Category Archives: Transhuman News

AUGUSTA, Ga. (WJBF) Researchers at the Medical College of Georgia are finding promising results when using glycerin to treat psoriasis, an inflammatory condition in which cells build up and create dry, scaly patches on skin.

Dr. Wendy Bollag and her team have found glycerin stages a four-pronged attack against psoriasis.

It inhibits the growth and promotes maturation in skin cells, Bollag, a cell physiologist and skin researcher at the Medical College of Georgia and Charlie Norwood VA Medical Center, explains. It also shows when its converted to fat, it can inhibit inflammation. Even the glycerin itself tends to be good at decreasing oxidative stress, which is another byproduct of inflammation. It also seems to be good at helping to repair the barrier. It helps with the normalization of skin cells.

Glycerin is sold at pharmacies, and is an ingredient found in moisturizers and even sports drinks, according to Bollag. Her team found that when applied to skin topically, psoriasis symptoms were alleviated.

Its a moisturizer. It improves the barrier. It softens the skin. It helps get rid of skin cells that are piling up.

Because its a moisturizer, it tends to reduce the scaling that you tend to see with psoriasis, she adds.

Bollag suggests glycerin be mixed with water in a one-to-one ratio before it is applied onto effected areas of skin. If used daily, she says results can be seen within two weeks. However, Bollag admits this treatment may be best suited for mild cases of psoriasis. She suggests people with more severe cases use their prescribed medications and treatments to clear the psoriasis first, and then use glycerin to keep it from flaring up.

Go here to see the original:
MCG scientists see results treating psoriasis with glycerin - WJBF-TV

Clinically and statistically significant improvement in PASI-50 score achievedEDP1815 safety and tolerability data comparable to placebo in studyEDP1815 advancing towards registration studies in psoriasisManagement to host conference call at 8:00 a.m. ET

CAMBRIDGE, Mass., Sept. 27, 2021 (GLOBE NEWSWIRE) -- Evelo Biosciences, Inc. (Nasdaq:EVLO), a clinical stage biotechnology company developing SINTAX medicines as a new modality of orally delivered treatments for inflammatory disease, today announced positive data from its Phase 2 study evaluating EDP1815 versus placebo for the treatment of mild and moderate psoriasis. A statistically significant reduction in the Psoriasis Area and Severity Index (PASI) score, as measured by the proportion of patients achieving at least 50% improvement in PASI from baseline at the week 16 timepoint, was observed in the study. EDP1815 is an investigational oral biologic currently in development for the treatment of a broad range of inflammatory diseases, including clinical programs in psoriasis, atopic dermatitis, and COVID-19.

These clinical results represent a significant advancement for those who live with inflammatory disease. This is the first Phase 2 study to demonstrate that we can harness the small intestinal axis to make a clinical impact on patients with an oral product candidate with safety and tolerability data comparable to placebo, said Simba Gill, Chief Executive Officer of Evelo. Based on these data, we intend to advance EDP1815 towards registration studies in psoriasis. We look forward to discussing our proposed next steps with health and regulatory authorities. This milestone brings us one step closer to realizing our vision of transforming healthcare by developing broadly acting oral, safe, effective, and affordable medicines to address the unmet needs of hundreds of millions of patients who live with inflammatory diseases.

In the Phase 2 study, the PASI scores were assessed by both mean changes from baseline and responder rates. The primary endpoint was the mean percentage change in PASI between treatment and placebo and was prespecified as a Bayesian analysis. The Bayesian approach provides an estimate of the probability that EDP1815 is superior to placebo. The 16-week primary endpoint gave probabilities that EDP1815 is superior to placebo ranging from 80% to 90% across the prespecified analyses and cohorts.

Story continues

The responder endpoint reports the proportion of patients who had a meaningful clinical response, which is defined as PASI-50 or greater. 25% to 32% of patients across the three cohorts who were treated with EDP1815 achieved a PASI-50 at week 16 compared to 12% on placebo. In cohorts 1 and 2 this difference in response rate was statistically significant (p <0.05). Cohort 3 was directionally similar (25% vs. 12%). The pooled PASI-50 response across all three EDP1815 cohorts, an exploratory analysis, was 29% vs. 12% for placebo and was also statistically significant with a p-value of 0.027. An increase in the number of capsules of EDP1815 did not lead to a dose response.

Additionally, several patients on EDP1815 achieved a PASI-75 or better, which was sustained or improved post treatment. For individuals who had a PASI-50 response or better, consistent effects in secondary and exploratory endpoints, including improvements in patient reported outcomes such as Dermatology Life Quality Index (DLQI) and Psoriasis Symptom Inventory (PSI), were observed.

EDP1815 was observed to be well tolerated in the Phase 2 study. The safety data were comparable to placebo and consistent with what was previously reported in a Phase 1b study. Adverse events (AEs) classified as gastrointestinal were comparable between active and placebo groups, with no meaningful differences in rates of diarrhea, abdominal pain, nausea, or vomiting. There were no related serious adverse events.

I am very encouraged to see this Phase 2 data of EDP1815 in psoriasis, said Benjamin Ehst, M.D., Ph.D., Board-certified Dermatologist, Investigator and Clinical Associate Professor with the Oregon Medical Research Center, and Chief Investigator of EDP1815-201. It advances our scientific understanding of how to treat systemic inflammatory diseases and offers the prospect of a truly novel modality of treatment for patients with psoriasis. A drug with the combination of efficacy and safety results as observed here will likely be well received by dermatologists and their patients with mild and moderate disease, who are often faced with limited treatment options.

EDP1815-201 is a double-blind, placebo-controlled, dose-ranging Phase 2 study designed to evaluate three doses of an enteric capsule formulation of EDP1815 versus placebo in 249 patients with mild and moderate psoriasis over a 16-week treatment period. In the study, the PASI scores were assessed by both mean changes from baseline and responder rates. The primary endpoint is mean percentage reduction in PASI score at 16 weeks. Secondary endpoints include the proportion of study participants who achieve a PASI-50 response or greater and other clinical measures of disease such as Physicians Global Assessment (PGA), Body Surface Area (BSA), PGA x BSA, PSI, and DLQI. Todays results report out on the initial treatment phase of the study, which is now complete, and includes the 16-week treatment period with a 4-week follow-up. A six-month follow-up phase of the study is ongoing.

Conference CallEvelo will host a conference call and webcast at 8:00 a.m. ET today. To access the call please dial (866) 795-3242 (domestic) or (409) 937-8909 (international) and refer to conference ID 5177247. A live webcast of the event will also be available under News and Events in the Investors section of Evelo's website at http://ir.evelobio.com. The archived webcast will be available on Evelo's website approximately two hours after the completion of the event and will be available for 30 days following the call.

About PsoriasisPsoriasis is a common chronic immune-mediated inflammatory skin disease, affecting up to 3% of the population worldwide. The disease is driven by Th17-inflammation, which results in the formation of thick red plaques with scaling. Psoriatic lesions can appear anywhere on the body but are most often seen on the knees, elbows, scalp, and lumbar area. In addition to the skin lesions, there are systemic manifestations including arthritis and fatigue, and a strong association with depression and metabolic syndrome.

Patients with mild and moderate psoriasis are underserved by current treatments. Topical therapies do not control systemic inflammation, have low rates of compliance, and in the case of topical steroids are not recommended for long-term use. The majority of novel therapies, including injectable high-cost biologics, are only approved for patients with moderate and severe disease. Even in the severe patient population, the majority of eligible patients do not receive biologics, instead opting for topical therapies or oral systemic therapies, which are associated with tolerability issues and/or with monitoring requirements tied to safety concerns.

About Evelo BiosciencesEvelo Biosciences is a clinical stage biotechnology company developing orally delivered medicines that are designed to act on the small intestinal axis, SINTAX, with systemic therapeutic effects. SINTAX plays a central role in governing the immune, metabolic, and neurological systems. Evelos first product candidates are pharmaceutical preparations of single strains of microbes selected for their potential to offer defined pharmacological properties. Evelos therapies have the potential to be effective, safe, and affordable medicines to improve the lives of people with inflammatory diseases and cancer.

Evelo currently has four product candidates in development: EDP1815, EDP1867, and EDP2939 for the treatment of inflammatory diseases and EDP1908 for the treatment of cancer. Evelo is advancing additional product candidates in other disease areas.

For more information, please visit http://www.evelobio.com and engage with Evelo on LinkedIn.

Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including statements concerning the development of EDP1815, the promise and potential impact of EDP1815, the timing of and plans for clinical studies, and the timing and results of clinical study readouts.

These forward-looking statements are based on management's current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: the impact of the COVID-19 pandemic on our operations, including our preclinical studies and clinical studies, and the continuity of our business; that we have incurred significant losses, are not currently profitable and may never become profitable; our need for additional funding; our limited operating history; our unproven approach to therapeutic intervention; the lengthy, expensive, and uncertain process of clinical drug development, including potential delays in regulatory approval; our reliance on third parties and collaborators to expand our microbial library, conduct our clinical studies, manufacture our product candidates, and develop and commercialize our product candidates, if approved; our lack of experience in manufacturing, selling, marketing, and distributing our product candidates; failure to compete successfully against other drug companies; issues with the protection of our proprietary technology and the confidentiality of our trade secrets; potential lawsuits for, or claims of, infringement of third-party intellectual property or challenges to the ownership of our intellectual property; our patents being found invalid or unenforceable; risks associated with international operations; our ability to retain key personnel and to manage our growth; the potential volatility of our common stock; our managements and principal stockholders ability to control or significantly influence our business; costs and resources of operating as a public company; unfavorable or no analyst research or reports; and securities class action litigation against us.

These and other important factors discussed under the caption "Risk Factors" in our Quarterly Report on Form 10-Q for the three months ended June 30, 2021, and our other reports filed with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management's estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, except as required by law, we disclaim any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release.

ContactInvestors:Kendra Sweeney, 239-877-7474ksweeney@evelobio.com

Media:Jessica Cotrone, 978-760-5622jcotrone@evelobio.com

Read the original post:
Evelo Biosciences Announces Positive Phase 2 Clinical Data with EDP1815 in Psoriasis; Confirms Ability to Harness the Small Intestinal Axis, SINTAX,...

Psoriatic arthritis (PsA) is an inflammatory disease that leads to both pain and swelling in your joints. In most cases, people with PsA develop psoriasis first.

Overall, PsA in the hips is less common than other areas of the body. You might notice swelling and pain in smaller joints first, including your fingers and toes. In fact, its estimated that less than 10 percent of people with PsA will experience symptoms in the hips.

Still, if youre experiencing hip pain and also have certain risk factors for PsA, take note of your symptoms and obtain a diagnosis from a doctor. They can help recommend a combination of medications, natural remedies, and other therapies to help reduce underlying inflammation and improve your quality of life.

If you have PsA in the hips, you may experience symptoms on one or both sides (asymmetrical or symmetrical).

PsA in the hip may include the following symptoms in the affected area(s):

If you have PsA, you may notice these symptoms in other affected joints. Additional symptoms of PsA include:

PsA is an autoimmune condition that develops when your body mistakenly identifies healthy cells as invaders, thereby attacking them. Its also possible to have more than one autoimmune disease at once, such as IBD.

Psoriasis is linked to PsA, and many people with this skin disease go on to develop PsA, with some estimates citing a rate of 7 to 48 percent.

Its estimated that PsA can develop in some people 7 to 10 years afterpsoriasis begins. The mean age for the onset of PsA is 39 years old.

You may also be at an increased risk of developing PsA if you:

Like other types of autoimmune diseases, PsA is more common in adults, though anyone can develop it.

Diagnosing hip PsA may be challenging at first. This is because joint pain and swelling arent unique to PsA. These symptoms may also be seen in rheumatoid arthritis (RA), lupus, osteoarthritis (OA), ankylosing spondylitis, and conditions with inflammatory arthritis.

While you shouldnt self-diagnose PsA of the hip, there are some key signs that differentiate this condition from other types of arthritis. For example, hip PsA may cause pain around the buttocks, groin, and outer thigh, while hip OA primarily affects the groin and the frontof the thigh.

Other conditions that can lead to hip pain may include muscle strains and stress fractures. A dislocated hip may occur from a recent accident or injury.

A doctor can help you determine whether your hip pain is attributed to PsA, another autoimmune disease, or a different condition entirely. They may also refer you to a rheumatologist, a specialist trained in diagnosing and treating autoimmune diseases of the joints, bones, and muscles.

While theres no single test to diagnose PsA, a healthcare professional may help identify this condition based on the following criteria:

Theres currently no cure for PsA. Instead, the condition is largely managed with both lifestyle changes and medications. Depending on the extent of pain and inflammation in your hip joints, your doctor may also recommend therapies or surgery.

If your hip pain is significantly impacting your overall quality of life, your doctor may recommend either over-the-counter (OTC) or prescription pain medications to help you manage your symptoms.

Possible medication options for hip PsA may include:

Other medications may also reduce underlying inflammation thats causing your hip pain. These types of medications are called disease-modifying antirheumatic drugs (DMARDs). Along with reducing inflammation, DMARDs can help prevent PsA from progressing.

While theres no natural cure for PsA, there are natural remedies and lifestyle habits that may help alleviate pain, decrease inflammation, and complement your medications. Consider talking with your doctor about:

Your doctor may recommend physical therapy as a complement to medications and natural remedies for PsA. The goal of physical therapy is to help you move better with PsA in the hip, the focus is to help increase your range of motion so you can walk more comfortably.

Each physical therapy program is tailored to the individual, but can include the following:

Surgery may be an option for severe PsA in the hip that isnt responding to other treatment measures. Your doctor might recommend a hip arthroplasty, also known as a total hip replacement.

A hip replacement is considered a major surgery, so your doctor will determine if youre a candidate based on the severity of PsA, along with your age and overall health.

There are numerous causes of hip pain, including PsA. You may be at an increased risk for developing PsA in the hips if you have certain risk factors such as psoriasis. Its important not to self-diagnose this condition so that you arent treating the wrong issue.

Even if your hip pain is notcaused by PsA, its still important to get a correct diagnosis as soon as possible. Letting diseases or injuries of the hip go can worsen your symptoms, and perhaps even affect your long-term mobility.

Go here to see the original:
Psoriatic Arthritis Hip Pain: Symptoms, Causes, and Treatments - Healthline

At UCB, we believe that collaborating with physicians, researchers and patients is fundamental to addressing the unmet needs of people living with immuno-dermatological diseases, such as psoriasis. We recognize that there is potential to improve the lives of people with psoriasis and we're looking forward to discussing the latest scientific advancements in this field with the dermatology community at the virtual European Academy of Dermatology and Venereology (EADV) Congress, taking place from 29 September - 2 October 2021. Now in its 30th year, the EADV Congress 2021 will bring together leading clinical experts across the fields of dermatology and venereology in a celebration of outstanding data and scientific exchange.

At this year's EADV Congress, we will be sharing the latest findings from our ongoing research in dermatology across 13 e-posters and one platform presentation. Attending healthcare professionals will also be able to virtually join five UCB-sponsored educational meetings, including our satellite symposium, and hear about the newest approaches and advances in psoriasis care from world-leading experts in dermatology. Following the congress close, delegates will also have virtual access to these meetings and sessions up until the end of the year.

We are proud to be sponsors of this year's EADV Congress. Platforms such as EADV 2021, which allow us to further our understanding of immuno-dermatological diseases like psoriasis remain as important as ever - particularly when we consider the impact these conditions continue to have on the lives of patients. Psoriasis affects approximately 125 million people worldwide and is a life-long condition, for which there is no cure. Much more than 'just a skin condition', psoriasis has been shown to have a profoundly detrimental impact on a person's quality of life. UCB's approach - from discovery to development to delivery - is designed around patient needs and their journey, we therefore remain determined to better understand the impact of immuno-dermatological conditions such as psoriasis, to help find solutions that allow patients to live life to the fullest.

EADV 2021 promises to be an outstanding educational learning experience with stimulating sessions, late-breaking science and an opportunity to connect with experts in dermato-venereology. We're ready to shine a light on how we are advancing care for people living with psoriasis and to be inspired by other groundbreaking work from our colleagues in the dermatology community. If you are a healthcare professional attending EADV 2021, we look forward to welcoming you to the UCB virtual booth and at our educational sessions.

Disclaimer

UCB SA published this content on 27 September 2021 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 27 September 2021 09:51:04 UTC.

The rest is here:
EADV 2021: Shining a light on the latest science in dermatology - marketscreener.com

When Amgen bought marketing rights to psoriasis pill Otezla for $13.4 billion two years ago, the company was likely counting on not having to compete against early generics. And now, thanks to a win in court, Amgen appears poised to enjoy several more years of exclusivity in the key U.S. market.

After facing legal challenges from generics makers Sandoz and Zydus Pharmaceuticals, Amgen's patent portfolio on the blockbuster medicine has held up in court. With the win and pending potential appeals, Amgen's drug should be free from having to face those competitors until early 2028.

Before the trial, Novartis' Sandoz unit admitted that its Otezla generic infringed a range of patents that expire between 2023 and 2034. For its part, Zydus admitted that its copycat infringes some of the same patents but not a key one that expires in 2023.

With that, the trial was centered on the issue of whether Zyduss generic infringes a 2023 patent, Amgen said Tuesday. After reviewing the arguments, the U.S. District Court for the District of New Jersey upheld four patents but ruled against Amgen on some claims in a 2034 patent.

RELATED: Amgen's psoriasis pill Otezla thrives amid pandemic against injectable rivals

Thats a big win for the branded drugmaker, which picked up Otezla from Celgene before that company sold to Bristol Myers Squibb in 2019s largest biopharma M&A deal.

Still, a Novartis spokesperson said Sandoz is "pleased" with the ruling as it "held as invalid a key 2034-expiring Amgen patent covering specific dosage regimens for treating psoriasis" with the drug. The ruling "enables Sandoz to launch our generic apremilast product in the US in 2028, 6 years prior to the expiry date of the latest-expiring Amgen patent asserted in litigation," Novartis' spokesperson said.

Since taking over Otezla marketing, Amgen has generated some hefty sales with its new med. Thanks to the drugs oral mode of delivery, it has succeeded against injectable rivals during the pandemic. During a conference call last summer, Amgens executive vice president of global commercial operations Murdo Gordon said that more patients started on the medicine during the first few months of the pandemic than those who started on Otezlas psoriasis rivals. That came despite the fact that COVID-19 caused a decline in new patient starts across the treatment class.

Overall for 2020, the drug generated $2.2 billion. In the first half of the 2021, sales declined 5% in part thanks to lower prices, but the drug continued to maintain first-line share leadership in psoriasis, the company said.

RELATED: Under-pressure Amgen insists Otezla can withstand Bristol Myers' forthcoming psoriasis rival

While it appears Amgen won't have to worry about generics right away, the company's key med could face forthcoming competition from Bristol Myers Squibb's TYK2 inhibitor deucravacitinib, an oral med that has outperformed Otezla in head-to-head trials. Even amid that potential competition, Amgen and analysts believe the company can still succeed in mild to moderate patients.

Editor's note: This story was updated with a statement from Novartis.

Read more:
Amgen scores Otezla patent win, protecting its blockbuster from Sandoz and Zydus generics until 2028 - FiercePharma

A biosimilar is a biologic medical product that is similar to another already approved biological medicine, in terms of quality, safety, and efficacy. Biosimilars are a class of therapeutic drugs that provide additional treatment options and help reduce healthcare costs. Thus, there is an increasing demand for biosimilar drugs due to increasing prevalence of autoimmune diseases, key factor driving the growth of the biosimilars market. According to the National Stem Cell Foundation (NSCF), around 4% of the worlds population is affected by one of more than 80 different autoimmune diseases, the most common of which include multiple sclerosis, type 1 diabetes, scleroderma, Crohns disease, lupus, psoriasis and. rheumatoid arthritis.

Request Here For PDF Brochure @ https://www.coherentmarketinsights.com/insight/request-pdf/750

Autoimmune diseases are a family of more than 80 chronic, often debilitating and, in some cases, life-threatening illnesses. Moreover, growth of the biosimilars market is being driven by the increasing research and development and speedy approvals of biosimilars, especially in the North America. For instance, in 2019, the United States Food and Drug Administration (FDA) approved Amgens AVSOLA (infliximab-axxq), for all approved indications of the reference product, Remicade (infliximab), for the treatment of rheumatoid arthritis, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, Crohns Disease, and chronic severe plaque psoriasis. However, stringent regulations and manufacturing complications are major factors expected to restrain the biosimilars market growth.

Furthermore, the biosimilar market, in Europe, is witnessing robust growth due to the growing adoption of biosimilars due low price and rapid entry of biosimilars in the region. For instance, in 2018, European Commission (EC) approved Sandozs Zessly, a biosimilar for use in Europe, confirming that Zessly matches safety, efficacy, and quality of reference medicine. Zessly is approved for the treatment of adult and pediatric Crohns disease, adult and pediatric ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis. However, the adoption rate varies from country to country, always associated with regulatory and market access issues. This in turn is also expected to hamper the biosimilars market growth.

Growth of the biosimilars market can also be attributed to rich pipeline of biosimilar products and expiry/termination of existing drugs. As of June 2020, FDA has approved 27 biosimilars, plus four follow-on biologicals. The pipeline for biosimilars continues to grow, however, of the 27 approved biosimilars, only 17 have been launched so far. Biosimilars on average can cost 30% less than reference biologicals. Thus, pharmaceutical and biotechnology companies are focusing on developing safe and effective biosimilars, because a small variations in the manufacturing process can potentially alter the medicines safety and efficacy.

Major Key Players Include In Biosimilars Market: Novartis AG, Pfizer, Inc., Teva Pharmaceutical Industries Ltd., Celltrion Healthcare Co., Ltd., Biocon Limited, Amgen, Inc., Dr. Reddys Laboratories, and Sanofi S.A.

Main points in Biosimilars Market Report Table of Content

Chapter 1 Industry Overview1.1 Definition1.2 Assumptions1.3 Research Scope1.4 Market Analysis by Regions1.5 Biosimilars Market Size Analysis from 2021 to 202711.6 COVID-19 Outbreak: Biosimilars Industry Impact

Chapter 2 Global Biosimilars Competition by Types, Applications, and Top Regions and Countries2.1 Global Biosimilars (Volume and Value) by Type2.3 Global Biosimilars (Volume and Value) by Regions

Chapter 3 Production Market Analysis3.1 Global Production Market Analysis3.2 Regional Production Market Analysis

Chapter 4 Global Biosimilars Sales, Consumption, Export, Import by Regions (2016-2021)Chapter 5 North America Biosimilars Market AnalysisChapter 6 East Asia Biosimilars Market AnalysisChapter 7 Europe Biosimilars Market AnalysisChapter 8 South Asia Biosimilars Market AnalysisChapter 9 Southeast Asia Biosimilars Market AnalysisChapter 10 Middle East Biosimilars Market AnalysisChapter 11 Africa Biosimilars Market AnalysisChapter 12 Oceania Biosimilars Market AnalysisChapter 13 South America Biosimilars Market AnalysisChapter 14 Company Profiles and Key Figures in Biosimilars BusinessChapter 15 Global Biosimilars Market Forecast (2021-2027)Chapter 16 ConclusionsResearch Methodology

Continued.

Buy instant copy of this research report with Flat US $ 2000 Off@ https://www.coherentmarketinsights.com/promo/buynow/750

About Coherent Market Insights:

Coherent Market Insights is a prominent market research and consulting firm offering action-ready syndicated research reports, custom market analysis, consulting services, and competitive analysis through various recommendations related to emerging market trends, technologies, and potential absolute dollar opportunity.

Contact Us

Mr. ShahCoherent Market Insights1001 4th Ave, #3200Seattle, WA 98154Phone: US +12067016702 / UK +4402081334027Email: sales@coherentmarketinsights.com

Link:
Biosimilars Market, will grow at 35.2% CAGR, to be valued at US$ 70 Billion by 2027: Impact of COVID - PharmiWeb.com

Introduction

Connective tissue disease (CTD) is a histopathological concept proposed by the American pathologist Paul Klemperer in 1942.1 It is used to describe acute or chronic diseases characterized by abnormalities including diffuse denaturation of the connective tissue (dermis, ligament, tendon, bone, cartilage), particularly extracellular components, such as collagen. Currently, six diseases including rheumatic fever, rheumatoid arthritis (RA), polyarteritis nodosa, systemic lupus erythematosus, systemic scleroderma and dermatomyositis are termed classic CTDs.2,3 CTD is a clinical diagnosis term for a single disease group with similar histopathological characteristic but not similar etiologies or genetics.46 In the current classification, several CTD-related intractable-disease (CTD-IDs) other than classic CTDs have been proposed including polymyositis, mixed CTD, Sjogrens syndrome, vasculitis syndrome, juvenile idiopathic arthritis, adult Stills disease (ASD), Behcets disease (BD), and anti-phospholipid syndrome.79

Biological therapeutics are commonly used for the treatment of immunological disease and malignancy, because they are high effective compared with conventional treatments using small molecules.10 High polymer preparations, termed biological therapeutics, which block cytokines are used to treat CTD and rheumatic disease whereas molecules targets are required for the treatment of malignant tumor.10 First, rituximab was approved for the treatment of malignant lymphoma, resulting in a breakthrough for blood disorders.11 Infliximab has been used to treat Crohns disease and RA.12 Researchers predicted RA symptoms could be improved by blocking inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-1, because these cytokines were strongly related to the pathophysiology in RA. Then, biological therapeutics for BD, vasculitis, psoriatic arthritis (PsA), ankylosing spondylitis (AS), and systemic lupus erythematosus were developed and recommended by medical treatment guidelines for the treatment of each disease.1316

In the field of medicine, biological therapeutics consist of proteins as well as insulin, immunoglobulin (Ig) preparations, and vaccines. However, in the field of CTD and CTD-ID, biological therapeutics describe drugs that inhibit the production or function of cytokines or kill specific lymphocyte populations. Biological therapeutics include monoclonal antibodies and protein fusion preparation (receptor molecules). In general, monoclonal antibodies destroy cytokine- or antibody-producing cells by the binding to a cell surface receptor or target antigen. Receptor molecules, also called decoy molecules, are fused to a receptor that binds to IgG, which prevents the binding of the target (eg, cytokine) to its receptor.17 The first monoclonal antibody preparations were from mice, but their immunogenicity prevented their long-term use for clinical applications. To reduce immunogenicity, chimeric model antibodies, humanized antibodies, and human antibodies were developed. Human antibodies encoded by human antibody gene contain no mouse molecules (Figure 1). In this review, we discuss the current situation of biological therapeutics for CTD-IDs including BD, PsA, AS, anti-neutrophil cytoplasmic antibody (ANCA)-related arthritis, and ASD, as well as the choice of biological therapeutics for clinical practice.

Figure 1 Three types of therapeutic immunoglobulins. (A) Human antibody; (B) Humanized antibody; (C) Chimeric model antibody Immunoglobulins consist of a complementarity determining region, variable site, and constant region.

BD is characterized by inflammation of the skin, mucous membranes, and uvea.18 Uveitis, particularly posterior uveitis, rarely causes altitude inflammation, which leads to blindness.8,18 Intestinal, vascular, and nervous BD often affect the disease prognosis.18 The pathogenesis of BD is related to TNF.19 T cells in BD patients respond to a small amount of staphylococcal exotoxins and produce cytokines.20 Two anti-TNF monoclonal antibodies (infliximab and adalimumab) have been adapted for BD treatment and infliximab has been approved for all types of BD. It is necessary to administer a combination therapy of methotrexate (MTX) and infliximab in RA patients because of the influence of anti-infliximab antibody production. However, this combination with MTX is unnecessary in BD patients. Furthermore, the addition of MTX does not provide benefit compared with infliximab treatment alone. However, when an immunosuppressant was used with adalimumab it was reported that there might be the clearance drop of adalimumab by combination with MTX and uses it together and warns us. The frequency of uveitis is related to blindness. Therefore, for the treatment of BD uveitis, it is important to control eye inflammation. The whole-body dosage of glucocorticoids improves symptoms related to BD, but the long-term control of BD is unknown. Oral immunized suppressants to treat uveitis have been superseded by infliximab. The 2018 EULAR Recommendations for BD indicate infliximab as a first-choice treatment for ophthalmitis although there is concern regarding its functional decline over time.21 Adalimumab is not approved for BD uveitis because no related clinical studies were initiated at the time of development.22,23 However, some studies have reported adalimumab suppressed uveitis in BD.24,25

Intestinal type BD often forms an ulcer in the ileocecum as well as the gastrointestinal tract but rarely causes perforation. It accounts for 1520% of all BD cases and usually requires surgery. Intestinal type BD is treated with GCs and 5-aminosalicylic acid or salazosulfasalazine according to the therapeutic guidelines for inflammatory bowel disease. However, the long-term use GC causes complications including perforation caused by a delay in wound healing. Infliximab and adalimumab are effective in patients who are resistant to GCs and 5-aminosalicylic acid or salazosulfasalazine.2628 In addition, adalimumab and infliximab were highly effective in clinical trials of cases with a typical ulcer 1 cm in diameter in the ileocecum where GCs or immunosuppressants were not effective part.26,29 However, TNF inhibitor treatment is unsuccessful in approximately 20% of patients.

Nervous type BD can be classified as an acute model/ANB (acute neurological attacks in BD) and chronic progressive/CPNB (chronic progressive neurological BD). Both types require treatment because they reduce the quality of life for patients. Infliximab has been used in a model of nervous BD, but evidence is lacking for its use in multi-cases. Conventional treatment consisting of GCs and pulse therapy is used for the induction of remission in ANB. However, the effects of infliximab on attack prevention have only been reported for backward cohorts and cases.30 MTX generally improved convalescence in CPN,31 and infliximab was effective in cases where MTX was ineffective.32

Vascular type BD describes numerous diseases that can develop in a single patient related to lesions of the vein and artery system. Genuine and false aneurysms appear in arteries and clot formation occurs in veins. The symptoms of vascular type BD are likely to be worsened by stimulation, similar to intestinal tract type BD. In addition, in this type BD, false aneurysms occur in blood vessel anastomotic regions after aneurysms are substituted with artificial blood vessels, making it difficult to treat. The use of glucocorticoids or immunosuppressants for vascular lesions in BD has been recommended by EULAR, although robust evidence for their effects is lacking.33,34 Anti-TNF preparations (infliximab and adalimumab) were reported to be effective in cases resistant to glucocorticoids or immunosuppressants.35,36 Anti-TNF preparations are often used in intractable cases and those requiring surgical management, such as those with intestinal tract type BD. Discontinuation studies in RA and the dosage period of biological therapeutics have been reported, but there is no clear evidence for discontinuation in BD. However, remission was maintained without uveitis for one year even when substitute treatments, such as immunosuppressants were used in cases that could not continue infliximab.37

PsA is broadly classified as a form of vertebral pain (spondyloarthritis: SpA). There is often a peripheral phenotype in which patients symptoms mainly comprise synovium inflammation similar to that in RA. However, some cases exhibit body axis characteristics symptoms, and these cases are difficult to identify with AS in X-ray views. In addition, dactylitis that shows enthesitis and swelling in all fingers and toes has various joint symptoms. Body axis-related joint symptom is stronger in inflammation of the ligament than in synovium, and hardening lesions resulting from the ossification of the ligament is the primary problem, rather than bone destruction. Body axis-related joint lesions were reported in 2570% of cases.38 It is important to know which cytokines are related to joint symptoms because the recommended drugs differ for peripheral joint pain, body axis-related joint pain, enthesitis, and dactylitis in PsA.39,40

It was previously reported that cyclosporine was effective for treating skin lesions in patients with psoriasis when psoriasis patient incorporated the examination to check the effectiveness of cyclosporine for RA.41 Another report suggested that T cell-related immunity (T helper (Th)1 reactions) participated in the skin symptom of psoriasis patient. Then, IL-17 and IL-22 were shown to be involved in psoriasis lesions, indicating Th17 cells were also involved.42,43 IL-12 produced by dendritic cells is important for the differentiation of Th1. In addition, IL-23 produced by dendritic cells increases and maintains IL-17 cells. IL-12 and IL-23 form a heterodimer comprising a subunit of p35/p40 and p19/p40, respectively. p40 is the subunit common to IL-12 and IL-23. The expression of p40, but not p35, was increased in the skin lesions of psoriasis patients,44 and IL-17 and IL-22 (Th17-related molecules) in psoriasis skin lesions were related to treatments, such as etanercept and cyclosporine.40,45 In addition, psoriasis-like exanthem and expression of IL-17A occurred when IL-23 was injected to the skin of mice.46 It is thought that Th17 cells contribute more significantly to skin lesion compared with Th1 cells. As for TNF, it turns out that it is involved in the condition of patients dendritic cells, Th17, and epidermal cornification cells, both situations broadly. Although PsA exhibits various joint symptoms, the cytokines involved might vary according to the symptoms. The participation of TNF is strongly suggested in peripheral arthritis, because TNF inhibitors suppressed inflammation in peripheral joint pain in RA and prevent joint destruction. However, local cells in tissues produce IL-23, IL-17 and IL-22, which might participate in enthesitis.47,48 Previous studies reported enthesitis was IL-17A-dependent in animal models.47,49 Enthesitis might have a similar cytokine profile to skin lesions in psoriasis, because T cells in the human vertebral column spinous process produce IL-17A by an IL-23-independent mechanism.50

The priority of biological therapeutics for the treatment of joint symptoms of PsA is shown in Table 1. TNF inhibitors have the best efficacy against peripheral joint pain. The IL-17A inhibitor has a superior effect to the IL-12/23p40 inhibitor, but similar efficacy to TNF inhibitor.5153 However, the effects of brodalumab, an IL-17 receptor A inhibitor, on preventing joint destruction are unclear.54 In addition, guselkumab, an IL-12/23p19 inhibitor, is superior to IL-12/23p40 inhibitors for the improvement of clinical joint, and has similar efficacy to TNF inhibitors and the IL-17 inhibitor.55 Although the benefit of IL-12/23p40 for peripheral joint pain is unclear, improvements in joint pain and joint destruction were significant compared with placebo in a clinical study.56,57 In addition, an IL-12/23p40 inhibitor significantly improved enthesitis compared with a TNF inhibitor,58 and had benefit for dactylitis. In addition, a high percentage of cases continue ustekinumab treatment because it has very low accumulation rate, which reduces the potential for harmful phenomena.58 TNF inhibitors and anti-IL-17 biological therapeutics are considered first choice for the treatment of axis-related joint pain. The EULAR recommendations suggest TNF inhibitors are the first choice for treatment, but IL-17A inhibitors are also recommended as first choice in some cases.59 IL-17A inhibitors were superior regarding the rapidity of effect and reducing disease severity in psoriasis exanthem, similar to TNF inhibitors. However, IL-17A inhibitors should be used with caution for inflammatory bowel disease, because IL-17A is necessary for maintenance of the enterobacterial flora.

Table 1 Priority of Biological Therapeutics for the Treatment of Joint Symptoms of PsA

AS, a chronic inflammatory disease that develops at a young age, is characterized by ankylosis observed in sacroiliac joint by imaging. Furthermore, lesions occur along the vertebral column from the upper part to the lower part, finally causing total ankylosis of the vertebral column. The classification standard (revision New York standard) comprises clinical and X-ray imaging.60 Without a specific spot that meets the criteria of more than grade 3 on one side and more than grade 2 on both sides in sacroiliac joint with X-rays, we cannot make a diagnostic decision. This was the classification standard in 1984 and only non-steroidal anti-inflammatory drugs (NSAID) were available, which did not alter the disease course.60 Currently, TNF inhibitors are administered, which markedly improve symptoms leading to an early cure. The Assessment of Spondyloarthritis International Society (ASAS) classified axial spondyloarthritis (axSpA) in 2009.61 Although the main disease of this classification is AS, it includes axSpA, which is not present in the revised New York standard of AS. Actually, axSpA, which meets the x-ray standard, almost matches AS according to the revised New York standard.62 However, non-axSpA does not necessary occur in early AS.63,64 AS is characterized by negative CRP, and non-axSpA tends to have negative or low CRP values. Therefore, inflammation assessed by magnetic resonance imaging is likely to be low.65 Because the ASAS standard includes diseases other than AS, we should carefully consider the diagnosis. However, the ASAS standard is very useful for the diagnosis of AS.

TNF, IL-17A and IL-23 are increased in patient with AS.6668 It is thought that TNF is important at the final stage of inflammation, and many studies have reported that TNF inhibitors are effective for AS. It is thought that IL-17A participates in the maintenance of chronic inflammation related to TNF receptor signaling and IL-23 participates in the differentiation and IL-17 production of Th17 cells.69 TNF inhibitors and IL-17 inhibitors are effective in AS. However, when AS was treated with TNF inhibitors, serum IL-17A levels unchanged regardless of the treatment effect.70,71 Therefore, IL-17 inhibitors might be used for patients who derive no benefit from TNF inhibitors.72 In addition, IL-17 inhibitors have similar efficacy to TNF inhibitors in active AS patients without biological therapeutics.73 These results suggest IL-17A participates uniquely in the pathophysiology of AS. Although IL-23/p19 or IL-23/p40 inhibitors did not show a statistically significant improvement, they were effective in patients with AS.74,75 From this, although PsA and As are related diseases, the role of IL23 in enthesitis is different between these diseases.

MTX has not been confirmed for sacroiliac joint and the vertebral column, the central lesions in AS and non-axSpA. Salazosulfasalazine is validated only for peripheral joints when accompanied by peripheral joint pain.76 Therefore, TNF inhibitors or IL-17 inhibitors are used when NSAIDs can be used and BASDAI score is greater than 4. Recommendations by ACR, Spondylitis Association of America (SAA) and Spondyloarthritis Research and Treatment Network (SPARTAN) were updated in 2019.77 The first-line drug is usually a TNF inhibitor. Uveitis in the front of the eye is detected in about 1/3 of AS cases. Therefore, in such cases, TNF inhibitors should be given priority. TNF and IL-17 inhibitors are highly effective when lesions are evaluated clinically by BASDAI, but their effects on suppressing bone lesion progress are unclear. This is because no system to evaluate bone lesions in AS patients has been established compared with RA and PsA patients. However, the possibility has been suggested that TNF inhibitor and IL-17 inhibitor allow for gentle and quiet long-term incorruptibility.78 In addition, one report indicated the possibility that bone deterioration was inhibited after 2 years of secukinumab treatment.79 Therefore, we anticipate the results of analyses of other examples of this treatment over longer periods. At present, it is not recommended to discontinue or reduce TNF inhibitors or IL-17 inhibitor use, even if disease activity has slowed according to evaluations such as BASDAI.

Vasculitis syndrome is classified according to the size of affected blood vessel by the Chapel Hill Consensus Conference (CHCC) classification (CHCC, 2012).80 The classification of small vasculitis in CHCC 2012 are an immune complex type and an ANCA-related vasculitis type. The former type comprises anti-glomerular basement membrane antibody disease, IgA vasculitis, and cryoglobulinemia-related vasculitis. ANCA-related vasculitis includes microscopic polyangiitis (MPA), polyangiitis-related granulation tissue class symptom (granulomatosis with polyangiitis (GPA) or Wegener granulomatosis), and eosinophil- and polyangiitis-related granulation tissue class symptom (eosinophilic granulomatosis with polyangiitis (EGPA), Churg-Strauss syndrome, or allergic granulomatous vasculitis).80 MPA and GPA require similar therapeutic strategies although they are different diseases.

The pathogenesis of MPA and GPA is thought to involve neutrophil extracellular traps (NETs) released from ANCA-activating neutrophil, which affect endothelial cells via inflammatory cytokines.81,82 EGPA is different from MPA and GPA because it is an eosinophil-related tissue disorder. In EGPA, Th1/17 cells participate in granuloma formation, TRh2 produce IL-4, IL-5, and IL-13, and B cells secrete IgE and ANCA. IL-5 activates eosinophil, which causes the tissue disorder. Anti-IL-5 biological therapeutics is used for the treatment of EGPA and anti-B-cell therapy is used for MPA and GPA.

Rituximab is a monoclonal antibody that recognizes CD20 expressed on the surface of B-cells. After binding to CD20, rituximab kills B-cells by antibody-dependent cellular cytotoxicity. Rituximab is covered by health insurance for the treatment of MPA and GPA in Europe and the USA.8385 However, GCs plus rituximab is positioned as an alternative to GCs plus cyclophosphamide treatment for MPA and GPA. In MPA and GPA, rapidly progressive glomerulonephritis is often complicated as an organ disorder, and clinicians often hesitate to use GCs plus rituximab because cyclophosphamide used in standard regimen can affect liver function test outcomes. However, because there is no need for weight loss, and rituximab used in limited quantities does not cause renal failure, there are many clinical situations where its use is appropriate.

Mepolizumab, a monoclonal antibody that recognizes IL-5, is covered by health insurance for the treatment of severe bronchial asthma. This drug has a strong eosinophilic suppressive effect mediated by IL-5 inhibition and is covered by health insurance for the treatment of EGPA.86 GCs are a first-line drug for the treatment of EGPA, but not MPA and GPA, because not many cases require immunosuppression in the early stages of disease. Mepolizumab can achieve rapid drug weight loss of GCs compared with placebo and can achieve longer-term remission maintenance.86 The use of mepolizumab is considered in cases where the use of GCs or immunosuppressants is difficult because of the occurrence of side effects.

ASD is not an autoimmune disease because it lacks autoreactive T-cells and autoantibodies. Its pathogenesis involves the activation of monocytes/macrophages and the production of inflammatory cytokines. Therefore, ASD is classified as a CTD-ID, but it is considered an autoinflammatory disease.87 IL-6, IL-18, and TNF are present at high levels in patients with ASD, although many cytokines have been reported.87,88 The characteristics of ASD include high levels of ferritin and IL-18. In ASD, increased IL-18 is related to fever, joint pain, and skin symptoms, which are normalized by GC treatment.89 In addition, IL-6 located downstream to IL-18 might be increased or decreased in ASD.90

Regarding biological therapeutics for ASD, TNF, IL-1, and IL-6 inhibitors have shown benefit. A meta-analysis of clinical studies reported the IL-1 inhibitor, anakinra, improved the remission rate and GC-induced weight loss.91 In addition, another IL-1 inhibitor, canakinumab, improved juvenile idiopathic arthritis similar to ASD in a clinical trial.92 A TNF inhibitor was also effective for ASD in a forward open clinical study.93 Furthermore, Kaneko et al94 reported that tocilizumab had a high remission rate for ASD compared with placebo in a double-blind study. Based on these studies, tocilizumab was approved for ASD.

The condition of patients requiring a prescription of life convalescence of ASD includes macrophage activation syndrome (MAS). MAS defines the prognosis of ASD. Although there is no specific treatment for ASD, an adaptation of tocilizumab treatment can cause MAS. It is assumed that MAS develops in patients where ASD that the effect is insufficient by existing treatment, which is an adaptation of tocilizumab. Therefore, it is necessary to consider MAS development after tocilizumab treatment or the use of TNF or IL-1 inhibitors.9597 However, it is reported that a clear cause-effect between the tocilizumab dosage and MAS onset could not be found from the results of analyzed cases which MAS developed after administration of tocilizumab for juvenile idiopathic arthritis resembling ASD.98 Pathology resembling cytokine storm might cause MAS. Therefore, biological therapeutics might cause changes in the cytokine cascade and trigger MAS onset. Therefore, it is necessary to consider the usefulness of tocilizumab against ASD patient developing MAS.

The cost of biological therapeutics per patient with RA is approximately 100 times the costs of treatment with a combination of conventional disease-modifying antirheumatic drugs (DMARD). Graudal et al99 reported a meta-analysis of randomized trials of combination therapy with and without TNF inhibitors in RA. They concluded the RA guidelines should recommend combination treatment before the initiation of TNF inhibitors. The effect of combination therapy including biological therapeutics was also reported in patients with CTD-ID.100,101

AS is a chronic and inflammatory disease, and the management of this disease consists of pharmacological and nonpharmacological modalities. Until recently, pharmacological treatment options have been very limited. However, as mentioned earlier, the development of novel biological therapeutics has revolutionized the management of this disease. In addition, the usefulness of combination therapy with TNF inhibitor and NSAID and DMARD was also reported.102104

Skin and joint manifestations associated with psoriasis and PsA can significantly impact a patients quality of life. Successful treatment is imperative to improve the signs and symptoms of disease. For patients with moderate to severe active PsA, combination therapy with methotrexate and TNF inhibitors is considered first-line treatment.105 These new therapeutic concepts for PsA include a high efficacy of combination therapy in those unable to tolerate or who have failed TNF inhibitor treatment.106

Relapsing ocular involvement is a major manifestations of BD and occurs in 6080% of patients, resulting in retinal vasculitis, neuropathy or panuveitis.107 TNF inhibitors are effective and safe in these patients, especially regarding its corticosteroid- and immunosuppressive drug-sparing effects.108

Biological therapeutics are more expensive compared with small molecule drugs, such as JAK inhibitors. Drug costs are more likely to be reduced if generics, such as JAK inhibitors are available.109111 Depending on the disease, this approach is likely to become more mainstream. However, autoimmune or self-inflammatory disease have an abnormal cytokine production indicating the potential benefit of biological therapeutics. The recent marketed recycling antibodies are the preparation which was developed so that antibody preparation binds to the antigen repeatedly in vivo.112 It is thought that even if it leads to such a technique reducing the dosage number of times of biological therapeutics, it becomes useful in economic aspect.

Cytokines, such as IL-6, have pleiotropic effects and promote various effects in numerous cell types. Cytokines also have overlapping and sometimes redundant effects. Therefore, even if the effects of a specific cytokine are completely blocked, similar effects can be mediated by another cytokine. This might explain why some cases treated with biological therapeutics show no beneficial effect and the blocking a specific cytokine does not always cause serious side effect.

When disease activity is controlled by biological therapeutics, autoimmune diseases can sometimes occur. For example, psoriasis exanthema develops during treatment for RA or BD, a phenomenon termed paradoxical reaction, which is thought to be caused by the overlapping functions of cytokines. When the activity of a disease is inhibited by blocking a specific cytokine, levels of another cytokine are thought to be increased in vivo leading to the induction of autoimmune disease. An example is the onset of MAS by tocilizumab treatment for ASD.

The biological therapeutics contributes to greatly improving convalescence around RA. Other CTD are also experiencing the calming of the disease activity by the development of new biological therapeutics and adaptation expansion of such drugs. In this review, we addressed the current situation of biological therapeutics for CTD-ID including Behcet's disease, psoriatic arthritis, ankylosing spondylitis, anti-neutrophil cytoplasmic antibody-related arthritis, and adult Stills disease, as well as the choice of biological therapeutics in the clinical practice. Further developing biological therapeutics is expected in the scleroderma and the inflammation of muscle-related disease that there remained it.

This review was supported in part by grants (15K08657 and 19K07948 to S.N.) from the Ministry of Education, Culture, Science and Technology of Japan. We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

The authors declare no conflicts of interests regarding the publication of this article.

1. Klemperer P, Pollack AD, Baehr G. Diffuse collagen disease: acute disseminated lupus erythematosus and diffuse scleroderma. JAMA. 1942;119(4):331332. doi:10.1001/jama.1942.02830210023006

2. Mosca M, Tani C, Vagnani S, et al. The diagnosis and classification of undifferentiated connective tissue diseases. J Autoimmun. 2014;4849:5052. doi:10.1016/j.jaut.2014.01.019

3. Fernandez AP. Connective tissue disease: current concepts. Dermatol Clin. 2019;37(1):3748. doi:10.1016/j.det.2018.07.006

4. Kunkel HG, Tan EM. Autoantibodies and disease. Adv Immunol. 1964;27:351395. doi:10.1016/s00658-2776(08)60711-7

5. Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972;52(2):148159. doi:10.1016/0002-9343(72)90064-2

6. Stefanski AL, Tomiak C, Pleyer U, et al. The diagnosis and treatment of Sjogrens syndrome. Dtsch Arztebl Int. 2017;114(20):354361. doi:10.3238/arztebl.2017.0354

7. Gerfaud-Valentin M, Jamilloux Y, Iwaz J, Seve P. Adult-onset Stills disease. Autoimmun Rev. 2014;13(7):708722. doi:10.1016/j.autrev.2014.01.058

8. Kanakis MA, Vaiopoulos AG, Vaiopoulos GA, Kaklamanis PG. Epididymo-Orchitis in Bechets disease: a review of the wide spectrum of the disease. Acta Med Iran. 2017;55(8):482485.

9. Chaturvedi S, McCrae KR. Diagnosis and management of the antiphospholipid syndrome. Blood Rev. 2017;31(6):406417. doi:10.1016/S0140-6736(13)60594-2

10. Roy A, Nair S, Sen N, et al. In silico methods for design of biological therapeutics. Methods. 2017;131:3365. doi:10.1016/j.ymeth.2017.09.008

11. Weiner G. Rituximab: mechanism of action. Semin Hematol. 2010;47(2):115123. doi:10.1053/j.seminhematol.2010.01.011

12. Smolen JS, Han C, Bala M, et al. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum. 2005;52:10201030. doi:10.1002/art.20982

13. Greco A, De Virgillo A, Ralli M, et al. Behcets disease: new insight into pathophysiology, clinical features and treatment options. Autoimmun Rev. 2018;17(6):567575. doi:10.1016/j.autrev.2017.12.006

14. Ogdie A, Coates LC, Gladman DD. Treatment guidelines in psoriatic arthritis. Rheumatology (Oxford). 2020;59(suppl 1):i37i46. doi:10.1093/rheumatology/kez383

15. Blair HA. Secukinumab: a review in ankylosing spondylitis. Drugs. 2019;79(4):433443. doi:10.1007/s40265-019-01075-3

16. Tanaka Y. State-of-the-art treatment of systemic lupus erythematosus. Int J Rheum Dis. 2020;23(4):465471. doi:10.1111/1756-185X.13817

17. Abbasi M, Mousavi MJ, Jamalzehi S, et al. Strategies toward rheumatoid arthritis therapy; the old and the new. J Cell Physiol. 2019;234(7):1001810031. doi:10.1002/jcp.27860

18. Mendoza-Pinto C, Garcia-Carrasco M, Jimenez-Hernandez M, et al. Etiopathogenesis of Behcets disease. Autoimmun Rev. 2010;9(4):241245. doi:10.1016/j.autrev.2009.10.005

19. Mege JL, Dilsen N, Sanguedolce V, et al. Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behets disease. A comparative study with familial Mediterranean fever and healthy subjects. J Rheumatol. 1993;20:15441549.

20. Hirohata S, Kikuchi H. Behets disease. Arthritis Res Ther. 2003;5:139146. doi:10.1186/ar757

21. Hatemi G, Christensen R, Bang D, et al. 2018 update of the EULAR recommendations for the management of Behets syndrome. Ann Rheum Dis. 2018;77:808818. doi:10.1136/annrheumdid-2018-213225

22. Jaffe GJ, Dick AD, Brzin AP, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016;375:932943. doi:10.1056/NEJMoa1509852

23. Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016;388:11831192. doi:10.1016/S0140-6736(16)31339-3

24. Interlandi E, Leccese P, Olivieri I, et al. Adalimumab for treatment of severe Behets uveitis: a retrospective long-term follow-up study. Clin Exp Rheumatol. 2014;32:S58S62.

25. Fabiani C, Vitale A, Emmi G, et al. Efficacy and safety of adalimumab in Behets disease-related uveitis: a multicenter retrospective observational study. Clin Rheumatol. 2017;36:183189. doi:10.1007/s10067-016-3480-x

26. Tanida S, Inoue N, Kobayashi K, et al. Adalimumab for the treatment of Japanese patients with intestinal Behets disease. Clin Gastroenterol Hepatol. 2015;13:940948. doi:10.1016/j.cgh.2014.08.042

27. Hibi T, Hirohata S, Kikuchi H, et al. Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study. Medicine (Baltimore). 2016;95:e3863. doi:10.1097/MD.0000000000003863

28. Vallet H, Riviere S, Sanna A, et al. Efficacy of anti-TNF alpha in severe and/or refractory Behets disease: multicenter study of 124 patients. J Autoimmun. 2015;62:6774. doi:10.1016/j.jaut.2015.06.005

29. Kinoshita H, Kunisaki R, Yamamoto H, et al. Efficacy of infliximab in patients with intestinal Behets disease refractory to conventional medication. Intern Med. 2013;52:18551862. doi:10.2169/internlmedicine.52.0589

30. Fujikawa K, Aratake K, Kawakami A, et al. Successful treatment of refractory neuro-Behcets disease with infliximab: a case report to show its efficacy by magnetic resonance imaging, transcranial magnetic stimulation and cytokine profile. Ann Rheum Dis. 2007;66:136137. doi:10.1136/ard.2006.056804

31. Hirohata S, Kikuchi H, Sawada T, et al. Retrospective analysis of long-term outcome of chronic progressive neurological manifestations in Behcets disease. J Neurol Sci. 2015;349:143148. doi:10.1016/j.jns.2015.01.005

32. Kikuchi H, Aramaki K, Hirohata S. Effect of infliximab in progressive neuro-Behets syndrome. J Neurol Sci. 2008;272:99105. doi:10.1016/j.jns.2008.05.002

33. Ntatsaki E, Mooney J, Scott DG, et al. Systemic rheumatoid vasculitis in the era of modern immunosuppressive therapy. Rheumatology (Oxford). 2014;53:145152. doi:10.1093/rheumatology/ket326

34. Turesson C, Schaid DJ, Weyand CM, et al. Association of HLA-C3 and smoking with vasculitis in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:27762783. doi:10.1002/art.22057

35. Adler S, Baumgartner I, Villiger PM. Behets disease: successful treatment with infliximab in 7 patients with severe vascular manifestations. A retrospective analysis. Arthritis Care Res (Hoboken). 2012;64:607611. doi:10.1002/acr.21557

36. Aamar S, Peleg H, Leibowitz D, et al. Efficacy of adalimumab therapy for life-threatening pulmonary vasculitis in Behets disease. Rheumatol Int. 2014;34:857860. doi:10.1007/s00296-013-2693-4

37. Kawaguchi T, Kawazoe Y, Kamoi K, et al. Clinical course of patients with Behets uveitis following discontinuation of infliximab therapy. Jpn J Ophthalmol. 2014;58:7580. doi:10.1007/s10384-013-0283-3

38. Feld J, Chandran V, Haroon N, et al. Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison. Nat Rev Rheumatol. 2018;14:363371. doi:10.1038/s41584-018-0006-8

39. Coates LC, Kavanaugh A, Mease PJ, et al. Group for research and assessment of psoriasis and psoriatic arthritis 2015 treatment recommendations for psoriatic arthritis. Arthritis Rheumatol. 2016;68:10601071. doi:10.1002/art.39573

40. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75:499510. doi:10.1136/annrheumdis-2015-208337

41. Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med. 1979;301:555. doi:10.1056/NEJM197909063011016

42. Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, et al. Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J Immunol. 2008;181:74207427. doi:10.4049/jimmunol.181.10.7420

43. Harper EG, Guo C, Rizzo H, et al. Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis. J Invest Dermatol. 2009;129:21752183. doi:10.1038/jid.2009.65

44. Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199:125130. doi:10.1084/jem.20030451

45. Haider AS, Lowes MA, Surez-Farias M, et al. Identification of cellular pathways of type 1, Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis. J Immunol. 2008;180:19131920. doi:10.4049/jimmunol.180.3.1913

46. Zheng Y, Danilenko DM, Valdez P, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445:648651. doi:10.1038/nature05505

47. Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-t+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18:10691076. doi:10.1038/nm.2817

48. Ahlfors H, Morrison PJ, Duarte JH, et al. IL-22 fate reporter reveals origin and control of IL-22 production in homeostasis and infection. J Immunol. 2014;193:46024613. doi:10.4049/jimmunol.1401244

49. Benham H, Rehaume LM, Hasnain SZ, et al. Interleukin-23 mediates the intestinal response to microbial -1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheumatol. 2014;66:17551767. doi:10.1002/art.38638

50. Cuthbert RJ, Watad A, Fragkakis EM, et al. Evidence that tissue resident human enthesis T-cells can produce IL-17A independently of IL-23R transcript expression. Ann Rheum Dis. 2019;78:15591565. doi:10.1136/annrheumdis-2019-215210

51. Mease P, van der Heijde D, Landew R, et al. Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study. Ann Rheum Dis. 2018;77:890897. doi:10.1136/annrheumdis-2017-212687

52. Mease PJ, van der Heijde D, Ritchlin CT, et al.; SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76:7987. doi:10.1136/annrheumdis-2016-209709

53. van der Heijde D, Gladman DD, Kishimoto M, et al. Efficacy and safety of ixekizumab in patients with active psoriatic arthritis: 52-week results from a phase III study (SPIRIT-P1). J Rheumatol. 2018;45:367377. doi:10.3899/jrheum.170429

54. Mease PJ, Genovese MC, Greenwald MW, et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med. 2014;370:22952306. doi:10.1056/NEJMoa1315231

55. Deodhar A, Gottlieb AB, Boehncke WH, et al.; CNTO1959PSA2001 Study Group. Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2018;391:22132224. doi:10.1016/S0140-6736(18)30952-8

56. McInnes IB, Kavanaugh A, Gottlieb AB, et al.; PSUMMIT 1 Study Group. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382:780789. doi:10.1016/S0140-6736(13)60594-2

57. Kavanaugh A, Ritchlin C, Rahman P, et al.; PSUMMIT-1 and 2 Study Groups. Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials. Ann Rheum Dis. 2014;73:10001006. doi:10.1136/annrheumdis-2013-204741

58. Araujo EG, Englbrecht M, Hoepken S, et al. Effects of ustekinumab versus tumor necrosis factor inhibition on enthesitis: results from the enthesial clearance in psoriatic arthritis (ECLIPSA) study. Semin Arthritis Rheum. 2019;48:632637. doi:10.1016/j.semarthrit.2018.05.011

59. Kerschbaumer A, Smolen JS, Dougados M, et al. Pharmacological treatment of psoriatic arthritis: a systematic literature research for the 2019 update of the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis. 2020;79:778786. doi:10.1136/annrheumdis-2020-217163

60. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27:361368. doi:10.1002/art.1780270401

61. Rudwaleit M, van der Heijde D, Landew R, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 2009;68:777783. doi:10.1136/ard.2009.108233

62. Boel A, Molto A, van der Heijde D, et al. Do patients with axial spondyloarthritis with radiographic sacroiliitis fulfil both the modified New York criteria and the ASAS axial spondyloarthritis criteria? Results from eight cohorts. Ann Rheum Dis. 2019;78:15451549. doi:10.1136/annrheumdis-2019-215707

63. Wang R, Gabriel SE, Ward MM. Progression of nonradiographic axial spondyloarthritis to ankylosing spondylitis: a population-based cohort study. Arthritis Rheumatol. 2016;68:14151421. doi:10.1002/art.39542

64. Dougados M, Sepriano A, Molto A, et al. Sacroiliac radiographic progression in recent onset axial spondyloarthritis: the 5-year data of the DESIR cohort. Ann Rheum Dis. 2017;76:18231828. doi:10.1136/annrheumdis-2017-211596

65. Braun A, Saracbasi E, Grifka J, et al. Identifying patients with axial spondyloarthritis in primary care: how useful are items indicative of inflammatory back pain? Ann Rheum Dis. 2011;70:17821787. doi:10.1136/ard.2011.151167

66. Sieper J, Braun J, Dougados M, et al. Axial spondyloarthritis. Nat Rev Dis Primers. 2015;1:15013. doi:10.1038/nrdp.2015.13

67. van Tubergen A. The changing clinical picture and epidemiology of spondyloarthritis. Nat Rev Rheumatol. 2015;11:110. doi:10.1038/nrrheum.2014.181

Link:
Treatment of Connective Tissue Disease-Related Intractable Disease wit | OARRR - Dove Medical Press