Acthar® Gel Treatment for Patients with Autoimmune and Inflammatory Diseases: An Historical Perspective and Characterization of Clinical Evidence.

Acthar® Gel (repository corticotropin injection) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that is believed to have both steroidogenic and nonsteroidogenic immunomodulatory effects via activation of melanocortin receptors in various cells throughout the body. Since 1952, Acthar has been approved by the US Food and Drug Administration to treat a variety of autoimmune and inflammatory diseases. Since 2014, Mallinckrodt Pharmaceuticals has conducted a large number of preclinical, clinical, and real-world-evidence studies of Acthar for the treatment of rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, multiple sclerosis relapse, ophthalmic disorders, sarcoidosis, and nephrotic syndrome. To date, Acthar has been the subject of more than 500 publications, many of which demonstrate the safety and efficacy of Acthar in patients with inflammatory diseases for whom standard treatments were ineffective or intolerable. Here, we review the history of Acthar and the findings of studies that have investigated the mechanism of action, safety, efficacy, and real-world effectiveness of Acthar for the treatment of inflammatory diseases.

Acthar^® Gel is an anti-inflammatory drug that directly affects the immune system in a manner that differs from other anti-inflammatory drugs, such as corticosteroids. Since 1952, Acthar has been approved by the U.S. Food and Drug Administration to treat a variety of diseases involving inflammation. The commercial rights to produce Acthar have changed hands several times over the years, beginning with Armour Pharmaceuticals and most recently ending with Mallinckrodt Pharmaceuticals in 2014. Since then, Mallinckrodt has conducted multiple studies in animals to demonstrate the function of Acthar compared with other anti-inflammatory drugs. Further, several clinical trials in humans and studies of hospital or clinical practice records have confirmed the safety and effectiveness of Acthar as a treatment for many inflammatory diseases. INFOGRAPHIC: A podcast discussion by the authors on Acthar^® Gel treatment for patients with autoimmune and inflammatory diseases, including their own personal reflections and experiences with Acthar^® Gel. For a transcript of the podcast see the electronic supplementary material. (MP4 177883 kb).

Guided therapy selection in rheumatoid arthritis using a molecular signature response classifier: an assessment of budget impact and clinical utility.

BACKGROUND: Patients with moderate to severe rheumatoid arthritis (RA) can be treated with a range of targeted therapies following inadequate response to conventional synthetic disease-modifying antirheumatic drugs such as methotrexate. Whereas clinical practice guidelines provide no formal recommendations for initial targeted therapies, the tumor necrosis factor alpha inhibitor (TNFi) class is the prevalent first-line selection based on clinician experience, its safety profile, and/or formulary requirements, while also being the costliest. Most patients do not achieve adequate clinical response with a first-line TNFi, however. A molecular signature response classifier (MSRC) test that assesses RA-related biomarkers can identify patients who are unlikely to achieve adequate response to TNFi-class therapies. OBJECTIVE: To model cost-effectiveness of MSRC-guided, first-line targeted therapy selection compared with current standard care. METHODS: This budget impact analysis used data sourced from August to September 2020. The prevalence of each first-line targeted therapy was obtained using market intelligence from Datamonitor/Informa PLC Rheumatology Dashboard Forecast 2020, and the average first-year cost of treatment for each class was calculated using wholesale acquisition costs from IBM Micromedex RED BOOK Online. Average effectiveness for each class was based on manufacturer-reported ACR50 response rates (American College of Rheumatology adequate response criteria of 50% improvement at 6 months after therapy initiation). The impact of MSRC testing on first therapy selection was predicted based on a third party-generated decision-impact study that analyzed potential alterations in rheumatologist prescribing patterns after receiving MSRC test reports. Sensitivity analysis evaluated potential impacts of variation in first-year medication cost, adherence to MSRC report, and test price on the first-year cost of treatment. Cost for response (first-year therapy cost therapy divided by probability of achieving ACR50) was compared between standard care and MSRC-guided care. RESULTS: The estimated cost for first-year, standard-care treatment was $65,117, with 80% of patients initiating treatment with a TNFi. Cost for achieving ACR50 response was $177,046. After applying MSRC-guided patient stratification and therapy selection, the first-year cost was $56,543, net of test price, with 49.0% of patients initiating with a TNFi. First-year MSRC-guided care cost, including test price, was estimated at $117,103, a 33.9% improvement over standard care. Sensitivity analysis showed a net cost improvement for guided care vs standard care across all scenarios. Patients predicted to be inadequate TNFi responders, when modeled with lower-priced alternatives, were predicted to show increased ACR50 response rates. Those with MSRC test results indicating a first-line TNFi were predicted to show an ACR50 response rate superior to that for any other class. In this model, if implemented clinically, MSRC-guided care might save the US health care system more than $850 million annually and improve ACR50 by up to 31.3%. CONCLUSIONS: Precision medicine using MSRC-guided patient stratification and therapy selection may both decrease cost and improve efficacy of targeted RA therapies. DISCLOSURES: This work was funded in full by Scipher Medicine Corporation, which participated in data analysis and interpretation and drafting, reviewing, and approving the publication. All authors contributed to data analysis and interpretation and publication preparation, maintaining control over the final content. Arnell, Withers, and Connolly-Strong are employees of and have stock ownership in Scipher Medicine Corporation. Bergman has received consulting fees from AbbVie, Gilead, GlaxoSmithKline, Novartis, Pfizer, Regeneron, Sanofi, and Scipher Medicine and owns stock or stock options in Johnson & Johnson. Kenney, Logan, and Lim-Harashima are consultants for Scipher Medicine Corporation. Basu has nothing to disclose.

Stimulatory and inhibitory killer Ig-like receptor molecules are expressed and functional on lupus T cells.

T cells from lupus patients have hypomethylated DNA and overexpress genes normally suppressed by DNA methylation that contribute to disease pathogenesis. We found that stimulatory and inhibitory killer cell Ig-like receptor (KIR) genes are aberrantly overexpressed on experimentally demethylated T cells. We therefore asked if lupus T cells also overexpress KIR, and if the proteins are functional. T cells from lupus patients were found to overexpress KIR genes, and expression was proportional to disease activity. Abs to the stimulatory molecule KIR2DL4 triggered IFN-gamma release by lupus T cells, and production was proportional to disease activity. Similarly, cross-linking the inhibitory molecule KIR3DL1 prevented the autoreactive macrophage killing that characterizes lupus T cells. These results indicate that aberrant T cell KIR expression may contribute to IFN overproduction and macrophage killing in human lupus, and they suggest that Abs to inhibitory KIR may be a treatment for this disease.

Effect of race and ethnicity on perceptions of inflammatory bowel disease.

BACKGROUND AND AIMS: Historically, inflammatory bowel disease (IBD) was thought to predominantly affect whites. However, IBD is now increasingly recognized in diverse ethnic populations. There is a paucity of studies of IBD in nonwhite populations, especially in Mexican Americans. The aims of this study were to compare the impact of IBD on the quality of life of whites, African Americans, and Mexican Americans and to evaluate differing patient understanding and beliefs regarding IBD. MATERIALS AND METHODS: A questionnaire was administered to 148 patients between June 1999 and November 2003 at a university gastroenterology practice in Houston, Tex. RESULTS: Caucasians (W) comprised 40%, African Americans (AA) 37%, and Mexican Americans (MA) 20% of the respondents. AA and W had predominantly Crohn's disease (CD), whereas MA had predominantly ulcerative colitis (UC; P<0.05). We therefore compared W and AA with CD and W and MA with UC. W were more likely to tell their employers (57% vs 27.5%, P=0.02), fellow employees (68% vs 43.8%, P=0.02) and friends (100% vs 79%, P=0.034) that they had CD. W and AA were equally as likely to have regular checkups by a physician, and there was no difference in the access to gastroenterologists or surveillance colonoscopy. There were fewer differences between MA and W with UC. MA were more likely to believe that UC was caused by stress (70% vs 37%, p=0.044) and cigarette smoking. CONCLUSIONS: Significant differences appear among racial and ethnic groups with IBD regarding attitudes toward disease and impact on daily life. Appreciation of varying ethnic and racial perceptions, attitudes, and beliefs among patients with IBD may be critical to more effective management.

Changing spectrum of the diffuse infiltrative lymphocytosis syndrome.

OBJECTIVE: To describe the changing clinical spectrum of patients with diffuse infiltrative lymphocytosis syndrome (DILS) after the introduction of highly active antiretroviral treatment (HAART), and to carry out HLA class II oligotyping in these patients. METHODS: A retrospective chart review of patients with DILS who were referred to an outpatient facility for human immunodeficiency virus (HIV)-positive individuals between 1994 and 2003 was performed. DILS was diagnosed as suggested by previous criteria. Demographic features and relevant clinical, laboratory, and radiologic data were recorded and results analyzed. RESULTS: A total of 129 patients with DILS were identified. Of them, 56 (43%) were African American, 41 (32%) were white, and 32 (25%) were Hispanic. Parotid gland swelling appeared to be the sine qua non of DILS. Twenty-seven percent of patients had opportunistic infections. The status of 103 patients was available as of December 2003: 26 (25%) had died, of which only 6 (6%) succumbed to opportunistic infections. The prevalence of DILS had significantly decreased in the post-HAART era (1998 onwards) compared with that of the pre-HAART period (P < 0.000001). The prevalence of lymphocytic interstitial pneumonitis had also dropped significantly following introduction of HAART therapy (P = 0.015). A higher frequency of certain HLA class II alleles (DRB1) was found in African Americans with DILS compared with those with HIV without DILS (P = 0.006). CONCLUSION: The epidemiology, clinical presentation, and certain extraglandular manifestations of DILS have changed, concomitant with the introduction of HAART, further suggesting that DILS is an antigen (viral)-driven response and the primary treatment for it is anti-HIV therapy.

Impact of race and ethnicity on inflammatory bowel disease.

INTRODUCTION: Inflammatory bowel disease (IBD) is now increasingly recognized in diverse ethnic populations. In the United States, IBD among the minority populations, especially Mexican Americans, has not been extensively studied. Apart from the known genetic influences that differ among the IBD subtypes [ulcerative colitis (UC) vs. Crohn's disease (CD)], serologic markers may differentiate UC and CD, including perinuclear antineutrophilic cytoplasmic antibody (p-ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) in UC and CD. METHODS: One hundred forty-eight patients with IBD seen in a university gastroenterology practice in Houston, Texas, between June 1999 and November 2003 were analyzed to determine whether there were significant differences among racial/ethnic groups. Whites comprised 40%, African Americans 37%, Mexican Americans 20%, and Asians 3% of the total IBD patients. RESULTS: We found that African Americans and whites predominantly had CD, whereas Mexican Americans predominantly had UC. There was no difference between African Americans and Mexican Americans when separately compared to whites in terms of intestinal manifestations of CD and UC, respectively. However, African Americans with CD had a significantly higher incidence of IBD-associated arthritis (p= 0.004) and ophthalmological manifestations, notably uveitis (p= 0.028), compared to whites with CD. Among UC patients, in comparison to the Mexican Americans, whites had significantly higher incidences of joint symptoms (p < 0.0001) and osteoporosis (p= 0.001). Whites had a stronger family history of IBD and colorectal carcinoma compared to the other ethnic groups. p-ANCA served as a sensitive marker for UC among Mexican Americans. All the Mexican Americans with UC tested had positive p-ANCA compared to only 40% of whites (p= 0.033). CONCLUSION: There are significant differences in IBD subtypes and serologic markers among racial/ ethnic groups with IBD in the United States.

Anti-scl-70.

OBJECTIVE: To develop an overview focusing on the utility of anti-Scl-70 autoantibody determinations in the rheumatic diseases. METHODS: Articles from electronic literature searches were retrieved, critiqued and data were extracted and pooled on anti-Scl-70 (topoisomerase I) in relation to history, optimal tests used for its detection, sensitivity, specificity, positive and negative likelihood ratios, indications, interpretation and pitfalls. RESULTS: Anti-Scl 70 antibodies are very useful in distinguishing systemic sclerosis (SSc) patients from healthy controls, from patients with other connective tissue diseases, and from unaffected family members. Among patients with SSc, anti-Scl-70 positivity is useful in predicting those at higher risk for diffuse cutaneous involvement and interstitial fibrosis/restrictive lung disease, though the latter has not been universally observed. Of the four different techniques notably immunodiffusion, immunoblotting, immunoprecipitation and enzyme-linked immunosorbent assay (ELISA) used to assay anti-Scl-70, immunodiffusion has been the most extensively validated. ELISAs are somewhat less specific than other techniques, especially in distinguishing SSc patients from those with other rheumatic diseases, though newer generation ELISAs have been developed to overcome the problem of low specificity inherent with the traditional techniques. As of yet, the need for serial testing of anti-Scl-70 has not been established. CONCLUSIONS: Evidence-based guidelines suggest that anti-Scl-70 antibodies are very useful in the diagnosis and clinical management of SSc patients and also to establish prognosis in these patients, particularly those with diffuse skin involvement.