During her initial rheumatology clinic visit, a thin, pale 60-year-old Caucasian woman related the following history:
Approximately 4 years ago, she began to have pain in both hands and noticed mild swelling of several joints. She also noticed
morning stiffness, which usually resolved by the time she arrived at her job as a cashier in a local market (about 1 hour
later). She tried over-the-counter medications - ibuprofen and acetaminophen - which did not provide much relief. She then
consulted her primary care physician (PCP) who prescribed diclofenac sodium, 75 mg bid. The PCP ordered lab tests, but no
x-rays.
The patient returned to the PCP 3 weeks later and reported some improvement in her symptoms. She learned that her test
for rheumatoid arthritis was negative but her "sed rate was just a little bit high." The PCP prescribed prednisone 5 mg daily
in addition to diclofenac sodium. She felt considerably improved and did not return for continuing care. She eventually was
well enough to take these medications on a PRN basis.
She continued to do well for the next 2½ years, tolerating some morning stiffness and a variable degree of pain and swelling,
which responded adequately to prednisone and ibuprofen. She saw her PCP only to refill her prednisone prescription.
At this time, she began to notice increasing pain and stiffness, which was not relieved by the medications she had on
hand. After approximately 2 months of worsening symptoms, she saw a new PCP, who noted swollen and tender wrists and metacarpophalangeal
(MCP), proximal interphalangeal (PIP) and metatarsophalangeal (MTP) joints. He gave her a prescription for naproxen 500 mg
bid and referred her to the rheumatology clinic for evaluation. No lab studies or x-rays were done.
Social history revealed that she was born in Europe and emigrated with her mother to the United States at age 15.
After graduating from high school, she held numerous jobs primarily as a clerk. She had a short lived and childless
marriage. She lives alone and is self supporting.
She gave a history of pain, stiffness, and swelling in both hands and wrists and reported difficulty with grooming and
dressing. She has difficulty combing her hair and feels pain putting her hands behind her back to hook her bra. She also has
pain in her groin when putting on her right stocking. Recently, she has been getting into her car by backing herself into
the driver's seat and turning her body forward into the driving position. She has pain in her feet while standing or walking,
fatigues easily, and has difficulty completing her usual work shift. She began to miss work due to her increasing pain and
disability.
On examination, her weight was 118 lbs, height 5' 4", and BMI 21. Her vital signs were normal. She had swelling and tenderness
of her MCPs and PIPs. Although she could make a closed fist, her grip strength was weak. Wrists were swollen, tender, and
painful on flexion to 40 degrees. Both extensor carpi ulnaris tendon sheaths were visibly swollen and minimally tender. Her
right elbow lacked 10 degrees of full extension; her shoulders were tender and painful on abduction and external rotation
to 70 degrees.
Right hip examination revealed decreased internal and external rotation and decreased abduction. Both knees were
mildly swollen and painful on flexion beyond 100 degrees. Moderate pes planus was noted. Metatarsal joints were swollen and
tender on lateral compression. She had limited flexion of her lumbar spine and a moderate dextroscoliosis.
General examination was unremarkable except for an irregular heartbeat and redness at the inner canthi of both eyes.
The patient has right groin pain and difficulty with putting on her right stocking, a motion that requires flexion and external
rotation of her hip. Her difficulty with entering her car is probably the result of impaired hip abduction. The likelihood
of her having right hip disease is high. This joint may be at further risk due to abnormal load bearing as a consequence of
her scoliosis.
Another diagnostic possibility is avascular necrosis, possibly related to irregular corticosteroid use. If indeed, the
right hip has radiologic changes attributable to RA, this would portend more aggressive disease. If avascular necrosis is
a serious consideration, MRI would be the diagnostic procedure of choice. Useful
This patient has had RA for at least 4 years. Initial disease activity was followed by a more quiescent period during
which she had "tolerable" disease.
Clearly, a significant percentage of patients with a 4-year history of RA have radiologic changes, ie, periarticular
demineralization, joint space narrowing, and/or erosions, which may develop even in the absence of marked pain and swelling.
Soft tissue swelling and gross joint damage (eg, subluxation) may be appreciated clinically, but radiographs are needed to
assess joint damage, which frequently defies physical examination. Baseline radiographs of hands/wrists and MTP joints may
help to determine the efficacy of treatment over time, since the goal of newer disease remitting therapies is the complete
arrest of radiologic progression. Very useful
Anti-CCP is a highly specific marker for RA. The autoantigenic targets for anti-CCP are citrullinated peptides that contain
the epitope recognized in antikeratin, antiperinuclear factor, and antifilaggrin assays. All of these tests are virtually
specific for RA, but are technically difficult to standardize. Testing for anti-CCP antibodies is probably most appropriate
in patients who are rheumatoid factor seronegative or equivocally positive, but whose clinical picture suggests a diagnosis
of RA.
Although the specificity of traditional immunoglobulin M rheumatoid factor in RA is around 75% to 80%, the specificity
of FDA approved assays for anti-CCP in RA may be as high as 96%. About 40% of seronegative RA patients are likely to be anti-CCP
positive. There is some speculation that anti-CCP positivity may be predictive of more erosive disease. Since this patient
was RF+, the information that an anti-CCP assay would have provided would be marginally useful. Not useful
This woman is currently postmenopausal, has used glucocorticoids over many months, and has an inflammatory polyarthropathy,
all of which are independent risk factors for osteoporosis and a future fracture. In addition, her small stature (118 lbs)
suggests that peak bone mass may have been low. Generally, a weight of less than 127 lbs predisposes one to osteoporosis.
Moreover, the possibility exists that she will need corticosteroids to some degree in her future therapy. A baseline bone
density study would help to determine the existence of osteoporosis/osteopenia and the efficacy of prescribed anti-resorptive
therapy. Useful
On examination, her weight was 118 lbs, height 5' 4", and BMI 21. Her vital signs were normal. She had swelling and tenderness
of her MCPs and PIPs.
Although she could make a closed fist, her grip strength was weak. Wrists were swollen, tender, and painful on flexion
to 40 degrees. Both extensor carpi ulnaris tendon sheaths were visibly swollen and minimally tender. Her right elbow lacked
10 degrees of full extension; her shoulders were tender and painful on abduction and external rotation to 70 degrees.
Right hip examination revealed decreased internal and external rotation and decreased abduction. Both knees were mildly
swollen and painful on flexion beyond 100 degrees. Moderate pes planus was noted. Metatarsal joints were swollen and tender
on lateral compression. She had limited flexion of her lumbar spine and a moderate dextroscoliosis.
General examination was unremarkable except for an irregular heartbeat and redness at the inner canthi of both eyes
The patient was started on celecoxib 200 mg daily, prednisone 7.5 mg daily, and MTX 15 mg po once weekly. She was told
to take acetaminophen 1 gm q8h PRN for break-through pain. In addition she was given a prescription for folic acid 1 mg daily.
Since her dietary intake of calcium was less than optimal, she was advised to take supplemental calcium (1,200 mg/day) and
vitamin D (800 IU daily).
She was given an appointment to return in 3 weeks, but failed to show. Four weeks later, however, she appeared at the
clinic for an unscheduled visit (ie, about 7 weeks after her last visit). At this time, she reported a marked increase in
stiffness and pain in her hands, which was increased by motion. Her wrists, shoulders, and knees were stiff and painful. Her
feet were painful on weight bearing. She had difficulty with grasping small objects and walking more than 50 feet. She was
unable to lie on her right side. She stated that she had had a marked improvement in her symptoms shortly after her first
clinic visit, to the point where she was even able to work overtime hours.
However, after 2 weeks of being compliant with her medications, one of her regular customers told her that prednisone
"would deteriorate my bones." She abruptly discontinued this medication. After her 2-week supply of celecoxib samples ran
out, she failed to fill her prescription, because she was uncertain as to whether it was "worth the money." She also noted
a "gritty" sensation in her eyes. Following this, her symptoms rapidly worsened.
Examination revealed multiple swollen and tender PIPs and MCPs. She was unable to make a closed fist. Both wrists were
swollen and tender and evoked pain with passive motion. Her right elbow was swollen and tender and had a 20-degree flexion
contracture.
Both shoulders had pain on abduction, which was intensified by minimal passive external rotation. Right hip findings
were unchanged, but there was marked tenderness of the right greater trochanter. Her knees and MTP joints were essentially
the same as on her initial visit. Two or three tender nodules in a "crop" were noted at the left olecranon. The "pink eye"
noted on her first clinic visit appeared more diffuse.
A review of laboratory studies done on her first visit revealed the following:
CBC: normal except for a low-grade normochromic and normocytic anemia
Hemoglobin: 11.5 g/DL ;Hematocrit: 33.4% ;ESR: 54 mm/hr
(Westergren) ;CRP: 3X upper limit of normal; RF: positive 320 IU (normal = 0-30) ;ANA: positive 1/80 speckled pattern
(not considered significant) ;Metabolic panel: normal except for a borderline albumin of 3.5 g/DL ;Urinalysis: within normal
limits
Radiographic studies of her hands: narrowing of both radiocarpal articulations and erosions of both ulnar styloid processes.
Juxta-articular demineralization involved most joints of both hands. On the right, there was narrowing of the 1st, 2nd, and
3rd MCP joints. A small erosion was present at the base of the 2nd right proximal phalanx. On the left, erosions were also
noted at the radial aspects of the 2nd and 4th metacarpal heads. All PIP joints were narrow, but no erosions were noted.
Radiographs of her feet revealed "punched out" erosions of the lateral aspects of both 5th metatarsal heads. The 1st
right MTP revealed joint space narrowing (JSN). Other changes were minor. Pelvic radiographs revealed uniform loss of cartilage
(JSN) of the right hip. No erosions, bone cysts, or protrusion, were present.
Given the chronicity of her joint disease, changing NSAIDs is unlikely to alter her clinical status much. The pathologic
nature of her synovitis likely has an acute component, which may be affected to some degree by COX inhibition.
However, the chronic nature of her illness and the presence of JSN and erosions suggest that her synovitis has evolved
into an invading granulation tissue, ie, pannus. The cytokine products of this "aggressive" synovial tissue, which drive the
process of joint destruction at the cartilage-pannus junction are not likely to be inhibited by COX inhibition alone. Therefore,
whereas NSAIDs may have a significant effect on the synovitis of early RA, their use in later stages is generally less helpful.
However, this patient was not compliant in taking her celecoxib on a b.i.d. basis, as prescribed. Switching her to an
NSAID given on a once-daily dosing schedule, (eg, piroxicam, oxaprozin, rofecoxib) might offer an advantage in this respect.
Somewhat useful
This is likely to suppress the inflammatory response more quickly and predictably than any other modality. Not only can
one expect relief of pain and stiffness, but more "systemic" problems, such as fatigue, weight loss due to lack of appetite,
and "no energy" are likely to be improved. In addition, a rapid change in objective measures of inflammation are likely to
be seen, ie, decreases in ESR and CRP and an increase in hemoglobin.
The use of local (intra-articular) corticosteroids can predictably decrease the inflammatory process rapidly in specific
joints. This may allow the patient to do things she otherwise would be unable to do. Although corticosteroids have many potential
adverse effects, the most significant is the loss of bone strength (decreased bone density) in a patient population already
at higher risk of fractures. However, the prophylactic use of bisphosphonates has had a dramatic effect on mitigating this
problem. Very useful
Current standard-of-care RA management calls for rapidly increasing the dose of MTX, if tolerated, to 20 mg to 25 mg
weekly. This patient has been tolerating her MTX quite well. If the MTX dose is increased at this point, consideration should
be given to administering the drug parenterally to ensure complete bioavailability. Very useful
There are data showing that the addition of a second or even third DMARD is likely to yield greater ACR20 and ACR50 responses
than MTX used as monotherapy. The addition of HCQ and/or SSZ may be considered in this patient's clinical setting. However,
the time lag for each of these medications to become effective, if indeed they do become effective, is likely to be weeks
or months.
Using more than one standard-of-care DMARD in this case should depend on the physician's assessment of how quickly the
pathologic processes must be halted in order to prevent further progression of her already established erosive disease.
Somewhat useful
Anti-tumor necrosis factor-alpha (TNF-alpha) therapy and inhibition of the action of IL-1 have been shown to be extremely
effective in the management of aggressive RA, both as monotherapy (adalimumab, etanercept, and anakinra), and when combined
with MTX (all available biologics). Frequently, the therapeutic response to even a single dose of a TNF-alpha inhibitor is
noted within days. Most rheumatologists have seen a more predictable response with the inhibition of TNF-alpha than with down-regulating
the effect of interleukin-1 (IL-l) using anakinra.
TNF-alpha is the central cytokine that drives the destructive pathohistologic processes seen in RA. It is produced primarily
in macrophages and increases the production of IL-l and IL-6, ultimately up-regulating the production of matrix metalloproteases
that degrade connective tissue matrix, contributing to the loss of cartilage and bone.
TNF inhibition clinically depresses all pathological events leading to joint deterioration, including angiogenesis and
osteoclastogenesis. Rheumatologists experienced in the use of these biologic agents have witnessed profound improvement in
their patients and are increasingly considering the use of these agents in earlier disease, particularly in patients profiled
to be at high risk for joint destruction.
These might include patients with multiple joint involvement at the time of presentation, high RF titers, rapid and early
functional decline, the presence of erosions in early disease, and the presence of extra-articular features. It should be
noted that this patient not only had nodules, but also evidence at her initial visit of a sectoral episcleritis, which later
became more diffuse. When patients are properly selected for biologic therapy, TNF inhibitors appear to be quite safe.
Some patients do not respond sufficiently to TNF-alpha inhibition, but for those who do, the improvement in quality of
life is often dramatic. The percentage of patients who actually achieve a full remission is difficult to assess, but for the
most part, the majority of patients derive a degree of benefit unlikely to be obtained with any other treatment modality.
The choice of which biologic agent to use is influenced by a number of factors. Occasionally, third party payor reimbursement
issues play a role in this decision. For some patients, the ability or desire to self-inject may influence this decision.
Some physicians who have used infliximab have observed the phenomenon of "dosage creep." This effect may be diminished
by using higher doses of MTX and/or adding a low dose of prednisone. Etanercept and adalimumab presently have suggested fixed
doses. Some physicians who have used these medications have the impression that an increase in dose has the potential to yield
a greater clinical response in some patients.
Although the use of anakinra has not been associated with opportunistic or cardiac complications, most rheumatologists
have not seen in this agent the rapid efficacy of TNF-alpha inhibitors. However, those patients who fail TNF-alpha inhibition
may respond to anakinra. In addition, the efficacy of anakinra may occasionally increase over time (usually 2-3 months), so
that premature discontinuation of anakinra should be avoided if the patient is tolerating the daily subcutaneous injections
well. Very useful
This patient's compliance to the prescribed medications has been dismal. It is conceivable
that she was never really informed about the potential seriousness of her disease. Alternatively, she might be more concerned
with possible side effects of medications than with the effects of the disease itself.
Clearly, spending some time with her to discuss the nature of RA, the newer targeted therapies, and the need to be compliant
might be helpful here. It is important to give her the hope that deformity and disability are not inevitable, and that with
rigorous attention to clinical details and the use of these newer, more effective therapies, her quality of life and functional
capacity are likely to improve.
Switching her to parenteral MTX and requiring her to be seen weekly, at least for a time, might be helpful in monitoring
her compliance. This would also allow the nursing staff to play a role in educating her about her illness. Very useful
The patient was switched from celecoxib to rofecoxib in order to enhance the likelihood of compliance. She was also restarted
on prednisone, 10 mg/day, and was reassured that the lowest effective dose of prednisone would be used with the expectation
that it could be discontinued altogether as her disease activity waned. Her MTX dose was increased to 20 mg IM once weekly
and was to be given by the clinic nurse, at least initially, to monitor compliance.
The decision to use a TNF-alpha inhibitor was also made at this time, since it offered the most predictive response in
a rapidly deteriorating clinical situation.
Also, considerable time was spent on educating her about RA.
At this clinic visit, her right greater trochanteric bursa was injected with 20 mg of triamcinolone diacetate and lidocaine.
In addition, 8 ml of synovial fluid were aspirated from her right shoulder and 15 mg of triamcinolone hexacetonide were instilled.
Preparation for using a TNF inhibitor, which of the following studies is likely to be helpful?
Purified Protein Derivative (PPD) skin test: Treatment with anti-TNF-alpha compounds has resulted in the reactivation
of latent tuberculosis (TB) and other opportunistic infections, including histoplasmosis and coccidioidomycosis in endemic
areas, listeriosis, pneumocystosis, and herpes simplex type II. TNF-alpha plays a significant role in granuloma development
and maintenance, allowing Mycobacterium tuberculosis to reside intact and viable for years within macrophages confined in
stable granulomata. Inhibition of TNF-alpha has the potential to disrupt this stability, leading to reactivated infection.
Tuberculosis associated with TNF-alpha inhibition has often been very virulent, occasionally presenting with disseminated
disease, including lymph node involvement. Mortality rates, even with treatment, have been as high as 20%. Very useful
Chest x-ray: Pulmonary abnormalities, especially evidence of past granulomatous disease, may well alter the decision
to postpone or abandon anti-TNF therapy until the nature of the abnormal findings are established and treated if possible.
Very useful
The use of anti-TNF therapy in patients with recurrent or chronic urinary tract infections may be contraindicated or
require long-term antibacterial suppression. This problem may be particularly applicable in the setting of benign prostatic
hypertrophy in men or in women with a cystocele. Useful
ECG: TNF-alpha is elaborated by failing myocardial tissue in response to pressure or volume overload. Although increased
levels of TNF-alpha are found in plasma samples from patients with congestive heart failure (CHF), the use of anti-TNF therapy
in patients with CHF has resulted in worsening of their clinical state. Clearly, patients with Class III or IV CHF are not
candidates for TNF-alpha inhibition. Its use in lesser degrees of CHF should be approached cautiously, eg, with lower dosing,
if at all. An ECG is unlikely to be helpful in determining the existence of CHF. Not useful
The patient returned to the rheumatology clinic 3 days after her PPD, chest x-ray, and urinalysis were done. A chest
x-ray revealed the presence of a small right upper lobe density consistent with "old granulomatous disease." Her PPD was strongly
positive. Further history obtained from the patient at this time revealed that her father had died in a "sanitarium" while
she was a child in Europe. A diagnosis of latent tuberculosis was made. Urinalysis was unremarkable.
At this visit, she was given a prescription for isoniazide (INH) 300 mg once daily with the expectation that she would
remain on this therapy for 9 months. Liver function tests at appropriate intervals were to be obtained to monitor possible
INH toxicity.
After starting treatment for latent tuberculosis, what is the earliest you would consider starting
anti-TNF therapy? 1 day. Once anti-tuberculosis therapy has been initiated, it is possible to start anti-TNF therapy immediately.
This patient was begun on an anti-TNF regimen 1 week after INH was started. Her response, in terms of joint pain, swelling,
and stiffness, was dramatic. Even after 2 years of anti-TNF therapy, she has continued to show improvement in various measures
of functional assessment. She has returned to work without restrictions and has had no absences due to her RA.
