on the response of the target organ system. Lung involvement was the primary treatment indication in only 26 (53%) of all patients. Of the 29 patients who completed the three months of treatment, 15 had lung involvement as the target organ, and only one patient experienced disease improvement. In contrast, ten of the fourteen patients with extra pulmonary target organs improved with Acthar gel (Fisher's exact test, p < 0.0005). Table 1 also lists other organs affected by sarcoidosis. Overall, most patients (38/47 [81%]) had lung involvement at drug initiation, and other commonly affected organs included central nervous system (14 [30%]), skin (10 [21%]), and eye (7 [15%]).
      Table 1Primary indication for treatment and other organ systems affected.
      Primary indication for therapy
      LungCentral nervous systemEyeSkinLiverHypercalcemiaOther
      Status
      Completed three months of treatment
       Improved142211
       Stable1231
       Relapsed2
      Less than three months treatment
       Death11
       Cost211
       SAE821
       Noncompliance1
      Other organ systems affected
      Status
      Completed three months of treatment
       Improved91221 each heart, sinus, spleen
       Stable211211 each sinus, spleen, bone marrow
       Relapsed1
      Less than three months treatment
       Death1
       Cost1111
       SAE1111 heart
       Noncompliance1 kidney
      Total381471053
      Table 2 summarizes the variety of treatments prescribed for these patients. There was no statistical difference in the treatments prescribed for patients who received Acthar gel for less than three months compared to those treated for more than three months. All patients had received glucocorticoids and all but one had also received at least one anti-metabolite. One patient had declined taking anti-metabolite therapy. All patients were prescribed prednisone except one who was treated with dexamethasone. Two patients were not receiving glucocorticoids at time of Acthar gel institution. Methotrexate and azathioprine were the most commonly prescribed antimetabolites, although some patients received either leflunomide or mycophenolate. Seventeen patients had been treated with monoclonal antibodies against tumor necrosis factor (anti-TNF) infliximab or adalimumab with eleven of these patients still receiving anti-TNF therapy at Acthar gel commencement. For those patients receiving anti-TNF treatment, no difference was noted in the proportion of patients treated for less than three months versus those treated for three months or longer.
      Table 2Current and past sarcoidosis treatments at institution of Acthar gel.
      Treated for ≥3 monthsTreated for <3 monthsTotal
      CurrentPastCurrentPastCurrentPast
      Glucocorticoids272180452
      Methotrexate107541511
      Azathioprine7441115
      Leflunomide401050
      Mycophenolate001010
      Hydroxychloroquine501161
      Thalidomide030104
      Infliximab741286
      Adalimumab102030
      Rituximab202040
      As shown in Fig. 1, 29 patients continued therapy for more than three months. Eleven of these 29 patients were classified as improved, sixteen remained stable, and only two had relapsed. Table 3 gives the treatments for the 29 patients who completed at least three months of therapy. The dose of prednisone at time of initiating Acthar gel is shown. In addition, current and past non-steroidal therapy is listed. There was no statistically significant difference between the three groups in terms of their current or past treatment or the dose of prednisone.
      Table 3Initial therapy of 29 patients who completed at least three months of therapy.
      ResponseDose of prednisone initiallyCurrent non-steroidal therapyPast non-steroidal therapy
      Improved
      30MTX, AZA, LEF
      ADA: adalimumab; AZA: azathioprine; INF: infliximab; HYD: hydroxychloroquine; LEF: leflunomide; MTX: methotrexate; RIT: rituximab; THA: thalidomide.
      40MTX, AZA
      20MTX, LEF, RIT
      30LEF
      40MTXINF
      40MTX
      0MTX, AZA
      10INF, RIT, THAMTX
      0AZA, ADA
      40LEF, INF, HYDMTX, AZA, THA, ADA
      10AZA, INF
      Stable
      40AZA, INFMTX
      30MTX
      40MTX
      20INFAZA
      20MTX
      20AZAINF
      20THA
      25MTX
      10AZAMTX
      20MTX, INF
      20MTX, HYD
      10MTX, HYD
      5ADA, HYD
      10AZA
      5AZA
      15
      Relapsed
      5INF, HYD
      40MTX, INF
      a ADA: adalimumab; AZA: azathioprine; INF: infliximab; HYD: hydroxychloroquine; LEF: leflunomide; MTX: methotrexate; RIT: rituximab; THA: thalidomide.
      At the University of Cincinnati, 29 patients were treated for at least six months. These patients were treated for a median of 274 days (range 180–609 days). Fig. 2 summarizes the initial and final prednisone daily dosages of the 19 patients at the University of Cincinnati receiving prednisone at the time of Acthar gel initiation. Eight improved patients experienced a 50% or more reduction in prednisone dosage. Of the remaining three patients, two were not receiving prednisone at Acthar commencement, and the third maintained a stable prednisone dose but discontinued her intravenous cyclophosphamide treatments. She noted resolution of her nausea and fatigue which was associated with her cyclophosphamide treatments. This patient demonstrated subjective clinical improvement as well as a seventy five percent reduction in the SuV of the highest activity in lymph node (from 12.09 to 2.99) (Fig. 3). In all 16 objectively stable patients the daily prednisone dosage was reduced by greater than 50%. One patient with lupus pernio refused to take prednisone again. She had allergic reaction to infliximab. She was treated with Acthar gel for seven months. Fig. 4 demonstrates her skin lesions on her face before and after treatment. The one patient objectively non responding patient also had no change in his prednisone dosage by study completion. Three patients totally discontinued prednisone by the end of the study. All three patients had clinically significant improvement.
      Figure thumbnail gr2
      Fig. 2Twenty-seven or twenty-nine patients receiving Acthar gel for more than six months were receiving prednisone at institution of Acthar gel. Initial and lowest prednisone dose achieved by the nineteen patients treated with Acthar gel for six months or longer is shown. Patients were divided into three groups based on clinical outcome: improved, stable, and relapsed. The black bars are prior to therapy and gray bars are after therapy.
      Figure thumbnail gr3
      Fig. 3Total body PET scan results of patient with multi-organ sarcoidosis receiving prednisone, rituximab, and cyclophosphamide at time of starting Acthar gel (A). The SUV of the right paratracheal lymph node was 12.09. B demonstrates the repeat PET scan after six months of Acthar gel. Cyclophosphamide treatment was withdrawn when Acthar was initiated, but prednisone and rituximab treatments were continued. The SUV of the right paratracheal lymph node area decreased to 2.99.
      Figure thumbnail gr4
      Fig. 4Patient with lupus pernio. Photographs of face before (A) and after (B) nine months of Acthar gel 80 units twice a week. Patient was on no other treatment for her sarcoidosis at this time. She had been on prednisone and infliximab in past. Both were discontinued due to toxicity. She had no toxicity with Acthar gel. Patient provided written consent for the publication of these photographs.
      Within three months of initiating therapy, five patients experienced peripheral edema or agitation which led to Acthar gel discontinuation. Although an additional six patients complained of these side effects, they were able to continue after the drug was reduced to 40 units once to twice a week. In three cases, spironolactone was added to block the mineralocorticoid effect of Acthar gel. One patient noted skin hyperpigmentation during treatment which did not necessitate change in dosage. We reviewed the medical records of the patients for treatment of diabetes before and during Acthar therapy. Of the 47 patients treated with Acthar, 23 were being treated for diabetes and 33 were on treatment for systemic hypertension. During the course of the observation, there was no need to significantly increase treatment for either diabetes or hypertension. There was also no clinically significant reduction in their medication for either diabetes or hypertension in the first six months of Acthar therapy.

      4. Discussion

      We report on the effectiveness of Acthar gel treatment in patients with progressive sarcoidosis despite treatment with various agents. Patients were treated with Acthar gel in an attempt to avoid the toxicity that these patients had previously encountered with increased doses of prednisone or dexamethasone. Over two thirds of patients were treated for three months or longer. Eleven (38%) had objective improvement of their disease. Sixteen (55%) remained clinically stable when their glucocorticoid dosages were reduced. Only two patients relapsed as their glucocorticoids were withdrawn. Acthar gel increases endogenous serum cortisol levels. It was associated with significant glucocorticoid toxicity in some cases. Eighteen patients discontinued therapy in less than six months for various reasons, including cost of treatment, toxicity, fungal infections and progression of disease.
      Evidence based recommendations for the treatment of sarcoidosis propose a step wise approach [
      • Baughman R.P.
      • Nunes H.
      • Sweiss N.J.
      • et al.
      Established and experimental medical therapy of pulmonary sarcoidosis.
      ,
      • Judson M.A.
      The treatment of pulmonary sarcoidosis.
      ] with oral glucocorticoids usually the first systemic step. Randomized trials have demonstrated benefit of oral glucocorticoids for pulmonary sarcoidosis [
      • Gibson G.J.
      • Prescott R.J.
      • Muers M.F.
      • et al.
      British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment.
      ,
      • Pietinalho A.
      • Tukiainen P.
      • Haahtela T.
      • et al.
      Early treatment of stage II sarcoidosis improves 5-year pulmonary function.
      ]. However, the improvement in these trials was modest and the impact on the long term outcome of these patients remains unclear [
      • Paramothayan S.
      • Jones P.W.
      Corticosteroid therapy in pulmonary sarcoidosis: a systematic review.
      ]. To avoid toxicity, therapy is usually reduced or discontinued over time. Toxicity from oral glucocorticoids usually leads to treatment with anti-metabolites as steroid sparing agents [
      • Schutt A.C.
      • Bullington W.M.
      • Judson M.A.
      Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study.
      ]. For patients who fail to respond to those drugs, the anti-TNF biologics, infliximab or adalimumab, may be prescribed [
      • Baughman R.P.
      • Nunes H.
      • Sweiss N.J.
      • et al.
      Established and experimental medical therapy of pulmonary sarcoidosis.
      ,
      • Judson M.A.
      The treatment of pulmonary sarcoidosis.
      ,
      • Schutt A.C.
      • Bullington W.M.
      • Judson M.A.
      Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study.
      ]; however, these agents are associated with significant morbidity and require close monitoring [
      • Drent M.
      • Cremers J.P.
      • Jansen T.L.
      • et al.
      Practical eminence and experience-based recommendations for use of TNF-alpha inhibitors in sarcoidosis.
      ]. Not all patients respond to anti-TNF treatment. Additionally, some patients treated with anti-TNF agents develop granulomatous disease and are at increased risk for opportunistic infections [
      • Daien C.I.
      • Monnier A.
      • Claudepierre P.
      • et al.
      Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases.
      ].
      Acthar has been approved for treatment of pulmonary sarcoidosis based upon reports of the effectiveness of corticotrophin in treating sarcoidosis [
      • Miller M.A.
      • Bass H.E.
      Effect of Acthar-c (ACTH) in sarcoidosis.
      ,
      • Sones M.
      • Israel H.L.
      • Dratman M.B.
      • et al.
      Effect of cortisone in sarcoidosis.
      ]. In the 1950s Acthar was also approved for several other conditions with a wide array of inflammatory and autoimmune mechanisms in their pathogenesis, including multiple sclerosis [
      • Berkovich R.
      • Agius M.A.
      Mechanisms of action of ACTH in the management of relapsing forms of multiple sclerosis.
      ]. Acthar gel appears to have anti-inflammatory activity based on stimulation of several MCRs [
      • Berkovich R.
      • Agius M.A.
      Mechanisms of action of ACTH in the management of relapsing forms of multiple sclerosis.
      ,
      • Gong R.
      The renaissance of corticotropin therapy in proteinuric nephropathies.
      ]. Recent reports found Acthar gel associated with less toxicity than high dose glucocorticoids in certain clinical conditions [
      • Hladunewich M.A.
      • Cattran D.
      • Beck L.H.
      • et al.
      A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar(R) Gel) in nephrotic syndrome due to idiopathic membranous nephropathy.
      ,
      • Fiechtner J.
      • Montroy T.
      Treatment of moderately to severely active systemic lupus erythematosus with adrenocorticotropic hormone: a single-site, open-label trial.
      ].
      Hladunewich et al. [
      • Hladunewich M.A.
      • Cattran D.
      • Beck L.H.
      • et al.
      A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar(R) Gel) in nephrotic syndrome due to idiopathic membranous nephropathy.
      ] measured serum cortisol after Acthar gel 40–80 IU given subcutaneously twice a week. They found that the serum cortisol peaked at 16 h and returned to baseline within 20 h of the treatment. Despite the transient effect on serum cortisol, the treatment was effective for controlling nephrotic syndrome due to idiopathic membranous nephropathy. Although Hladunewich et al. noted that patients who tolerated Acthar gel 80 IU twice a week for the full year of the study demonstrated the best responses, improvement was sometimes identified at lower doses [
      • Hladunewich M.A.
      • Cattran D.
      • Beck L.H.
      • et al.
      A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar(R) Gel) in nephrotic syndrome due to idiopathic membranous nephropathy.
      ]. Since one cannot calculate the cumulative dose of Acthar gel on serum cortisol, one would have to assume that this increased dose of Acthar gel led to some increase in serum cortisol dose.
      In the current study, major drug toxicities included peripheral edema and agitation, similar to previous case reports [
      • Hladunewich M.A.
      • Cattran D.
      • Beck L.H.
      • et al.
      A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar(R) Gel) in nephrotic syndrome due to idiopathic membranous nephropathy.
      ]. Peripheral edema may be related to mineralocorticoid release due to Acthar gel stimulation [
      • Martin Martins J.
      • do V.S.
      • Martins A.F.
      Mild adrenal steroidogenic defects and ACTH-dependent aldosterone secretion in high blood pressure: preliminary evidence.
      ]. In some patients, symptom improvement occurred with aldosterone blockade with spironolactone. Cryptococcal infections were reported in two cases (4%), and these infections have also been reported in other studies of sarcoidosis patients [
      • Jamilloux I.
      • Valeyre D.
      • Lortholary O.
      • et al.
      The spectrum of opportunistic diseases complicating sarcoidosis.
      ,
      • Baughman R.P.
      • Lower E.E.
      Fungal infections as a complication of therapy for sarcoidosis.
      ]. These opportunistic infections are more common in patients treated with glucocorticoids alone or with other immunosuppressants [
      • Baughman R.P.
      • Lower E.E.
      Fungal infections as a complication of therapy for sarcoidosis.
      ]. The two deaths in this study were attributed to progression of sarcoidosis, not to Acthar gel.
      A significant proportion of our patients witnessed improvement with Acthar gel despite extensive prior treatments. This improvement was statistically more likely to occur in patients with extra pulmonary disease. Similarly sarcoidosis patients with the extra pulmonary skin manifestation lupus pernio were more likely to experience clinical disease resolution with anti-TNF therapy compared to other treatments [
      • Stagaki E.
      • Mountford W.K.
      • Lackland D.T.
      • et al.
      The treatment of lupus pernio: results of 116 treatment courses in 54 patients.
      ]. Also infliximab therapy has successfully treated ocular [
      • Baughman R.P.
      • Lower E.E.
      • Ingledue R.
      • et al.
      Management of ocular sarcoidosis.
      ,
      • Erckens R.J.
      • Mostard R.L.
      • Wijnen P.A.
      • et al.
      Adalimumab successful in sarcoidosis patients with refractory chronic non-infectious uveitis.
      ] and neurologic [
      • Sodhi M.
      • Pearson K.
      • White E.S.
      • et al.
      Infliximab therapy rescues cyclophosphamide failure in severe central nervous system sarcoidosis.
      ,
      • Moravan M.
      • Segal B.M.
      Treatment of CNS sarcoidosis with infliximab and mycophenolate mofetil.
      ] disease which has failed conventional treatments. These conditions may require higher doses of glucocorticoids than needed to control pulmonary disease.
      Acthar gel is a long acting form of corticotropin. The FDA originally approved Acthar (corticotropin) for sarcoidosis based on a limited number of case reports [
      • Miller M.A.
      • Bass H.E.
      Effect of Acthar-c (ACTH) in sarcoidosis.
      ,
      • Salomon A.
      • Appel B.
      • Collins S.F.
      • et al.
      Sarcoidosis: pulmonary and skin studies before and after ACTH and cortisone therapy.
      ]. When Acthar gel was formulated as a long acting form of corticotropin, the FDA approved the drug for pulmonary sarcoidosis without new studies examining the effectiveness of Acthar gel in sarcoidosis. The current report is a retrospective review of our experience with this agent in patients who have failed usual therapy for sarcoidosis.
      This was a retrospective study with no placebo control. Therefore the assessment of response was subjective. We did try to provide specific criteria for response to treatment. For some disease manifestations, we were unable to detect changes in forced vital capacity or chest x-ray. In one patient, we demonstrated an improvement in PET scan. Although there are no published prospective studies yet, we and others have found serial PET scanning useful in assessing response [
      • Keijsers R.G.
      • van den Heuvel D.A.
      • Grutters J.C.
      Imaging the inflammatory activity of sarcoidosis.
      ]. In addition, we were able to reduce prednisone dose by more than fifty percent in most patients. The meaningfulness of this prednisone dose sparing is unclear, since we do not know whether the effect of Acthar gel on endogenous glucocorticoid release may lead to the same level of glucocorticoid toxicity. The lack of one specific end point for treatment success remains a noted limitation for most clinical trials of sarcoidosis [
      • Baughman R.P.
      • Drent M.
      • Culver D.A.
      • et al.
      Endpoints for clinical trials of sarcoidosis.
      ]. We also do not know whether the use of Acthar gel led to an overall reduction in glucocorticoid effects. Patients were exposed to an increased glucocorticoid effect after injection, and although the effect may have been transient [
      • Hladunewich M.A.
      • Cattran D.
      • Beck L.H.
      • et al.
      A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar(R) Gel) in nephrotic syndrome due to idiopathic membranous nephropathy.
      ], it may have led to persistent steroid associated toxicity. Due to the retrospective nature of this study, a standardized method for collecting steroid associated toxicity was not used. We did not routinely withdraw prednisone by any protocol prior to initiating Acthar. Therefore, it is possible that patients may have been able to have their prednisone dose reduced regardless of whether they were on Acthar or not. We do not know whether Acthar gel led to a reduction of glucocorticoid dose because it was truly steroid sparing. It has been suggested that Acthar gel's stimulation of other MCRs leads to anti-inflammatory activity beyond the stimulation of the glucocorticoid release [
      • Ross A.P.
      • Ben-Zacharia A.
      • Harris C.
      • et al.
      Multiple sclerosis, relapses, and the mechanism of action of adrenocorticotropic hormone.
      ]. However, this study was not designed to determine the mechanism of action of Acthar gel in treating sarcoidosis. While there are several theoretical reasons to think that Acthar gel may work in ways beyond its effect on the adrenal gland, this study was not designed to address the effect of Acthar gel on MCRs in sarcoidosis. That study will require the use of other, more specific MCR agonists.
      The role of Acthar gel in the treatment of advanced sarcoidosis remains unknown. In this study, there were no standard criteria for initiation of Acthar gel as new therapy. The treating physician felt the patient had progressive disease or toxicity with current the regimen of immunosuppressive therapy. For the patient who has failed first and second line therapy, the use of anti-TNF monoclonal antibodies is usually recommended [
      • Baughman R.P.
      • Nunes H.
      • Sweiss N.J.
      • et al.
      Established and experimental medical therapy of pulmonary sarcoidosis.
      ]. However, not all patients respond to or can tolerate anti-TNF monoclonal antibodies [
      • Drent M.
      • Cremers J.P.
      • Jansen T.L.
      • et al.
      Practical eminence and experience-based recommendations for use of TNF-alpha inhibitors in sarcoidosis.
      ]. Other options which have been reported include rituximab [
      • Sweiss N.J.
      • Lower E.E.
      • Mirsaeidi M.
      • et al.
      Rituximab in the treatment of refractory pulmonary sarcoidosis.
      ], vasoactive intestinal protein [
      • Prasse A.
      • Zissel G.
      • Lutzen N.
      • et al.
      Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis.
      ], and placental derived mesenchymal-like cells [
      • Baughman R.P.
      • Culver D.A.
      • Jankovic V.
      • et al.
      Placenta-derived mesenchymal-like cells (PDA-001) as therapy for chronic pulmonary sarcoidosis: a phase 1 study.
      ]. While lung transplantation has been performed in some advanced patients [
      • Arcasoy S.M.
      • Christie J.D.
      • Pochettino A.
      • et al.
      Characteristics and outcomes of patients with sarcoidosis listed for lung transplantation.
      ], it is often not an option for patients with multi-organ disease. None of these options is ideal and therefore the search for new agents persists.
      In conclusion, we found that prolonged treatment with Acthar gel was tolerated in two thirds of our patients. Those patients able to tolerate long term treatment were usually able to reduce prednisone or other treatments for sarcoidosis. For those patients able who were treated for three months or longer, a third of sarcoidosis patients experienced significant clinical improvement. The role of Acthar gel in the treatment of sarcoidosis remains uncertain and needs further study. Additional studies on duration of effect after completing therapy and its impact on long term endocrine outcomes such as lipid profiles and glucose metabolism are desperately needed.

      Conflict of interest statement

      RPB and JBB have been consultants for Mallinckrodt, the manufacturer of Acthar gel. RPB and EEL have research grants from Mallinckrodt that are different studies than the one reported here. However, Mallinckrodt has not been involved in any way in the design, execution, or preparation of this manuscript. RPB and EEL have research grants for treatment for sarcoidosis from the following companies: Actelion, Celgen, Janssen, Gilead, Pfizer, Bayer, and Novartis. JBB has had research grant support from Janssen, Gilead, Celgene, and Novartis. RPB, JBB, and EEL do not believe the research grants from these other companies represent a potential conflict of interest or have any bearing on this particular publication. LO has no conflicts of interest to declare. The authors do not believe that they will receive any financial gain by the publication of this manuscript.

      Acknowledgments

      There was no funding for this study.

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