Rheumatoid Arthritis Case File
Eugene C. Toy, MD, Gabriel M. Aisenberg, MD
Case 34
A 32-year-old nurse presents to your office with a complaint of intermittent episodes of pain, stiffness, and swelling in both hands and wrists for approximately 1 year. The episodes last for several weeks and then resolve. More recently, she noticed similar symptoms in her knees and ankles. Joint pain and stiffness are making it harder for her to get out of bed in the morning and are interfering with her ability to perform her duties at work. The joint stiffness usually lasts for several hours before improving. She also reports malaise and easy fatigability for the past few months, but she denies having fever, chills, skin rashes, and weight loss.
Physical examination reveals a well-developed woman, with blood pressure 120/70 mm Hg, heart rate 82 beats per minute (bpm), and respiratory rate 14 breaths per minute. Her skin does not reveal any rashes. Head, neck, cardiovascular, chest, and abdominal examinations are normal. There is no hepatosplenomegaly. The joint examination reveals the presence of bilateral swelling, redness, and tenderness of the most proximal interphalangeal (PIP) joints, metacarpophalangeal (MP) joints, the wrists, and the knees. Laboratory studies show a mild anemia with hemoglobin 11.2 g/dL, hematocrit 32.5%, mean corpuscular volume 85.7 fL, white blood cell count 7900/mm3 with a normal differential, and platelet count 300,000/mm3. The urinalysis is clear with no protein and no red blood cells. The erythrocyte sedimentation rate (ESR) is 75 mm/h, and the kidney and liver function tests are normal.
▶ What is the most likely diagnosis?
▶ What is your next diagnostic step?
ANSWERS TO CASE 34:
Rheumatoid Arthritis
Summary: A 32-year-old woman presents with
- A 1-year history of symmetric polyarticular arthritis and morning stiffness
- Bilateral swelling, redness, and tenderness of her PIP joints, MCP joints, wrists, and knees
- Mild normocytic anemia
- Normal complete blood count (CBC), urinalysis, renal, and liver function tests
- Elevated ESR, suggesting an inflammatory cause of her symptoms
Most likely diagnosis: Rheumatoid arthritis (RA).
Next diagnostic step: Rheumatoid factor (RF) and anti-CCP (cyclic citrullinated peptide) antibodies.
ANALYSIS
Objectives
- Differentiate the clinical presentation of RA from other symmetric polyarthritis syndromes. (EPA 1, 2)
- Describe the clinical course of RA. (EPA 1, 12)
- Review the different treatment options for RA. (EPA 4, 7, 9)
Considerations
This patient’s history, including the symmetric peripheral polyarthritis and duration of symptoms, is suggestive of RA. RA is a systemic autoimmune disorder of unknown etiology. Its major distinctive feature is a chronic, symmetric, and erosive synovitis of peripheral joints, which, if untreated, leads to deformity and destruction of joints due to erosion of cartilage and bone. The MP joints of the hands are often affected, and ulnar deviation of the fingers is a common finding. The diagnosis of RA is a clinical one, based on the presence of a combination of clinical findings, laboratory abnormalities, and, in later stages, if untreated, radiographic erosions.
APPROACH TO:
Polyarticular Arthritis
DEFINITIONS
ANTI-CCP (CYCLIC CITRULLINATED PEPTIDE) ANTIBODIES: Autoantibodies that are found early in RA and have greater specificity than RF.
POLYARTHRITIS: Inflammation of five or more joints.
CLINICAL APPROACH
Clinical Findings
The first and most important step in evaluating a patient with polyarticular joint pain is determining whether or not synovitis/arthritis is present, producing soft tissue swelling, joint effusion, tenderness, warmth of the joint, and limitation of both active and passive range of motion. If the only finding is pain without inflammatory changes, then the diagnostic considerations include noninflammatory diseases such as osteoarthritis (OA), fibromyalgia, hypothyroidism, neuropathic pain, and depression. The presence of soft tissue swelling and tenderness with limited active range of motion but normal passive range of motion suggests the problem is extra-articular soft tissue inflammation, such as bursitis or tendonitis.
If there is active synovitis/arthritis, it is clinically useful to distinguish between monoarticular/oligoarticular arthritis and polyarticular arthritis. In polyarticular disease, the next diagnostic clue is the duration of symptoms. If symptoms are relatively acute (< 6 weeks), the major considerations are arthritis due to viral infection (such as hepatitis B or C, rubella, or parvovirus B19) or the earliest manifestation of a true rheumatic disease. Viral serologies and compatible clinical history of exposure often can make the diagnosis at this point and obviate need for further rheumatologic evaluation. Treatment of a viral arthritis usually is limited to symptom relief with nonsteroidal anti inflammatory drugs (NSAIDs) because the conditions are generally self-limited.
Differential Diagnosis
Symmetric peripheral polyarthritis is the most characteristic feature of RA. It can also be seen in other autoimmune rheumatic diseases, such as systemic lupus erythematosus and psoriatic arthritis. Lupus, which may present with a symmetric polyarthritis, usually is characterized by the presence of other symptoms, such as malar rash, serositis (pleuritis and pericarditis), renal disease with proteinuria or hematuria, central nervous system manifestations, and hematologic disorders, such as hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia. Rheumatic fever, which can cause symmetric polyarthritis, is an acute febrile illness lasting only 6 to 8 weeks. In psoriatic arthritis, the pattern of joint involvement varies widely. The vast majority of patients have peripheral joint involvement of more than five joints. Others have a pauciarticular asymmetric arthritis or exclusive distal interphalangeal (DIP) involvement. Inflammation is not limited to the joints but also occurs at the periosteum, along tendons, and at the insertion points into the bone, resulting in the development of dactylitis or “sausage digits,” which are typical of psoriatic arthritis and reactive arthritis. Although the arthritis can precede the development of a skin rash, the definite diagnosis of psoriatic arthritis cannot be made without the evidence of skin or nail changes typical of psoriasis (nail pitting, scaly plaques). Reactive arthritis is an asymmetric inflammatory arthritis that follows infection of the gastrointestinal (GI) or genitourinary tract with bacteria such as Salmonella, Shigella, Campylobacter, Yersinia, or Chlamydia. Reactive arthritis can present with the triad of arthritis, uveitis, and urethritis.
The peripheral polyarthritis of RA most typically involves the wrists, MTP joints of the feet, and the MP or PIP joints of both hands; the DIP joints usually are spared. It is useful to contrast the typical pattern of joint involvement of RA with that of degenerative OA. Degenerative joint disease may affect multiple joints, but it occurs in older age groups, is usually not associated with inflammation or constitutional symptoms, and tends not to be episodic. Also, in OA the hand joints most commonly involved are the DIP joints, where the formation of Heberden nodes can be noted (Figure 34–1). In RA, ulnar deviation of the MP joints is often associated with radial deviation of the wrists; swan-neck deformities as well as the boutonnière deformity can develop (Figure 34–2). Swan-neck deformity results from contracture of the interosseous and flexor muscles and tendons, which causes a flexion contracture of the MP joint, hyperextension of the PIP joint, and flexion of the DIP joint. In the boutonnière deformity, there is a flexion of the PIP and hyperextension of the DIP joints. These findings are typical of advanced RA.
Clinical Presentation
Morning stiffness or stiffness after any prolonged inactivity is a common feature of many arthritic disorders. However, stiffness that lasts more than 1 hour is seen only in inflammatory conditions such as RA and reflects the severity of joint inflammation.
Rheumatoid nodules are subcutaneous nodules typically found over extensor surfaces of the proximal ulna or other pressure points. They only occur in 20% to 30% of patients with RA but are believed to have a high diagnostic specificity for RA.
RFs are immunoglobulins (Ig’s) that react to the FC portion of IgG molecules. The usual serologic tests used in clinical laboratories detect immunoglobulin M (IgM) RFs, which are found in 80% to 85% of patients with RA. RF is not specific for RA, as it is found in 5% of healthy patients, but it can support the diagnosis when clinical features are suggestive. High RF titers have a prognostic utility for more severe systemic and progressive disease.
Antibodies to anti-CCP are now recognized as very useful biomarkers with diagnostic and prognostic significance. Anti-CCP antibodies have the same sensitivity as RF but are highly specific, about 95%. The presence of anti-CCP also portends worse outcomes in RA. Current classification criteria for the diagnosis of RA are listed in Table 34–1.
Radiologic findings in RA, such as erosion of periarticular bone and cartilage destruction with loss of joint space, may support the diagnosis. Usually, though, the typical x-ray findings do not develop until later in the disease process after a diagnosis has been made based on clinical findings. Joint deformities in RA occur from several different mechanisms, all related to synovitis and pannus formation with resulting cartilage destruction and erosion of periarticular bone. The structural damage to the joint is irreversible and worsens with disease progression.
Figure 34–2. Boutonnière (A) and swan-neck (B) deformities.
There are several extra-articular manifestations in RA, including: vasculitic lesions with the development of ischemic ulcers, which imply systemic involvement, ocular manifestations with symptoms of keratoconjunctivitis sicca (Sjögren syndrome), respiratory manifestations caused by interstitial lung disease, cardiac manifestations, and several neurologic manifestations, such as myelopathy, related to cervical spine instability. Although not common, the continuous bone erosion may result in an atlantoaxial subluxation with cervical dislocation and spinal cord compression. Entrapment neuropathy may develop, such as carpal tunnel syndrome. Hematologic manifestations include anemia, typically anemia of chronic disease. The combination of RA, splenomegaly, leukopenia, lymphadenopathy, and thrombocytopenia is called Felty syndrome. Felty syndrome is most common with severe nodule-forming RA.
Abbreviations: ACR/EULAR, American College of Rheumatology/European League Against Rheumatism Collaborative Initiative; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
Data from Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid Arthritis Classification Criteria. Arth & Rheum 2010:62(9):2569-2581.
At this stage in the disease process, our patient is presenting with joint complaints, fatigue, and malaise. No other extra-articular manifestations have developed yet. At the very onset of RA, the characteristic symmetric inflammation of the joints and the typical serologic findings may not be evident. Therefore, initially distinguishing RA from other conditions, such as lupus, may be difficult. Usually, the development of extra-articular phenomena allows the clinician to make a more specific diagnosis.
Treatment
Several drugs are currently used for treatment of RA. NSAIDs or cyclooxygenase 2 (COX-2) inhibitors such as celecoxib may control local inflammatory symptoms but do not treat the underlying disease. Corticosteroids have an immediate and dramatic effect on joint symptoms but were historically thought not to alter the natural progression of the disease. Recent evidence suggests that low-dose corticosteroids may retard the progression of bone erosions.
Disease-modifying antirheumatic drugs (DMARDs) may have a favorable impact on the natural course of the disease, reducing joint inflammation and disease activity and slowing or preventing the structural progression of RA. The nonbiologic DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, minocycline, and leflunomide. There is controversy regarding which DMARD is the most effective, but methotrexate is often used as the first drug of choice because of its rapid onset of action and higher tolerability and patient compliance. Toxicity of the various DMARDs is often the most important determinant of which drug is used, and if the patient fails to respond or develops unacceptable side effects, the patient may be tried on a different agent.
In the last decade, the biologic DMARDs have revolutionized the treatment of RA. Tumor necrosis factor (TNF) antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab) have been found to reduce disease activity within weeks, unlike other DMARDs, which may take several months to act. TNF antagonists may also control signs and symptoms that have failed to respond to conventional DMARD therapy. Side effects of TNF blockers may include increased risk of infection, such as reactivation tuberculosis (TB), so all patients should first be screened for latent TB. Other biologics currently in use include anakinra, a recombinant interleukin (IL) 1 receptor antagonist; abatacept, a soluble fusion protein of IgG and human cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4); rituximab, a chimeric monoclonal antibody against CD20, a cell-surface molecule of B lymphocytes; tocilizumab, a monoclonal antibody against IL-6; and tofacitinib and baricitinib, Janus kinase (JAK) inhibitors.
CASE CORRELATION
- See Case 31 (Osteoarthritis/Degenerative Joint Disease) and Case 33 (Acute Monoarticular Arthritis—Gout).
COMPREHENSION QUESTIONS
34.1 A 26-year-old day care worker presents to her provider because of pain and swelling in her hands located at the MPs and wrist joints bilaterally for about 2 weeks. She has an otherwise negative review of systems. She had a complete blood count (CBC) and comprehensive metabolic panel (CMP) that were normal. She also had a serum RF drawn, and the results were negative. Which of the following other types of arthritis is most likely to be the diagnosis in this patient?
A. Parvovirus-associated arthritis
B. Osteoarthritis
C. Fibromyalgia syndrome
D. Celiac disease–associated arthritis
34.2 A long-term patient with RA presents to your clinic for follow-up. She has been on treatment for several years, but she does have some chronic changes in her hands. You expect to find which of the following radiographic changes in her hands?
A. Pencil-in-cup deformities
B. Osteophyte formation
C. Marginal erosions
D. Syndesmophytes
34.3 A 42-year-old man presents to clinic for follow-up of his RA. He is on methotrexate and adalimumab for treatment of his RA. He has been doing very well with respect to his arthritis, and he is considered to be in disease remission. However, he has been having some night sweats, cough, and weight loss for the past 3 months. He has not traveled recently, and he lives and works full time in Houston, Texas. Which of the following studies would you order next for evaluation of these symptoms?
A. Parvovirus titers
B. Acute hepatitis C titers
C. Influenza virus
D. Acid-fast bacilli culture
34.4 A 36-year-old woman is being seen by her physician in the office due to pain in her hands, wrists, and knees that has progressed over the past 6 months. She has tried over-the-counter ibuprofen without relief. Based on the distribution of the joint involvement, she is diagnosed with RA. Which of the following treatments will reduce joint inflammation and slow progression of this patient’s disease?
A. NSAIDs
B. Joint aspiration
C. Methotrexate
D. Systemic corticosteroids
ANSWERS
34.1 A. Parvovirus presents with a symmetric arthritis in the small joints of the hands that resembles RA. In adults who contract the virus, the arthritis is usually self-limiting. Children with parvovirus usually present with a rash on the face and often have no arthritis. The patient is young for OA (answer B), and the wrong joints (usually the DIP and PIP joints of the hands in OA) are affected. She does not describe widespread pain, which would be a feature of fibromyalgia syndrome (answer C). In addition, she has some systemic features, such as anemia, and she has not had GI symptoms suggestive of celiac disease (answer D). Celiac disease can be associated with arthritis as well that might mimic RA.
34.2 C. Marginal erosions, periarticular osteopenia, and uniform joint space narrowing are classic for RA. Pencil-in-cup radiographic changes (answer A) are seen in psoriatic arthritis. Osteophyte formation (answer B) is seen in OA, and syndesmophytes (answer D) are seen in ankylosing spondyloarthritis.
34.3 D. Acid fast studies should be obtained to assess for tuberculosis. This patient has been on treatment with an anti-TNF inhibitor, adalimumab, and has developed a cough and fever for 3 months. Therefore, it is possible the patient has reactivated TB, a known complication of the drug. Parvovirus (answer A) and acute hepatitis C (answer B) are not associated with a cough. The duration of symptoms is likely too long for influenza (answer C), making screening for TB the best choice. It is also important to remember that there are still active cases of TB in the United States, and one does not have to travel to contract TB.
34.4 C. Although NSAIDs (answer A) and corticosteroids (answer D) may help to relieve symptoms, they typically do not slow or prevent structural progression of disease. DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, and biologic agents. Of these agents, methotrexate is usually the drug of choice and is the anchor drug of most combination therapies. Joint aspiration (answer B) may relieve the acute symptoms of inflammation; it also will not slow the natural history of the disease.
CLINICAL PEARLS
▶ Rheumatoid arthritis is a chronic systemic inflammatory disorder characterized by the insidious onset of symmetric polyarthritis and extra-articular symptoms.
▶ Rheumatoid factor is found in the serum of 85% of patients with RA but is less specific than anti-CCP antibodies (specificity 95%).
▶ In nearly all patients with RA, the wrist, MP joints, and PIP joints are affected, whereas the DIP joints are spared.
▶ Distal interphalangeal joints and large weight-bearing joints are most commonly involved in OA.
▶ The typical x-ray finding in RA—periarticular osteopenia and the periarticular bone erosion—may not develop until later in the disease process, when the diagnosis has already been made based on clinical findings.
▶ DMARDs for RA include methotrexate, TNF antagonists, and other biologic agents.
REFERENCES
Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an ACR/EULAR collaborative initiative. Arthritis Rheum. 2010;62:2569-2581.
Shah A, St Clair EW. Rheumatoid arthritis. In: Jameson JL, Fauci AS, Kasper SL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018:2137-2149.
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