Treating Rheumatoid Arthritis

SUMMARY:

Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by progressive inflammatory joint disease. Delayed diagnosis and treatment can lead to permanent joint destruction and disability. Female sex, family history, and older age are associated with increased risk of RA development. Treatment focuses on the use of disease-modifying antirheumatic drugs (DMARDs) and steroids, depending on patient’s preferences, treatment history, and disease severity. The American College of Rheumatology (ACR) has updated their guidelines to assist providers with appropriate therapy and management.

General Principles of Therapy

Early diagnosis and initiation of treatment can help delay and prevent joint destruction and permanent disability
Following a diagnosis of RA, referral to a rheumatology specialist should be done to assist with management
Treatment decisions should be done using shared decision making
When prescribing, biosimilars are considered equivalent to FDA-approved originator bDMARDs
ACR recommends a “Treat-to-target” approach
- Systematic approach utilizing: Frequent disease monitoring | Use of validated monitoring instruments (see below) | Modification of therapy as needed | Goal or reaching a predefined “target” (e.g., low disease activity or remission)
- Setting an initial target of low disease activity with an eventual goal of remission may be preferred in some patients
Validated monitoring instruments include
- Clinical Disease Activity Index (CDAI) | Disease Activity Score in 28 joints (DAS28) | Patient Activity Scale (PAS) | Patient Activity Scale II (PAS‐II) | Routine Assessment of Patient Index Data 3 (RAPID3) | Simplified Disease Activity Index (SDAI)
Treatment decisions should be reevaluated within three months to determine efficacy and tolerance
Patients who achieve disease remission should remain on their DMARDs indefinitely as tolerated
- If a patient desires to or needs to decrease or discontinue their medication, then a decreased dose is preferred over discontinuation, and gradual discontinuation is preferred over immediate cessation
Dose reduction for patients at their target can be done by either: Lowering the total dose given | Extending the interval between doses
- Patients should be at their target disease activity for at least six months before considering tapering their medication
- Taper timeline should include gradual decreases for at least six months with frequent assessments to identify any worsening symptoms or disease progression

Disease-Modifying Antirheumatic Drugs (DMARDs)

Conventional Synthetic DMARDs (csDMARDs)

Hydroxychloroquine (Plaquenil)
- First line agent for DMARD naive patients with low disease activity
Sulfasalazine (Azulfidine)
- Second line agent for DMARD naive patients with low disease activity
Methotrexate
- First line agent for patients with moderate to high disease activity| Recommended as monotherapy for DMARD naive patients
- Oral dosing is preferred over subcutaneous or IV
- Should be Initiated and titrated to a weekly dose of ≥ 15mg within 4 to 6 weeks
- Prior to trialing a different DMARD, patients not tolerating Methotrexate can consider the following to increase tolerability: Splitting oral dose over 24 hours | Weekly subcutaneous injections | Increased folic acid supplementation
- Patients not reaching target disease activity with oral Methotrexate can consider switching to subcutaneous Methotrexate
Leflunomide (Arava)
- Second line agent for moderate to high disease activity | Recommended as monotherapy for DMARD naive patients | More expensive than methotrexate
“Triple Therapy”
- The combination of Methotrexate + Sulfasalazine + Hydroxychloroquine
- In general, the addition of a bDMARD or tsDMARD is preferred over the initiation of triple therapy for patients not reaching their target on maximal doses of methotrexate
- For patients on triple therapy who would like to taper their medicine, it is recommended to gradually discontinue sulfasalazine first (instead of Hydroxychloroquine)

Biologic DMARDs (bDMARDs)

TNF inhibitors: Etanercept (Enbrel) | Adalimumab (Humira) | Infliximab (Remicade) | Golimumab (Simponi) | Certolizumab pegol (Cimzia)
T cell costimulatory inhibitor: Abatacept (Orencia)
IL-6 receptor inhibitors: Tocilizumab (Actemra) | Sarilumab (Kevzara)
Anti-CD20 antibody: Rituximab (Rituxan)
- Reserved for patients with an inadequate response to other bDMARDs or who have a concurrent lymphoproliferative disease for which Rituximab is approved
Switching to a bDMARD or tsDMARD of a different class (e.g, switching from a TNF inhibitor to a IL-6 inhibitor) is conditionally recommended over switching to a bDMARD or tsDMARD belonging to the same class in patients not reaching their target
For patients on a bDMARD or tsDMARD + Methotrexate who wish to taper their medications, it is conditionally recommended to taper Methotrexate first

Targeted Synthetic DMARDs (tsDMARDs)

JAK inhibitors: Tofacitinib (Xeljanz) | Baricitinib (Olumiant) | Upadacitinib (Rinvoq)

Glucocorticoids

In general, the ACR recommends against the systematic prescription of glucocorticoids given the significant toxicities associated with steroid therapy
Short-term use (e.g., < 3 months) of glucocorticoids is often used to alleviate symptoms while awaiting response to DMARDs
- Despite this, monotherapy with DMARDs without adjunctive glucocorticoid use is preferred
When prescribed, glucocorticoids should be given at the lowest effective dose and for the shortest duration possible

Special Populations

Heart failure
- Patients with NYHA class III/IV heart failure may have worsening heart failure with TNF inhibitor use, so use of non-TNF inhibitor DMARDs are preferred in this population
Pulmonary Disease
- Methotrexate carries a risk of drug induced pneumonitis, but it is still the favored drug to treat patients with RA and concurrent pulmonary disease
Subcutaneous nodules
- Methotrexate is first line over other DMARDs for patients with nodules and moderate to high disease activity
- If patients on Methotrexate have progression of their subcutaneous nodules, the provider may consider switching to a non-Methotrexate DMARD
Hepatitis B infection
- Prophylactic antiviral therapy is strongly recommended in: Patients initiating Rituximab with positive HBc antibodies (regardless of antigen testing results) | Patients initiating any bDMARD or tsDMARD with positive HBc antibody + positive HBs antigen
- Providers may opt to only monitor viral load and liver function tests in patients starting any non-Rituxan DMARD with a positive HBc antibody and negative HBs antigen
Lymphoproliferative disorder
- Rituximab is conditionally recommended as first line therapy for patients with RA and a concurrent lymphoproliferative disorder, regardless of previous DMARD use
Non-alcoholic fatty liver disease
- Methotrexate may cause hepatotoxicity, and should only be utilized in patients with normal liver function tests without evidence of liver fibrosis
- Prior to initiating Methotrexate in patients with a history liver disease obtain: Liver function tests | Non-invasive imaging to diagnose and stage liver fibrosis | Hepatology consultation
- Patients with liver disease on Methotrexate should have more frequent monitoring (e.g., every 4 to 8 weeks)
Previous serious infection (e.g., Infection requiring hospitalization or IV antibiotics)
- Dual or triple therapy with csDMARDs is preferred over initiation of a bDMARD or tsDMARD in patients with a recent serious infection (e.g., Within the past 12 months)
- Steroids should be avoided in patients with a recent history of serious infection
Nontuberculous mycobacterial (NTM) lung disease
- Patients should be closely co-managed with infectious disease and pulmonary specialists
- Steroids, if used, should be de-escalated or discontinued
- CsDMARDs are preferred over bDMARDs and tsDMARDs
- If patients continue to have moderate to high disease acitivity despite csDMARD use, then Abatacept is the preferred non-csDMARD agent

KEY POINTS:

Rheumatoid Arthritis is a chronic inflammatory joint disorder that requires prompt diagnosis and treatment to prevent progressive joint destruction
Recommend therapies include different classes of disease-modifying antirheumatic drugs (DMARDs) depending on patient’s disease severity, history of medications used, medical co-morbidities and personal preference
Disease severity should be ascertained using ACR recommended scoring questionnaires
ACR recommends a “Treat-to-target” approach, with a target goal of disease remission or low disease activity, and regular follow up to reassess drug efficacy and tolerance
Treatment of RA should include a rheumatology consultation, and disease modifying medications should ideally be continued indefinitely