A 43-year-old female presents with body aches and stiffness, which are worse in the morning. She further describes a low-grade fever and pain in her hands, feet, and left knee. She feels that her grip strength is diminished. These symptoms started rather abruptly 2 weeks ago and have not responded to acetaminophen.
She frequently camps with her family. She remembers that 1 week they could not go because her 8-year-old daughter had a fever, mild diarrhea, abdominal pain, and a skin rash ("legs, arms, and especially face were red and warm, and she seemed 'flushed' all the time"). Her daughter's symptoms resolved in a few days, she did not see a doctor, and no one else was sick. She has no other illnesses, and review of systems is otherwise negative.
On physical examination, her vitals are normal. She is unable to close her hands completely. Although the physical examination is somewhat limited by pain, there appears to be swelling of all metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints, as well as mild erythema over the MCP joints bilaterally. In addition, upon examination of the left knee, the bulge sign (indicating effusion) is detected.
Question 11.1.1 If found on physical examination, which of the following would be LEAST useful in helping you in narrow your diagnosis?
A) Bilateral metatarsophalangeal (MTP) joint swelling and tenderness.
B) Painless oral ulcerations, with clean edges.
C) Firm, slightly tender subcutaneous nodules at the olecranon bursae.
D) A "bull's eye" rash in the right axilla.
E) Icterus and tender hepatomegaly.
Answer 11.1.1 The correct answer is "A." This patient presents with polyarticular inflammatory arthritis of unclear etiology. While important to note, MTP joint swelling would not add much to the picture of subacute, symmetrical, small joint polyarthritis that you have already found on examination. The differential diagnosis includes acute viral arthritis, specifically parvovirus B19 (due to the daughter's history of acute illness resembling erythema infectiosum), coxsackievirus, hepatitis B (hinted at in "E"), and HIV. Also on the differential will be Lyme disease ("D") (although small joint symmetrical arthritis would be atypical), RA ("C," the presence of rheumatoid nodules would be helpful although these would be unlikely in early disease), and other inflammatory disorders. "B," painless ulcerations, are classically associated with SLE (systemic lupus erythematosus), but it ought to be noted that lupus aphthae (ulcers) may be painful as well.
After you sneak off to do a little reading, you examine her again. She has no rash. You detect bilateral pain and swelling of the third and fourth MTP joints. There are no oral ulcerations and no lymphadenopathy. She is not icteric, and her abdomen is diffusely, mildly tender. There is no hepatomegaly. You decide to order some blood tests.
Question 11.1.2 If positive, which of the following tests would be MOST helpful in ruling in a specific rheumatologic diagnosis?
C) Positive parvovirus B19 IgM.
D) Positive urinalysis for white blood cells (WBCs).
Answer 11.1.2 The correct answer is "C." The presence of IgM antibodies to parvovirus B19—or rising titers of IgG antibodies—indicates acute viral infection, which may present with symptoms and signs seen in this patient. "A," positive ANA, will not help you rule in a diagnosis at this point. While the ANA is a highly sensitive test, it is not specific and has a low positive predictive value. "B," "D," and "E" are all important findings, but would not lead you toward a specific diagnosis. "D," WBC in the urine could be from interstitial nephritis, a UTI, a nephritic urine from other causes, etc. Table 11-1 presents a framework for who should be tested for and diagnosed with RA.
TABLE 11-1WHO LIKELY HAS RHEUMATOID ARTHRITIS? ||Download (.pdf) TABLE 11-1 WHO LIKELY HAS RHEUMATOID ARTHRITIS?
|Patients who: || |
Have at least 1 joint with definite clinical synovitis (swelling)
With the synovitis not better explained by another disease
| A. Joint involvement || |
| 1 large joint ||0 |
| 2–10 large joints ||1 |
| 1–3 small joints (with or without involvement of large joints) ||2 |
| 4–10 small joints (with or without involvement of large joints) ||3 |
| >10 joints (at least 1 small joint) ||5 |
| B. Serology (at least 1 test result is needed for classification) || |
| Negative RF and negative ACPA ||0 |
| Low-positive RF or low-positive ACPA ||2 |
| High-positive RF or high-positive ACPA ||3 |
| C. Acute-phase reactants (at least 1 test result is needed for classification) || |
| Normal CRP and normal ESR ||0 |
| Abnormal CRP or abnormal ESR ||1 |
| D. Duration of symptoms || |
| <6 weeks ||0 |
| >6 weeks ||1 |
Note that the diagnosis of RA no longer requires 6 weeks of symptoms, although a longer duration of polyarthritis makes RA more likely. Similarly, it would be unusual for parvovirus B19 to cause symptoms for 6 weeks. However, the virus can cause prolonged joint pain in 10% of affected adults.
Her laboratory results return as follows:
Hepatitis B: Surface antibody positive, surface antigen negative.
CMV: IgG positive, IgM negative.
Parvovirus: IgG positive, IgM negative.
RF: 200 (normal: <14 units)
Anti-citrullinated protein antibody (ACPA)∗: 64 units (strong positive >60 units)
ESR: 58 mm/hr.
Note that based on results so far and according to Table 11-1, she has seven points (4–10 joints involved, high titers of RF and CCP antibody, and elevated ESR).
∗Anti-citrullinated protein antibody (ACPA) is also known as anti-CCP (anti-cyclic citrullinated peptides). Anti-CCP antibodies are very specific for RA; however, their sensitivity is 67% and therefore may be negative in RA.
Question 11.1.3 Which of the following is the most appropriate next step?
A) Bilateral hand x-rays.
C) Smith antibody, double-stranded DNA (dsDNA), complement levels.
D) Start methotrexate 15 mg weekly by mouth and daily folic acid, with or without low-dose prednisone and follow up in 4 to 5 weeks.
E) Start prednisone 60 mg daily by mouth and follow up in 4 to 5 weeks.
Answer 11.1.3 The correct answer is "D." This patient most likely has seropositive RA (see criteria in Table 11-1). The patient should be started on a disease-modifying anti-rheumatic drug (DMARD), such as weekly methotrexate at a moderate dose, along with folic acid 1 mg daily and prednisone 10 to 20 mg daily. Evidence suggests that there is a "window of opportunity" when treating early RA and that an early remission may lead to sustained remission.
Note that investigating for any evidence of other systemic involvement should be included as part of the initial evaluation. It is appropriate to obtain CBC, liver function tests, electrolytes, BUN, creatinine, and urinalysis (to rule out glomerulonephritis). "A" is incorrect. She is presenting fairly early after the onset of symptoms, so it is unlikely that hand x-rays will provide any significant findings. "B" is also incorrect. Without further symptoms or signs of lung involvement (e.g., pulmonary osteoarthropathy and respiratory symptoms), a CT scan would be inappropriate. As to "C," she has no other symptoms of lupus and also had a negative ANA, so further testing for lupus (Smith antibody, dsDNA [also known as anti-native DNA antibodies], complement levels) is not appropriate. "E" is incorrect. Although steroids are indicated, low doses are fine; higher doses are rarely necessary and are associated with greater side effects. Therefore, early institution of a DMARD would be preferable.
HELPFUL (IF LONG) TIP:
In all cases of RA, and especially in those with a poorer prognosis, DMARDs should be instituted promptly, and escalated fairly rapidly, with goal being disease remission. Methotrexate is the most commonly used DMARD in the United States, but combination therapy (methotrexate plus hydroxychloroquine or sulfasalazine) or triple therapy (methotrexate, hydroxychloroquine, and sulfasalazine) improves outcomes over methotrexate alone. Low-dose prednisone is indicated for immediate symptomatic relief. Recent data suggests that low-dose prednisone in the first 6 months up to 2 years after diagnosis is associated with better prognosis and more sustained remission. Occupational therapy referral is helpful in identifying and treating functional impairment due to RA. Vitamin D 800 IU/day and calcium 600 to 800 mg BID should be initiated with prednisone therapy to help prevent corticosteroid-induced osteoporosis. Evaluation of bone density (DEXA scan) and a bisphosphonate (e.g., alendronate) should be considered if >5 mg of prednisone is to be used for >3 months.
RA typically has an insidious onset with a fluctuating course; however, a significant minority of patients (perhaps one-third) will experience rapid onset, over days to weeks.
She returns in 4 weeks and is now about 7 weeks into her illness. She reports a moderate response to your intervention (you started methotrexate 15 mg weekly with 1 mg folic acid daily, and prednisone 20 mg daily), but now she has 1 to 2 hours of morning stiffness. She continues to complain of pain in her hands and feet, with poor grip. In fact, she had to take time off from work during the last week. On examination, she has persistent swelling of MCPs 2 to 5 bilaterally and MTPs 3 and 4 bilaterally. You also note swelling in the left wrist and both knees, but tenderness is reduced and there is no erythema.
You take a step back and want to reassess the situation.
Question 11.1.4 What examination finding is so general that it would NOT help you support/reconsider your diagnosis?
A) Pleural rub auscultated on lung examination.
B) Firm, slightly tender subcutaneous nodules at the olecranon bursae.
C) Faint pink rash over chest, which is not visible 15 minutes later.
D) Reduced passive flexion in left knee.
Answer 11.1.4 The correct answer is "D." While important to note, limitation of passive movements of the knees is indicative only of knee effusion (or pain), which you have already observed, and is not specific for any particular etiology. She responded modestly to methotrexate and prednisone but clearly still has active arthritis. What can you use to expand or limit your differential diagnosis? Pleural friction rub ("A") is indicative of possible lupus. Diagnostic criteria for lupus include serositis, which may be detectable as a pleural rub on auscultation of the lungs (also, look for malar rash, discoid lesions, alopecia, and oral ulcerations). Although not part of the diagnostic criteria for the disease, RA may also present with pleuritis or pericarditis. Rheumatoid nodules ("B") are found in RA. A salmon-colored, evanescent macular rash ("C") would lead you to consider adult-onset Still disease. Still disease, also known as juvenile idiopathic arthritis (JIA, discussed in Chapter 13), presents with an evanescent rash, intermittent fever, and arthritis. "Adult onset" Still disease is Still disease with onset after age 16. In addition, RF and CCP antibodies are typically negative in adult-onset Still disease. A finding of isolated foot drop ("E") may be the result of mononeuritis multiplex, a feature of vasculitides, and paraneoplastic syndromes. In fact, foot drop is the most common weakness with mononeuritis multiplex followed by wrist drop. Mononeuritis multiplex is defined as injury of two or more named nerves secondary to a vasculitis.
Question 11.1.5 Since your patient is taking methotrexate, you caution her to avoid which of the following?
B) Sulfonamide antibiotics.
E) Penicillin antibiotics.
Answer 11.1.5 The correct answer is "B." Methotrexate is a folate antagonist. Anti-folate medications, such as sulfonamide antibiotics, must be avoided in patients taking methotrexate because the combination may result in pancytopenia. Supplemental folate, 1 mg daily, reduces the adverse effects of methotrexate. Patients with RA are often treated with aspirin or NSAIDs in combination with methotrexate. Penicillin antibiotics can be administered safely with methotrexate, although methotrexate levels may increase by 8% or so.
Drug interaction programs often warn about concomitant use of NSAIDs and methotrexate, as well as aspirin and methotrexate. These warnings are most relevant to high-dose methotrexate used to treat cancer, not the lower doses used for inflammatory arthritis.
At her first return visit, she had only mild improvement so you (rightly) added hydroxychloroquine (good job!). Initial hand x-rays demonstrate mild periarticular osteopenia. Liver function tests, urinalysis, CBC, BUN, and creatinine are normal. She returns 6 weeks after starting the hydroxychloroquine and is much improved, having returned to work full-time. She tells you that she still has problems with opening jars and about 45 minutes of morning stiffness, "but nothing like it was."
Question 11.1.6 What is the BEST course of action to follow now?
A) Continue her current therapy and follow up in 6 to 12 months with transaminases, RF, and hand x-rays.
B) Continue her current therapy and follow up in 3 to 4 months with transaminases, RF, and hand x-rays.
C) Continue current therapy and follow up in 3 to 4 months; arrange for monthly BUN, creatinine and CBC; and schedule for an annual ophthalmology examination.
D) Begin prednisone taper, continue other medications, and arrange for monthly transaminases and CBC; schedule for baseline ophthalmology exam; and schedule follow-up in another 2 to 3 months.
E) Instruct her to discontinue methotrexate, taper the prednisone dose, and continue hydroxychloroquine; arrange follow-up in 1 year.
Answer 11.1.6 The correct answer is "D." She seems to be responding to therapy, and a 3-month trial on her current medications (during which the methotrexate dose may be increased) is indicated. A slow prednisone taper should be initiated to minimize the cumulative dose of corticosteroids. Close follow-up is critical; she should contact you should symptoms return during the steroid taper. Guidelines for monitoring her DMARD regimen recommend measurement of transaminases and CBC every 8 to 12 weeks for methotrexate and routine eye examination to assess for hydroxychloroquine-related retinal toxicity. A baseline eye examination is necessary when starting hydroxychloroquine; annual screening should begin after 5 years, unless the patient is at high-risk for complications. Hand x-rays are recommended at 2-year intervals. "E" is incorrect: DMARD therapy reduces her risk of joint destruction and disease progression, and should not be discontinued.
At her next visit 3 months later, she feels better. Although she still has difficulty opening jars, she now has <30 minutes of morning stiffness and almost no pain. On examination, she has no rash, nodules, or evidence of serositis. She now has swelling over MCPs 2 to 4 on the right and 2 to 3 on the left. Her grip is still somewhat weak but improved. Laboratory data shows an ESR of 28 mm/hr, CRP 0.7 mg/dL, and normal transaminases and CBC. Her symptoms increased when she tapered prednisone to less than 10 mg/day, so she is taking 20 mg/day once again.
Question 11.1.7 Which of the following is the most appropriate next step?
A) Increase methotrexate to 25 mg weekly, continue hydroxychloroquine, and refer to rheumatology.
B) Stop methotrexate and switch to leflunomide 20 mg/day.
C) Increase prednisone to 60 mg daily.
D) Discontinue all medications except methotrexate.
Answer 11.1.7 The correct answer is "A." Despite her initial response, she has evidence of ongoing inflammatory activity by history and examination. Discontinuing or reducing medication is inappropriate. According to published guidelines, consultation with a rheumatologist is now indicated—if it had not been sought sooner. She has had a fair initial response to methotrexate, prednisone, and hydroxychloroquine. Further benefit may be gained with increasing the methotrexate dose. Addition of sulfasalazine would also be appropriate. If "triple" therapy with methotrexate, hydroxychloroquine, and sulfasalazine fails, she will need a biological agent. "B" is incorrect: since she had an initial response to methotrexate, and may show further efficacy at a higher dose, it would be wise to further increase the methotrexate dose, rather than substituting another agent (leflunomide … leflunomide is a nonbiologic immunosuppressant which can cause liver injury). "C" is incorrect: doses of prednisone this high are not indicated for RA.
Question 11.1.8 This patient wants to become pregnant. You can tell her that:
A) Symptoms remit in 70% of women during pregnancy.
B) She should avoid pregnancy while taking methotrexate.
C) RA is a contraindication to pregnancy.
D) Prednisone cannot be taken during pregnancy.
Answer 11.1.8 The correct answer is "E," both "A" and "B" are correct. RA is an autoimmune disease, and it tends to remit during pregnancy when a woman is relatively immunosuppressed. Methotrexate is class X for pregnancy and is actually used in ectopic pregnancy to arrest fetal growth. Women taking methotrexate should use an effective form of contraception, and continue contraception for 3 months after stopping methotrexate. "D" is incorrect since prednisone is often used to control RA during pregnancy, when methotrexate is contraindicated. Prednisone does not cross the placenta, but use during pregnancy is associated with higher risk for gestational diabetes.
The patient is an avid runner and, prior to her diagnosis, participated in numerous outdoor activities. She is concerned about whether she will eventually become disabled.
Question 11.1.9 You can let her know that:
A) RA tends to progress without any remissions to involve almost all joints in all patients.
B) Prednisone-free disease remission has become the goal of treatment.
C) Patients with RA have the same life expectancy as the general public.
D) Renal involvement is common with RA and is a major source of morbidity and mortality.
E) She won't need to worry about having a life after she gets pregnant and has a child. All her energy will be absorbed by that little parasite … er, child.
Answer 11.1.9 The correct answer is "B." With the advent of new potent disease-modifying agents, it is now possible to achieve remission, that is, the absence or near absence of joint pain and swelling, in patients who have RA. "A" is incorrect. Untreated RA may progress to involve further joints, but not all joints are affected by RA. Classically, the distal interphalangeal joints are spared and, if there is DIP involvement, should prompt reassessment of the diagnosis. Moreover, treatment with DMARDs can, and frequently does, induce remission. "C" is incorrect. RA reduces the life expectancy by up to 10 years. "D" is incorrect. Renal disease is a rare complication of RA; however, it can be a result of some of the medications used to treat RA. Finally, "E". If she needs a life, she can buy them in bulk for cheap at Costco (Walmart also has them for cheap but they wear out too fast).