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Rheumatoid arthritis JAK-pot!

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Risk factors

Risks are divided into non-modifiable (genetic susceptibility and sex) and modifiable lifestyle-associated (eg dietary habits and smoking) factors. 

Risk factors for developing RA

Genetic susceptibility

The prevalence of RA ranges from 2% to 12% in first-degree relatives of patients, 5%-10% in same-sex dizygotic twins and almost 12%-30% in monozygotic twins.3

Sex

Women have a two- to three-fold greater risk of RA compared to men. Studies show a strong association between RA and sex hormones - in particular, oestrogen. Oestrogen regulates the immune response by favouring the survival of autoreactive clones that work against the body's proteins to attack joint tissues.4

Diet

Red meat and salt have been implicated in the onset of RA, while some diets and supplements, such as the Mediterranean Diet, vitamin D and probiotics, have a role as adjunctive therapy to standard RA treatment.5

Smoking

Cigarette smoking significantly increases the risk of not only various types of other diseases but has also been shown to play a key role in the onset of RA. Female smokers have a 1.3-times higher risk of RA compared to non-smokers.6

Environmental factors

Multiple studies have also consistently shown a link between exposure to occupational silica/dust and RA – particular the onset of anti-citrullinated protein antibody RA (ACPA). ACPA RA is associated with worse outcomes as a result of higher rates of erosive damage. There have also been findings linking increased exposure to air pollution and RA.7

Signs, symptoms, and diagnostic criteria

The most common and predominant symptoms include joint pain and stiffness, especially morning stiffness and swelling. The onset of symptoms is generally slow and insidious however, in some cases, an episodic pattern of symptoms can be seen and is defined as palindromic rheumatism (attacks or flare-ups of joint pain and inflammation that come and go)  and they symptomatically respond to hydroxychloroquine which supports the idea that palindromic rheumatism is a precursor of RA.8

RA involves small peripheral joints, usually of the hands. Axial joint involvement, especially in the lumbar region, is not common. However, cervical joint disease in long-standing RA can be present. Although multiple small joint involvements are a frequent feature, some patients may present with monoarticular and extraarticular involvement.8

On physical examination, the affected joint will be painful if pressure is applied to the joint or on movement with or without joint swelling. Synovial thickening with a ‘boggy’ feel on palpation will be noted.8

Joint erythema and warmth are usually absent, and wrist involvement may present with typical signs and symptoms of carpal tunnel syndrome. With multiple joint involvements, reduced grip strength will be seen in physical testing.8

The classical physical findings of ulnar deviation, metacarpophalangeal joint subluxation, ulnar deviation, swan neck deformity, Boutonniere deformity, and the ‘bowstring’ sign are seen in advanced chronic disease.8

Rheumatoid nodules are the most common cutaneous manifestations of RA. They are commonly found on pressure points such as the olecranon. RA patients can have ulcerative skin lesions as well which are thought to be due to venous stasis, arterial insufficiency, neutrophilic infiltration, and/or vasculitis.8

Vasculitis involving both medium and small-sized blood vessels can also be seen as a presenting symptom of RA. However, the prevalence of vasculitis among patients with RA is low. Patients with rheumatoid vasculitis may exhibit mono neuritis multiplex or asymmetric polyneuropathy. A secondary form of Sjögren disease is associated with RA. It comprises symptoms of ocular and/or oral dryness as the hallmark signs.8

Treatment recommendations

The 2021 American College of Rheumatology (ACR) guideline suggests a goal of low disease activity (LDA), and not full remission, as the initial target for treatment.9

In an interview with Healio Rheumatology, one of the co-authors of the guideline, Dr Bryant England, explained that the ‘patient voice was a key driver of the move to LDA. “If you are a new patient and you are talking to your doctor about treatment goals, then you fail to reach remission, it can be demoralising.”9

The 2022 European Alliance of Associations for Rheumatology (EULAR) states that treatment should be aimed at reaching a target of sustained remission or LDA in every patient.10

The updated EULAR RA recommendations include:10

  • Therapy with disease-modifying antirheumatic drugs (DMARDs) should be started as soon as the diagnosis of RA is made.
  • Methotrexate (MTX) remains the anchor drug in RA.
  • In patients with a contraindication to MTX (or early intolerance), leflunomide or sulfasalazine should be considered as part of the (first) treatment strategy.
  • Short‒term glucocorticoids (GCs) should be considered when initiating or changing conventional synthetic DMARDs(csDMARDs), in different dose regimens and routes of administration, but should be tapered and discontinued as rapidly as clinically feasible.
  • If the treatment target is not achieved with the first csDMARD strategy, when poor prognostic factors are present, a biological DMARD (bDMARD) should be added. Janus kinase inhibitors (JAKi) may be considered, but pertinent risk factors must be taken into account.
  • bDMARDs and tsDMARDs should be combined with a csDMARD. In patients who cannot use csDMARDs as comedication, interleukin (IL)-6 inhibitors and targeted synthetic DMARDs (tsDMARDs) may have some advantages compared with other bDMARDs.
  • If a bDMARD or tsDMARD has failed, treatment with another bDMARD or a tsDMARD should be considered. If one tumour necrosis factor inhibitor (TNFi) or IL‒6 receptor inhibitor therapy has failed, patients may receive an agent with another mode of action or a second TNF-α/IL‒6 receptor inhibitor.
  • After GC have been discontinued and a patient is in sustained remission, dose reduction of DMARDs (bDMARDs, tsDMARDs, and/or csDMARDs) may be considered.

Changes in the new ACR guidelines include:11

  • The 2015 guidelines recommend csDMARD monotherapy, preferably with MTX for patients with both low and moderate/high disease activity. The update recommends an initial trial of hydroxychloroquine or sulfasalazine for those with low disease activity.
  • The 2015 guidelines recommended DMARD tapering for patients who are in remission. In this update, tapering recommendations are made for patients who are in low disease activity or remission in the face of a paucity of data about when and how best to taper. The panel recommended that careful tapering might be considered if the patient wishes to cut back on their use of DMARDs. However, patients should be evaluated during any taper, and if a flare occurs, the prior regimen should be reinstituted promptly.

The update includes several recommendations against the use of GC therapy. These recommendations were made in recognition of the frequent difficulty tapering glucocorticoids leading to undesirable prolonged use and the increasing evidence of the negative impact of GC on long-term patient outcomes, including risk for infection, osteoporosis, and cardiovascular (CV) disease, in RA and other rheumatic diseases.12

JAKi changing the landscape of RA treatment

JAKi are categorised as tsDMARDs and are relatively new players in the treatment of RA. Some have described JAKi such as baricitinib as gamechangers in the treatment of RA.12

In South Africa, baricitinib is approved for the treatment of moderate to severe RA when standard treatment with DMARDs has not worked well enough or if patients cannot tolerate them. Baricitinib can be used either alone or in combination with MTX.13

Long-term safety and efficacy data

Genovese et al (2016) conducted a phase 3 study (n=527) in patients with an inadequate response to or unacceptable side effects associated with one or more TNFi, other bDMARDs, or both. Patients were randomly assigned in a 1:1:1 ratio to baricitinib (2mg or 4mg daily or placebo for 24 weeks. Significantly more patients receiving baricitinib at the 4mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs 27%).14

Taylor et al investigated the safety of baricitinib for the treatment of patients with RA over a median of 4.6 and up to 9.3 years of treatment. The safety profile of JAKi in clinical trials includes an increased risk of herpes zoster and associations with increased CV events, venous thromboembolic events (VTE) and malignancies. It should be noted that 79% of the patients included in this analysis had concomitant use of MTX.15

The integrated analysis (All-bari-RA) showed that the at risk rates per 100 patient-years were 2.6, 3.0 and 0.5 for serious infections, herpes zoster and major adverse CV events (MACE), respectively.15

In patients aged ≥50 with more than on CV risk factor, the incident rate for MACE was 0.77. The incident rate for malignancy (excluding non-melanoma skin cancer [NMSC]) during the first 48 weeks was 0.6 and remained stable thereafter (1.0).15

The standardised incidence ratios for malignancies excluding NMSC was 1.07 and the standardised mortality ratio was 0.74. All-bari-RA incident rates for deep vein thrombosis (DVT)/pulmonary embolism (PE), DVT and PE were 0.5, 0.4 and 0.3, respectively. No clear dose differences were noted for exposure-adjusted incidence (per 100 PYE) for deaths, serious infections, DVT/PE, and MACE. The authors concluded that baricitinib maintained a similar safety profile to earlier analyses. No new safety signals were identified.15

Conclusion

RA is a progressive, debilitating disease. Currently, there is no cure for this autoimmune disease, rather, symptoms are addressed on an individual basis. Treatment goals are to reduce the pain and stop/slow further damage.16

Left untreated RA can cause significant pain, deformity, loss of manual function and deterioration in overall quality of life. Since the late 1990s, MTX) has been the anchor DMARD) for RA. While MTX was an undoubted breakthrough in treatment options, not all patients achieve the desired response with about 30% discontinuing treatment within the first year due to a lack of efficacy or side effects.16

As a result, there has been a continued drive to better understand the pathophysiology of RA and explore other potential therapeutic targets in an effort to develop and bring to market more viable treatments and alternatives.16

The newest class of drugs in RA treatment are the JAKi and they offer the first truly clinically efficacious long-term oral option in RA.16

REFERENCES:
  1. Finckh A, et al.Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol, 2022.
  2. Almutairi K, Nossent J, Preen D, Keen H, Inderjeeth C. The global prevalence of rheumatoid arthritis: a meta-analysis based on a systematic review. Rheumatol Int, 2021.
  3. Korczowska I. Rheumatoid arthritis susceptibility genes: An overview. World of Orthopaedics, 2014.
  4. Gerosa M, et al. Rheumatoid arthritis: a female challenge. Women’s Health (Lond), 2008.
  5. Lucchino C, et al. Dietary Habits and Nutrition in Rheumatoid Arthritis: Can Diet Influence Disease Development and Clinical Manifestations? Nutrients, 2020.
  6. Chang K, et al. Smoking and rheumatoid arthritis. Int J Mol Sci, 2014.
  7. Deane KD et al. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol, 2018.
  8. Chauhan K, et al. Rheumatoid Arthritis. [Updated 2022 Jun 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022
  9. Volansky R. All or something: Experts debate LDA vs. remission as a target in rheumatoid arthritis. https://www.healio.com/news/rheumatology/20220407/all-or-something-experts-debate-lda-vs-remission-as-a-target-in-rheumatoid-arthritis
  10. Smolen JS, et al.Update of the EULAR recommendations on the management of rheumatoid arthritis. 2022 EULAR Recommendations for RA management and tips for implementing guidelines into clinical practice congress, 2022. https://cdn.doctorsonly.co.il/2022/06/9dda0a9b-a4e0-49d9-9892-4de28fa0e62a.pdf
  11. Fraenkel L, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care and Research, 2021.
  12. Lauper K, et al. Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the 'JAK-pot' collaboration. Ann Rheum Dis, 2022.
  13. Unamity.
  14. Genovese MC, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. NEJM, 2016.
  15. Taylor PC, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis, 2022.
  16. Harrington R, Nokhath SAI, Conway R. JAK Inhibitors in Rheumatoid Arthritis: An Evidence-Based Review on the Emerging Clinical Data. Journal of Inflammation Research, 2020.

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