Rheumatoid arthritis

Introduction

Rheumatoid Arthritis (RA) affects up to 1% and tends to manifest between the ages of 20 and 40. It is more common in women and developing countries1

Treatment guidelines emphasise the importance of early intervention to prevent joint damage and more severe consequences such as pain and deformity2

RA has an estimated total annual economic burden of €45.3 billion in Europe and €41.6 billion in the USA3

Burden of RA

The burden of RA may be substantial and extends beyond the joints

A systematic review found that RA is associated with multiple comorbidities and psychosocial impairments:4

Adapted from Cutolo et al.1

Impact

RA has implications for quality of life and ability to work

Quality of life
  • Health-related quality of life is impaired in RA owing to pain, fatigue, and functional deficits4
  • The reduction in health-related quality of life is associated with with decreased productivity, work loss and work disability4
Depression
  • Depression in RA patients is associated with increases in mortality, cardiovascular morbidity and disability4
  • Depression is common amongst RA patients, with an estimated prevalence of up to 20%4
Work ability
  • Up to 50% of RA patients are forced to leave the workforce within 10 years of disease onset5
  • Work disability has been related to treatment response, with the highest rates observed in non-responders4
Surgery
  • Surgery is still needed in refractory patients to relieve pain, restore function and prevent/correct deformity6

Treatment

Optimal management includes both non-pharmacological and pharmacological therapy2,7

In terms of pharmacological management:

  • Guidelines recommend an aggressive and tailored approach2,7
  • Early use of DMARDs is associated with higher chance of reaching remission/treatment success, and can prevent early joint damage2,7
  • Physiotherapy, ergotherapy, orthopaedic surgery
  • Preventative measures to reduce risk of cardiovascular disease and osteoporosis
  • Psychological and social assistance
  • Patient education (nutritional counselling, smoking cessation programmes)

Adapted from Gossec et al.8 and Smolen et al.2

1st line pharmacological therapy: Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs)

  EULAR recommendations
csDMARDs are 1st line therapy Should be used immediately after diagnosis
Options include:
  • Methotrexate
Should be part of the first treatment strategy in patients with active RA
  • Sulfasalazine
Where there are contraindications (or early intolerance) to methotrexate, these should be considered as part of the first treatment strategy
  • Leflunomide
  • Hydroxychloroquine
Can be used as part of combination therapy, or as monotherapy in patients with very mild disease

Adapted from Smolen et al.2

New treatments, such as Janus kinase (JAK) inhibitors are in development. These include tofacitinib, decernotinib and peficitinib.4 However, tofacitinib was refused authorisation upon first application in 2013 due to safety concerns. There were significant and unresolved concerns about the risk and type of serious infections seen with tofacitinib, which are related to the immunosuppressant action of the medicine.

Safety concerns also included a risk of other severe side effects including certain cancers, gastro-intestinal perforations, liver damage and problems with increased lipid levels in the blood. It was not clear that these risks could be managed successfully in medical practice.10

The manufacturer of tofacitinib (Pfizer) has submitted a review of the marketing authorisation, which was accepted by the EMA in March 2016.

Biologic therapies: Anti-TNFs

Since the introduction of the first TNF inhibitor in the early 1990s, biologic therapies have given relief to patients when conventional DMARDs have failed11

Mode of action of TNF inhibitors

sTNF, soluble TNF; tmTNF, transmembrane TNF; TNFRI, TNF receptor 1; TNFRII, TNF receptor 2.
Adapted from Moss et al.12

Anti-TNFs:12

  • Bind soluble and transmembrane TNF-α
  • Prevent TNF-α from interacting with its two receptors (TNFRI and TNFRII)
  • Prevent TNF-α mediated signalling

Biologic therapies: Other targets

  • Targeted therapies using monoclonal antibodies or receptor fusion proteins are directed against the key cytokines TNF, IL-1 and IL-6, or interfere with B-/T-cell signalling13
  • Emerging therapies will also target IL-17 (secukinumab),13 IL-2, IL-4 IL-7, IL-9 IL-15, IL-21 (tofacitinib, decernotinib, peficitinib)9

Adapted from Scott13 and Tanaka.9

Guidelines

The 2013 update of the EULAR recommendations reflect the recent changes in the treatment paradigm of RA

General principles

  • Start DMARD therapy:2
    • Immediately upon diagnosis
  • Treatment goal:2
    • Remission
    • Low disease activity (LDA), if refractory
  • Frequent monitoring:2
    • Every 1–3 months in active disease
  • Adjustment of therapy:2
    • If no improvement within 3 months of treatment initiation, or
    • If target not reached by 6 months

Adapted from Smolen et al.2

*Conventional synthetic DMARDs (csDMARDs) e.g. MTX, sulfasalazine and leflunomide. †Risk factors include a high disease activity state, autoantibody positivity (rheumatoid factor and/or antibodies to citrullinated proteins) and the early presence of joint damage. ‡Biological DMARD (bDMARD) e.g. TNF inhibitors, abatacept or tocilizumab, and, under certain circumstances, rituximab.

Support

Additional information

You can find additional information about RA by following these links:

NHS Choices:
http://www.nhs.uk/conditions/rheumatoid-arthritis/Pages/Introduction.aspx

National Rheumatoid Arthritis Society:
http://www.nras.org.uk/about-ra

American College of Rheumatology:
http://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Rheumatoid-Arthritis

1. World Health Organization. Chronic rheumatic conditions. http://www.who.int/chp/topics/rheumatic/en/ [last accessed 13 June 2016].
2. Smolen JF, et al. Ann Rheum Dis. 2014;73:492–509.
3. Taylor P, et al. Rheumatology Int. 2016;36(5):685-695.
4. Cutolo M, et al. Semin Arthritis Rheum. 2014;43:479–488.
5. Yelin L, et al. Arthritis Rheum. 1987;30:507–512.
6. Chim HW, et al. J Hand Ther. 2014;27:134–142.
7. Singh JA, et al. Arthritis Care Res (Hoboken). 2012;64:625–639.
8. Gossec L, et al. Joint Bone Spine. 2006;73:396–402.
9. Tanaka Y. Korean J Intern Med. 2016;31:210-218.
10. European Medicines Agency. Refusal of the marketing authorisation for Xeljanz (tofacitinib). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002542/WC500146629.pdf. Accessed July 2016.
11. Penn H. Clin Med. 2006;6:105–108.
12. Moss ML, et al. Nat Clin Pract Rheumatol. 2008;4:300–309.
13. Scott DL. Clin Pharmacol Ther. 2012;91:30–43.

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