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A 45 year-old female patient seeks your advice because of intermittent arthralgia in small-finger joints and both wrists.
Involved are primarily MCP II, III and IV of the right hand, PIP II of the right hand and the right wrist. Arthralgias in the
joints of the left hand are less prominent, and here only MCP II and the wrist are affected. In addition, the patient
recently noted mild swelling of MCP II of the right hand for a few days and about an hour of morning stiffness. The
swelling has “gone away― now, though. Symptoms started almost 6 months ago, but in the beginning the patient
thought that these were related to her work as a typist.
a. The patient is young and has some arthralgia. It could be early RA, but only 1% of the population develops RA.
Thus,it is quite likely that the complaints are indeed related to her work. I will advise her how to improve her working
environment and give her another appointment in about 6 months.
b. The complaints are non-specific. I will prescribe some NSAIDs and ask her to come back in 3-6 months. If
thecomplaints are relevant, they will persist and I will do a further work-up then.
.
c. Persisting arthralgia can be the first symptom for several rheumatic diseases. At such an early time point,
however, itis unlikely that I will find specific abnormalities in lab-test or on an X-ray. I will tell her to come back if joint
swelling returns. Meanwhile, I will prescribe NSAIDs.
False. Autoantibodies and rising CrP-levels can be detected in around 50% of patients with RA at disease onset. While it
is correct that X-rays will probably not show abnormalities at such an early stage, it cannot be excluded that erosions are
already present. Importantly, absence of clinically detectable joint swelling does not exclude the presence of synovitis.
d. Although the patient’s complaints are non-specific, they could indicate the start of a rheumatic disease. As
earlydiagnosis and treatment influences outcome for most rheumatic diseases, I will have to inquire in more detail.
True. Correct answer
e. Persisting arthralgia can be the first symptom for several rheumatic diseases. The patient’s age, current
absenceof swelling and lack of symmetry, however, make it unlikely to be RA. I will measure anti-nuclear antibodies. If
these are negative, I can exclude the most important rheumatic diseases.
False. While symmetry and swelling are characteristic of established RA, these findings are mostly absent in early RA.
Also, the age of the patient does not argue against RA. Although measuring anti-nuclear antibodies might be important
for the differential diagnosis, it can of course neither prove nor exclude the presence of a rheumatic disease.
c. Smoking habits
True. Smoking is the most important environmental risk factor for the development of (ACPA-positive) RA.
d. Family history of RA
True. Recurrence risk is dependent on the degree of relation to the index case. The risk for first degree relatives is
almost 5%.
f. Age at menarche
True. Women with lower age at menarche have a lower risk for RA-development.
h. Ethnic origin
True. Prevalence of RA varies quite strongly within different regions. Highest rates are found in North America.
3. Which five of the following diagnostic procedures would you like to perform? Choose procedures that will
allow you to better classify the patient's symptoms.
involvement rather than muscle weakness and therefore an inflammatory myopathy is very unlikely. d. MRI of the
right hand
False. MRI, although very sensitive in detecting synovitis, bone marrow oedema and bone erosions, it is expensive and
should only be used if other measures such as ultrasound do not suffice.
shared-epitope positivity only predisposes to the development of ACPA, and not to RA as such. i. X-ray of
both hands
True. Bone erosions at typical locations are the most specific finding for RA. Their presence cannot be excluded even
early arthritis.
Upon examination of the patient, you find that the patient has some tenderness on palpation of both shoulders, but they
are not swollen and her range of movement is only slightly restricted on the right; there are 9 tender joints in total. The
right wrist is warm and swollen, and MCP II and III are also swollen on the right, but these findings are asymmetrical,
with no detectable synovitis elsewhere. Although ACPA is negative, RF is weakly positive at 80 (normal Revised
classification criteria for RA have been developed which, it is hoped, will have improved predictive values over the 1987
criteria in an early arthritis setting (Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III et al. 2010
rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism
collaborative initiative 2010 Arthritis Rheum 62:2569-81). These criteria may be applied to newly presenting arthralgia
patients with 1 or more clinically swollen joint(s), whose presentation is not thought to be better explained by an
alternative diagnosis. This is particularly the case in the absence of joint erosions on plain x-rays at presentation. While
joint erosions of the PIP or the MCP joints are the hallmark of RA, they are not 100% specific as erosions may also be
seen in psoriatic arthritis and even osteoarthritis (although MCP joint involvement is much less common in these
diseases). For a given patient, a single score is assigned to each of four “domains― – (A) the pattern of
symptomatic joint involvement, (B) autoantibody levels, (C) acute phase response and (D) symptom duration. When the
sum of scores from the four domains is >6, the patient may be classified as having RA. See scoring system.
You now suspect that this patient has RA and that other diagnoses such as osteoarthritis or other forms of inflammatory
arthritis are much less likely.
4. At this stage, can we state that the patient fulfils either of the classification criteria for RA - the 1987 and/or
the 2010 criteria?
Okay, from now on, let's imagine this lady was in fact negative for both ACPA and RF.
5. Does she fulfill either set of classification criteria for RA now?
Answer : No, she doesn't. Using the 2010 criteria, she drops 2 points for her autoantibody status, and only achieves a
total score of 5. We cannot say she has RA, and her arthritis remains "undifferentiated".
b. 'information and mutual agreement': the patient should know her risk and possible treatment strategies. A
mildtreatment (e.g. low-dose prednisone or hydroxychloroquine) could be initiated if the patient agrees.
True. This question is difficult to answer and will generate different opinions. So far, there is no international agreement
on how UA-patients should ideally be treated, and research evaluating this question is ongoing. It is important to
emphasize that a 'hit hard and early' approach to the treatment of RA has proven superior in several trials compared to a
'wait and see' approach.
Answer 2 might be the choice of some rheumatologists, but patients should be informed about clinical trials and potential
risks and benefits (Answer 3). Answer 4 may be a reasonable approach. However, it should be borne in mind that in a
randomised placebo control trial ('PROMPT-study', Arthritis and Rheumatism 2007, 56(5):1424-1432), in which patients
with UA received methotrexate or placebo for one year, MTX-treatment was beneficial only in ACPA-positive patients in
terms of delaying radiographic progression and time to diagnosis of RA. Answer 5 refers to arm 4 of the BEST-study, in
which RA-patients received Infliximab and methotrexate for one year, after which Infliximab and, if possible, MTX were
tapered off. Indeed, the highest number of patients in remission can be found in this group, but none of the TNF-
antagonists yet has approval for UA.
c. 'information and novel strategies': the patient should know her risk and possible treatment strategies. Some
options,however, are not approved for UA-patients. Thus, the patient may be referred to a centre with an early arthritis
cohort that takes part in clinical trials evaluating novel targets in UA.
True. This question is difficult to answer and will generate different opinions. So far, there is no international agreement
on how UA-patients should ideally be treated, and research evaluating this question is ongoing. It is important to
emphasize that a 'hit hard and early' approach to the treatment of RA has proven superior in several trials compared to a
'wait and see' approach.
Answer 2 might be the choice of some rheumatologists, but patients should be informed about clinical trials and potential
risks and benefits (Answer 3). Answer 4 may be a reasonable approach. However, it should be borne in mind that in a
randomised placebo control trial ('PROMPT-study', Arthritis and Rheumatism 2007, 56(5):1424-1432), in which patients
with UA received methotrexate or placebo for one year, MTX-treatment was beneficial only in ACPA-positive patients in
terms of delaying radiographic progression and time to diagnosis of RA. Answer 5 refers to arm 4 of the BEST-study, in
which RA-patients received Infliximab and methotrexate for one year, after which Infliximab and, if possible, MTX were
tapered off. Indeed, the highest number of patients in remission can be found in this group, but none of the TNF-
antagonists yet has approval for UA.
d. Treat with a DMARD such as methotrexate. She has good evidence for a persistent inflammatory arthritis, whether
ornot she ever fulfils ACR criteria – she may even end up being diagnosed with a seronegative spondyloarthropathy
at some stage. We need to induce remission, whatever the cause, and we can always attempt to withdraw treatment
at a later date once the disease activity has settled. Methotrexate is generally a safe drug.
True. This question is difficult to answer and will generate different opinions. So far, there is no international agreement
on how UA-patients should ideally be treated, and research evaluating this question is ongoing. It is important to
emphasize that a ‘hit hard and early’ approach to the treatment of RA has proven superior in several trials
compared to a ‘wait and see’ approach.
Answer 2 might be the answer of choice of some rheumatologists, but patients should be informed about clinical trials
and potential risks and benefits (Answer 3). Answer 4 may be a reasonable approach. However, it should be borne in
mind that in a randomised placebo control trial (‘PROMPT-study’, Arthritis and Rheumatism 2007, 56(5):1424-
1432), in which patients with UA received methotrexate or placebo for one year, MTX-treatment was beneficial only in
ACPA-positive patients in terms of delaying radiographic progression and time to diagnosis of RA. The five year
outcomes of this trial similarly demonstrated no overall benefit of early treatment with MTX in the first year, with similar
rates of progression to classifiable RA, drug-free remission and radiological progression (Ann Rheum Dis 2013, Jan 19
Epub) Answer 5 refers to arm 4 of the BEST-study, in which RA-patients received Infliximab and methotrexate for one
year, after which Infliximab and, if possible, MTX were tapered off. Indeed, the highest number of patients in remission
can be found in this group, but none of the biological agents are currently approved for UA.
e. 'early anti-TNF': TNF-antagonists show the highest remission rates, thus this should be the drug of choice.
False.
7. Which of the additional features would support the decision to introduce a DMARD such as methotrexate?
a. swelling and redness of DIP joints, resulting in more than 10 involved joints
False. DIP joints are not included in the assessment of RA according to the 1987 and 2010 criteria. Involvement of DIP
joints can typically be seen in osteoarthritis, but also in psoriatic arthritis, where it is frequently associated with affection
of the nails. Redness does not exclude osteoarthritis, as it can be present in case of its acute (“activated―) form. It
is noteworthy that psoriatic arthritis can develop in patients with no history of psoriasis. Psoriasis is often subtle and a
thorough evaluation should be encouraged (including inspection of commonly neglected regions, such as the naval,
intergluteal and retro auricular area, as well as the scalp).
d. findings consistent with inflammation detected by ultrasound in several clinically quiescent PIP and MCP jointsTrue.
Due to its higher sensitivity compared to physical examination, ultrasound may detect inflammation in additional joints
that are clinically quiescent, increasing the total number of involved joints, hence increasing the score in the first
(“A―) domain of the 2010 classification criteria (Arthritis Research and Therapy 2013;14:R4). e. redness and
pain of the first MTP joint
False. As in the case of DIP and first CMC joints, the first MTP joint is excluded from the classification criteria.
Furthermore, this clinical presentation requires additional workup to exclude gout, such as ultrasound (a double contour
sign would be highly suggestive of gout), dual energy CT (DECT) and/or joint aspiration.
Clinical case 2
Mary, a 60 year old female secretary has suffered from morning stiffness and joint swelling in her fingers for 2-3 years.
She has noticed more pain and stiffness in her wrists over the last few months. She is referred to you as a
rheumatologist in the hospital outpatient department.
a. Ask her to have some blood tests before her visit to your office?
False. Blood tests should not be taken until you have a clear clinical hypothesis.
b. Send her for radiographic examination before her visit to your office?
False. Radiographic examination should not be performed until you can ask the radiologist a specific question and the
radiographic examination can give some important information regarding diagnosis and/or prognosis.
c. Continue with questioning and clinical examination?
True. The information in the case story is rather vague and you need additional information about her symptoms and
clinical findings.
2. Write down the joint areas that you would particularly focus on in your questioning and clinical examination if
you suspect that the patient may have rheumatoid arthritis, with hand osteoarthritis as a relevant alternative
diagnosis. Rank their relative importance and relevance and state why these areas would be of particular
interest.
Answer :
1 DIP-joints
2 PIP-joints
3 MCP-joints
4 CMC-joints
5 Wrists
6 Hips
7 Knees
8 MTP-joints
When you continue to question the patient she is telling you that she has noticed swelling of her DIP- and PIP-joints of
the hands for 2-3 years, but that she also has lost her grip strength over the last months and also noticed swelling of the
MCP-joints during the last couple of months. During this period she has also noticed swelling of her wrists and also felt
that shoes have become narrow.
3. What do you think is the most likely diagnosis based on this history? (You have to propose a correct ranking
of the diagnosis mentioned below)
a. Hand osteoarthritis
The information about involvement of PIP and DIP joints over 2 years strongly supports hand osteoarthritis (proposed
rank 3).
b. Rheumatoid arthritis
The involvement of MCP and wrist joints and also the feeling of tightening shoes suggest that she also has arthritis of
the feet (particularly the MTP joints) – which altogether support rheumatoid arthritis as a potential diagnosis (proposed
rank 2).
c. Psoriatic arthritis
Psoriatic arthritis is less likely. There is no information about skin involvement and the joint pattern and disease history is
not typical for psoriatic arthritis despite the involvement of the DIP joints (proposed rank 4) d. Gout
The least likely option. In gout the patient usually has more attacks that are acute and fewer joints involved (proposed
rank 5).
4. Would you examine all joint areas or just examine the joints that are symptomatic, according to the patient
report?
When examining the patient, you find that the PIP and DIP-joints are swollen, and interpret the swelling as bony
enlargement. You also find that the squeeze test is positive across the MCP-joints and you see, by inspection, swelling,
of MCP 2, 3 and 4. You also find swelling in these joint when you perform the palpation over the joint margins. In the
wrist joints you also find synovial swelling and reduced range of motion (dorsal extension as well as volar flexion).
Examination of shoulders, elbows and hips does not indicate any joint involvement in these areas. The right knee is
slightly swollen. You find bony swelling over MTP1 bilaterally, but also a positive squeeze test and probable synovial
swelling over MTP2-5 bilaterally. The joint counts are as follows: 10 out of 28 joints are swollen, 8 out of 28 joints are
tender.
5. Based on these findings, among the following diagnosis, which four diagnoses are still possible?
a. Hand osteoarthritis
True. Hand osteoarthritis is a very likely diagnosis based on the described clinical findings and symptoms. Typical joint
involvement in hand osteoarthritis includes the PIP and DIP joints and also the CMC joints which were not involved in
this patient. Sometimes you will also see secondary synovial swelling.
b. Generalized osteoarthritis
True. This patient also has bony enlargement of MTP1 and the effusion in the right knee may also be secondary to the
osteoarthritis. Thus, the clinical findings support that the condition may be classified as generalized osteoarthritis.
c. Rheumatoid arthritis
True. Rheumatoid arthritis. This diagnosis is also likely based on symmetric synovial swelling of the MCP joints, wrists
and also MTP 2-5 in both feet.
a. Yes
True. Aspiration of the right knee is justified, providing you feel it has the potential to alter management. For example, if
you suspect calcium pyrophosphate crystal deposition at this site, examination of the aspirate using polarised light
microscopy may be of value. An underlying diagnosis of RA would typically be associated with a high synovial fluid cell-
count comprising predominately polymorphs, whereas a low cell-count made up of mononuclear cells is more
suggestive of OA. These characteristics are however non-specific, and are unlikely to definitively influence the
diagnosis. You should bear in mind that, however small, any instrumentation of a joint has risks (bleeding, infection, etc.)
associated with it.
b. No
False. Clinically, the presentation is a polyarthritis and not a monoarthritis and this patient is very unlikely to have an
infected joint, and so it is reasonable to wait and consider joint aspiration later if clinically indicated (possibly in
combination with an intra-articular corticosteroid injection). Nevertheless, joint aspiration will help to exclude differential
diagnoses such as a crystal arthropathy.
a. Haemoglobin
b. ESR
True. ESR and CRP are both justified, as elevated levels will support the diagnosis of RA. However, the absence of
raised inflammatory markers does not exclude a diagnosis of RA. High ESR and CRP levels are predictors of a more
severe disease course.
c. CRP
True. ESR and CRP are both justified, as elevated levels will support the diagnosis of RA. However, the absence of
raised inflammatory markers does not exclude a diagnosis of RA. High ESR and CRP levels are predictors of a more
severe disease course.
e. Platelet count
True. White blood cell count and platelet count are justified since high levels may reflect high disease activity in RA.
Several of the medications that are used to treat RA can also suppress bone marrow and it is justified to have baseline
values before starting therapies.
g. Creatinine
True. Creatinine. Renal involvement can occur in rheumatic diseases and many medications can also be nephrotoxic. A
baseline assessment of renal function is therefore appropriate.
h. Urine examination
True. Urine should also be examined for the same reason as mentioned for serum creatinine.
True. Anti-CCP and rheumatoid factor. Both are important laboratory tests. If positive, the suspicion of rheumatoid
arthritis is supported. Positive tests also indicate a high risk of progressive and more severe disease. j. ANA
True. Often taken as a routine, but probably not mandatory in this patient since there are no symptoms indicating
systemic connective tissue disease. However, it would be useful to have baseline values of ANA as RA may be
associated with other connective tissue diseases (e.g. Sjögren’s) and some RA treatments (such as the aTNF
agents) may increase ANA levels.
8. Would you now also proceed with imaging procedures and if yes which?
a. No imaging procedure
False. Most rheumatologists would do some form of imaging at this stage, both to support the presumed diagnosis, but
also to have a baseline examination with which to compare future imaging.
d. Conventional radiographs
True. Conventional radiographs of hands and feet would be ordered by most rheumatologists. The typical x-ray findings
in osteoarthritis are osteophytes, subchondral sclerosis and joint space narrowing which could be expected to be seen in
the PIP and DIP joints. In RA, x-ray abnormalities are rather late. If erosions are detected at this early stage, it would be
a negative prognostic sign.
The results of the examinations revealed that the patient had normal cell counts, haemoglobin 12.0 g/l, ESR 35 mm/h,
CRP 30 mg/l, anti-CCP and IgM rheumatoid factor were both positive. X-ray examination of the hands and feet revealed
osteoarthritis abnormalities of the PIP and DIP-joints of the fingers and also MTP 1. No erosions or joint space
narrowing were detectable in MCP, wrists or MTP joints, consistent with RA of short duration. To further assess the
disease activity and severity you also score your assessment of disease activity on a 100 mm VAS (55 mm) and ask the
patient to assess the VAS global activity (70 mm).
9. How would you consider the prognosis based on the clinical information, radiographic examination and lab
tests?
Conclusion : Note that recently published classification criteria for RA (designed to improve predictive value in an early
arthritis setting) may be applied only to those patients in whom the observed synovitis is not better explained by another
diagnosis – including OA (Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III et al. 2010
rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism
collaborative initiative 2010 Arth Rheum 62:2569-81). You must be aware that "dual pathology" is common in this
setting, and consider both diagnoses according to the clinical, laboratory and radiological data available to you.