Rheumatoid Arthritis – An Analysis of the Global Clinical Development

By: Kyle J. Shimek

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Abstract

An overview of the development of new drugs and care for and treatment options for Rheumatoid Arthritis (RA).

Overview

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that attacks the synovial joints and surrounding tissues. RA can cause symptoms in other parts of the body including the lungs, skin, kidneys, eyes and others. RA can lead to joint destruction, joint deformity, and loss of function.  

Anemia is a very common extra-articular symptom of RA. Additionally, RA causes other joint problems, dermatological manifestations (rheumatoid nodules, vasculitis, and other rarer symptoms), lung problems (fibrosis, rheumatoid lung), renal problems caused by chronic inflammation, ocular disease (keratoconjunctivitis, and dry eye) and other problems.  

While it remains unknown what causes RA, genetics, environmental factors and hormones are all thought to contribute. The primary goal of treatment is to alleviate current symptoms and to slow the destruction of the joints. 

The global market for RA medications is estimated to be US$ 12 billion and, according to Research and Markets and Espicom, expected to grow to US$ 27 billion by 2015. The growth is due in large part to growth in sales of biological treatments. 52 53   

The market in the United States and Western Europe is increasing as the senior population grows. The Russian RA market is expected to reach $472 million by 2014. Growth factors include steady increases in RA cases, increased rate of diagnosis, greater use of biological agents and new product launches. 58 RA market in India estimated to double by 2013, reaching $672 million by 2013. This growth is being driven by increased patient access to healthcare, greater patient spending power and greater use of biologics. 57 

Treatments

The primary goal of treatment is to alleviate current symptoms and to slow the destruction of the joints. In the 1980s standard treatment for RA was to start gradually with physical therapy and NSAIDs, and then build up with more pharmacological treatments as the disease progressed. In the 1990s new clinical trials evaluated the use of aggressive DMARD therapy at the onset. Results from these studies let to changes in general standards for RA management, which includes early use of DMARDs, fast escalation of treatments, combination therapy, use of biologics after DMARDs failed response and using anti-inflammatory medications as supplementary treatments. 39 

Today, standard focus for treatment tends toward DMARDs and the impressive list of new biological agents, and there has been a renewed assessment of steroids. 39 

Since January 2007 the FDA has approved the following RA treatments:

  • Actemra, a monoclonal antibody IL-6 receptor blocker, approved on January 11, 2010
  • Vimovo, combination of naproxen (an NSAID) and esomeprazole (a proton-pump inhibitor), approved in April 2010
  • Cimzia, a TNF-inhibitor monoclonal antibody (mAb), approved by the FDA for Crohn’s Disease in April 2008, was later approved for RA in May 2009
  • Simponi, an injectable biologic, on April 24, 2009. 38

 

FIG. 1: Chart of treatment options 

Treatment Category Description Common Types
Traditional DMARDs DMARDs

(Disease modifying anti-rheumatic drugs)

Category of medications used to treat the underlying processes of RA; these medications can slow the progression of the disease Sulfasalazine, Hydroxychloroquine, Leflunomide, Azathioprine, Cyclosporine, Gold sodium thiomalate, Leflunomide
       Methotrexate The most common type of DMARD; it is an antimetabolite drug which inhibits dihydrofolate reductase, the enzyme responsible for folate synthesis Rheumatrex, Trexall
Biologics Biologics Proteins derived from human genes that have been genetically engineered to block specific components of the immune system; Drug types include TNF-inhibitors, Interleukin blockers (IL-1 and IL-6), monoclonal antibodies, and T-cell costimulation blockers; biological agents have been shown to slow the progression of RA Actemra, Kineret, Rituxan, Orencia
       TNF inhibitors

       (Tumor-necrosis

       factor inhibitors)

Biologics designed to block tumor necrosis factor, cytokines responsible for the inflammation involved with RA Enbrel, Humira, Remicade, Cimzia, Simponi
Anti-Inflammatory Agents NSAIDs

(Nonsteroidal Anti-Inflammatory Drugs)

Specially designed compounds used to reduce inflammation and suppress pain; Anti-inflammatory drugs are used to reduce the symptoms of RA but do not slow the progression of the disease Ibuprofen, Acetaminophen, Naproxen, Lodine
       COX-2 Inhibitors NSAIDs designed to selectively target cyclooxygenase-2, an enzyme involved with inflammation and pain Celebrex, Arcoxia
Glucocorticoids Steroidal anti-inflammatory drugs used to treat inflammation caused by RA Methylprednisolone, Prednisone
Other Non-Drug Other, non-drug treatments include physical therapy, occupational therapy, nutritional therapy, and orthoses. These treatments, however, do not stop progression of joint destruction. Surgery is also a treatment option.  

 
 

 

Epidemiology

Onset of RA can occur at any age, though it commonly affects people between 30 and 55 and risk gradually increases with age until about 70 years.1 Worldwide prevalence is estimated between 0.5% and 2% and prevalence is 2.5 times higher in women than in men.2 According to the World Health Organization (WHO), Eastern Europe and Latin America regions have the highest disability adjusted life years, which is a combination of mortality and morbidity.  
 

WHO Disability-Adjusted Life Years (DALY)

Fig. 2: Worldwide Rheumatoid Arthritis DALY Map

ematoid-Arthritis-WHO-2004-DALY-nocities-The higher disease burden of RA in Eastern Europe and Latin America is a combination of higher prevalence and financial access to modern treatments. Due to the importance of starting early treatment for RA and specialize care required, patients in developing countries face a greater burden. 

Genetics

Genetics play a crucial role in predisposition to RA, potentially up to 50% of the risk of developing RA. 4 Various single nucleotide polymorphisms (SNPs) have shown in studies to increase the risk of developing RA.  33 Native American populations in North America, Alaska, Chile and Brazil have all been found to have significantly higher prevalence of RA than other population groups. 16 , 20 Some studies have found prevalence of up to 7% among certain Native American populations. 21 These studies have revealed a high frequency of HLA-DRB1 alleles among Native Americans. 20 Studies have been conducted that found higher disease activity (more symptoms) in people of Hispanic decent. 37 

Eastern Europe has higher rates of RA: The Directorate-General for Health and Consumers for the European Commission 46(page 18)  45 and the WHO. 47 48 A comprehensive report on RA by the WHO in 2000 found higher prevalence in Central and Eastern Europe and in Latin America. 51 Eastern Europeans have higher rates of musculoskeletal conditions. 50(page 246)

Nearly ¼ of Europeans suffer from some form of rheumatism or arthritis. 49(page24) 

Environmental

Smoking is considered the main environmental factor attributing to RA. Studies have suggested that regular smokers (25 packs per year or greater) were 3.1 times more likely to develop RA. 5, 6  Other suspected factors include viral and bacterial infections, 8, air pollution, hormone levels, occupational exposure to certain chemicals, and lifestyle factors (such as diet and exercise). 



Clinical Trial Design

Standard Treatment Methods

New criteria to disease activity has been adapted and scoring systems for radiography.  

Also, assessment surveys have been designed to measure patients’ activity levels and disease-associated disability. These include the Stanford Health Assessment Questionnaire Disability Index 39 or the Activity Participation Questionnaire (APaQ). 35  These questionnaires have allowed for more accurate assessments of disease progression. 39  
 

Safety/Observational Studies/Health Outcomes/Patient Registries

 The growth of rheumatic registries is due to the growing portfolio of biological treatments and a lack of head-to-head comparisons on their effectiveness and safety. 43 Safety data generated from observational drug registers helps create recommendations for rheumatologists. 

Trial Design

Important things to consider when designing clinical trials for RA: comorbidity, clinical remission, progression of the disease, the current stage of the disease

Efficacy of treatment should be closely monitored, as well as changes in hemoglobin. 44  

RA medications can cause liver damage – it is important to monitor this during drug trials. Additionally, RA medications can greatly diminish the body’s ability to fight infections.  

More can be read about RA clinical trial design at these articles:  

  • Methods for Examining Outcomes in Rheumatic Diseases – Measurement of Risk Factors and Drug Exposures, Outcomes, Trial Design 43
  • Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis: Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers 60
  • Issues in the design of new clinical trials for rheumatoid arthritis therapeutics 61
  • Use of Placebo in Rheumatoid Arthritis Clinical Trials May Negatively Impact Patients, Study Suggests 62

 

As pointed out by David T Felson, Bin Zhang, and Jeffrey N Siegel in the article “Trials in Rheumatoid Arthritis: Choosing the right outcome measure when minimal disease is achievable,” published in the EULAR Journal in 2008: 

    “Since they are clinically achievable goals, one reasonable approach to trial outcome measurement in RA might be to focus on low disease activity and, as much as possible, on remission or cure. As suggested by a recent editorial, “Successful therapeutic strategies of the next decade will be measured by the percentage of patients able to achieve remission or at least achieve a very low disease activity state and not by how many patients improved by a certain amount”. 1 We shall contend that RA trial outcomes should not focus on remission or even low disease activity, but rather on outcomes that optimize the detection of treatment efficacy.”  22

Researchers T Pincus and T Sokka point out in their study and article published in the EULAR Journal in 2004, titled “Should contemporary rheumatoid arthritis clinical trials be more like standard patient care and vice versa?” state:

 

    “The information used by rheumatologists when delivering care to patients with rheumatoid arthritis (RA) is derived mainly from two sources: randomized controlled clinical trials and experience in clinical care. However, these two sources differ significantly because (a) the extensive inclusion and exclusion criteria result in clinical trial participants being recruited from only a minority of patients seen in standard clinical care; (b) assessments in clinical trials are conducted according to standard quantitative measures and indices, while standard clinical care of most patients with RA is generally conducted empirically, without collection of any quantitative data other than laboratory tests to estimate prognosis and document change in status; and (c) although baseline databases of various clinical trials (and observational studies) are 60–90% identical in content, they are not standardized and therefore not amenable to direct comparisons. Strategies to promote similarities between clinical trials and standard clinical care in patients with RA may include: more generalized inclusion criteria; incorporation of quantitative measurement into standard care, easily accomplished by asking each patient to complete a simple questionnaire at each visit to a rheumatologist; and consensus among rheumatologists for databases with standard content and format in clinical care and research involving patients with RA.”  34  
     

FIG. 3: Chart of recent recommendations for reporting RA disease activity in clinical trials published in the EULAR Journal 

(Source: Ann Rheum Dis 2008;67:1360-1364 http://ard.bmj.com/content/67/10/1360.full  – 18)

Point Description
1 Each trial should report the disease activity response and disease activity states
1a Response: ACR (ACR20, ACR50, ACR70; ideally also ACR Hybrid, after successful prospective validation in clinical trials) and EULAR response criteria (good, moderate and non-responders)
1b States: composite indices of disease activity should be used as continuous measures and with cut-points to define various disease activity states: they include DAS/DAS28, CDAI and SDAI; appropriate descriptive statistics of the baseline, the endpoint and change of the composite indices should be reported
2 Each trial should report the appropriate descriptive statistics of the baseline, the endpoint and change of the single variables included in the core set
3 Each trial should report the baseline disease activity levels, which could have relevance when interpreting the results
4 Each trial should report the percentage of patients achieving a low disease activity state and remission
4a Definitions that should be used for low disease activity include cut-points for low disease activity for DAS/DAS28, CDAI, SDAI and MDA
4b Definitions that could be used for remission include preliminary ARA remission criteria and respective cut-points for DAS/DAS28, CDAI and SDAI
5 Each trial should report the time to onset of the primary outcome (a particular response or a certain disease activity state)
6 Each trial should consider and report the sustainability of the primary outcome (as opposed to evaluating it at a single predefined time point during the trial)
7 Each trial should report on fatigue

 
 
 

Conclusion

With continued advancement in RA treatments and more awareness of how to handle the disease, researchers are developing better options for patients. Further understanding of RA is needed, but there have been major advances in the past 2 decades.

When designing clinical studies for RA, it is important to take into consideration several things, including the expression of the disease, the treatment methods, comorbidity, the current stage of the disease,  
 

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