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Rheumatology - Rheumatoid Arthritis - Fast Facts | NEJM Resident 360

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by a chronic, symmetric, inflammatory arthritis that classically affects multiple joints, particularly the the hands, wrists, and feet. It is more common among women than men, although both sexes are affected. If left untreated, RA may lead to destruction of affected synovial joints and tendons. Although RA is currently incurable, advances in management have led to substantial improvement in prognosis such that people with RA can live with remission or low disease activity for years without developing deformities.

Risk Factors

• female

• family history of RA

• history of cigarette smoking

• genetic susceptibility (particularly human leukocyte antigen DR4)

• presence of anti-citrullinated protein antibodies (ACPA), particularly anti-cyclic citrullinated peptides (anti-CCP)

• presence of rheumatoid factor (RF)

Diagnosis

Features suggesting the diagnosis of RA:

• early-morning stiffness lasting for >1 hour

• symptoms for >6 weeks*

• swelling in five or more joints*

• symmetry of the joints involved (e.g., metacarpophalangeal joints on both sides of the body)

• RF or ACPA positive at a high titer*

• elevated inflammatory markers with one or more of the above*

• plain radiographs demonstrating erosive changes at the marginal zones of affected joints and juxta-articular osteopenia

Diagnosis in the early stages can be difficult, as the clinical findings may not be obvious. In some cases, the clinical picture/serologic status will evolve and the diagnosis will be revealed with time.

Giving due consideration to a broad list of differential diagnoses for an acute inflammatory polyarthritis will minimize the chance of misdiagnosis.

Early diagnosis of RA is important, as initiation of treatment early in the disease process leads to better outcomes for the patient with respect to joint damage and disease control.

The following plain radiograph shows erosions of the metatarsal head from rheumatoid arthritis:

(Source: Bone Changes in Rheumatoid Arthritis. N Engl J Med 2005.)

Treatment

Treatment of RA has advanced considerably in the last 30 years. The gold standard of treatment currently is to aim for remission or low disease activity as quickly as possible after diagnosis, as this leads to the best outcomes for the patient.

Drugs that have demonstrated the ability to reduce the amount of bone erosion on plain radiographs are known collectively as disease-modifying antirheumatic drugs (DMARDs). The original drugs in this group are termed conventional synthetic DMARDs (csDMARDs), the newest monoclonal antibodies are termed biologic DMARDs (bDMARDs), and the medications that target intracellular enzymes or molecules are called targeted synthetic DMARDs (tsDMARDs).

Examples of Pharmacologic Treatment of Rheumatoid Arthritis

csDMARDs	tsDMARDs	bDMARDs
Methotrexate
Hydroxychloroquine
Sulfasalazine
Leflunomide
Glucocorticoids

Rarely used in current practice:
Azathioprine
Cyclosporine
Gold salts | Janus kinase inhibitors:
Tofacitinib
Baricitinib
Upadacitinib | Tumor necrosis factor inhibitors:
Etanercept
Infliximab
Adalimumab
Golimumab
Certolizumab pegol

Interleukin-6 inhibitor:
Tocilizumab

Costimulation inhibitor:
Abatacept

CD20 antagonist:
Rituximab

Interleukin-1-beta antagonist:
Anakinra |

• Methotrexate, up to a usual maximal dose of 25 mg weekly, is considered an “anchor” drug to which other DMARDs are added. Methotrexate works synergistically with almost all other DMARDs to prevent joint damage and reduce disease activity. For example, in the case of tumor necrosis factor (TNF) inhibitors, combination therapy with methotrexate and a TNF inhibitor has been shown in clinical trials to be more effective than either medication alone. Therefore, if methotrexate alone is insufficient, adding other agents to methotrexate is preferred to switching from methotrexate monotherapy to monotherapy with another DMARD.

• The aim of treatment is to reduce the disease activity to as low as possible to achieve remission or low disease activity based on validated assessment tools. This is known as a treat-to-target approach.

• The most significant complication of all DMARDs is infection. Reactivation of herpes simplex virus and Mycobacterium tuberculosis are particularly common.

• When a patient is taking DMARDs, the development of almost any infection, regardless of the microorganism, can be atypical. In some cases, there may be no fever, or there may be a low/normal C-reactive protein level in peripheral blood (especially with tocilizumab). The index of suspicion for infection must be high for all patients on DMARDs, and the threshold for treating suspected infections should be low.

• Adjunctive treatments to manage pain, such as nonsteroidal anti-inflammatory drugs, acetaminophen, and fish oil, are also used in RA, although these analgesics do not modify the progression of the disease.

(Source: 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheum 2021. Reproduced with permission.)

Algorithms for treatment of RA from the American College of Rheumatology (ACR) are provided below:

ACR Recommendations for the Treatment of Early RA

(Source: 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheum 2016. Reproduced with permission.)

ACR Recommendations for the Treatment of Established RA

(Source: 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheum 2016. Reproduced with permission.)

Extra-Articular Manifestations of RA

As with other autoimmune, inflammatory, rheumatic disease, RA can also lead to numerous extra-articular problems, including:

• interstitial lung disease

• sicca, episcleritis, or scleritis

• splenomegaly with neutropenia (Felty syndrome)

• secondary chronic kidney disease (due to amyloidosis)

• vasculitis

• rheumatoid nodules

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