| The term
palindromic rheumatism, our topic of discussion today, is
distinct from a palindrome, which is a phrase that is symmetric about a
central axis and hence reads the same forward as backward. Rather,
palindromic rheumatism is an idiopathic, periodic arthritis characterized by
multiple, transient, recurring episodes of mono- or oligo-arthritis
associated with tissue swelling around the involved joints. Episodes last
for a few hours or a few days and then spontaneously resolve. Between
episodes, there are no residual effects. The descriptor “palindromic” is
used based on its Greek root palindromos, which means "to come and to
come again,” which aptly describes this phenomenon.
Although
first described more than 60 years ago, not much is known about palindromic
rheumatism. It is an extremely rare condition, and often, doctors who don’t
recognize it treat it as rheumatoid arthritis. Today’s Rounds will hopefully
help to shed some light on it by discussing:
- The epidemiology of palindromic rheumatism;
- The clinical, pathological, and laboratory aspects of the disease;
- Its genetics;
- Prognosis and treatment; and
- Its progression to other more chronic forms of diseases, specifically
rheumatoid arthritis.
In reviewing these topics, we also will touch on two controversial issues
of this disease, that is, the mechanisms of its pathophysiology; and its
classification, or nosology.
First let's
examine the case of a 48-year-old woman who came to our clinic complaining
of joint pain, which had begun about 2½ years prior to her presentation. The
joint pain first presented as sudden, acute, intense pain localized to her
right shoulder. The pain was rated 7 out of 10 in intensity on the analog
pain scale, and it was described it as a burning, searing, and sharp
sensation. Swelling, redness and exquisite tenderness to touch were
associated with the joint pain. At that initial onset, it involved only her
right shoulder and the structures immediately around it. The pain quickly
evolved, and within a few hours it had reached its maximum intensity.
Interestingly, the patient had no preceding morning stiffness or other
constitutional symptoms. Movement exacerbated the pain. She tried Tylenol
and immobilization of her right arm, but these did not help. Her primary
care physician recommended ibuprofen, which also provided no relief. Then,
just as quickly as the pain came on, it spontaneously resolved. Our patient
suffered no subsequent complications or consequences.
However, a
month later, the pain returned in a very similar fashion. It came on very
quickly and again only involved one joint. It evolved over the course of a
few hours and was excruciatingly intense. This time, though, instead of
affecting her right shoulder, it was her left wrist. After 24 hours, the
pain again mysteriously abated. Over the course of the next year, our
patient had these attacks about once a month. They affected her fingers,
wrists, elbows, shoulders, hips, knees, and even her jaw at one point, with
each episode only attacking one joint. Throughout this, she had no
constitutional symptoms such as fevers, fatigue, or unintentional weight
loss. Between each of these episodes, she was completely asymptomatic, and
her activities of daily living were never compromised.
Our patient
had no history of Lyme disease or sexually transmitted diseases. Laboratory
studies drawn by her primary care physician were unremarkable: her
sedimentation rate was 11mm/hr; C-reactive protein was 0.9 mg/dL; rheumatoid
factor was negative on two occasions; ANA was negative; Lyme serologies were
negative, and all cultures, including those for gonorrhea and Chlamydia,
were negative. The patient had no significant past medical history, and her
social history and family history were non-contributory. Despite her
episodic arthritis, she never missed a day of work and was still able to
enjoy her hobbies. She did not take any prescription or over-the-counter
medications.
At our first
clinic visit with the patient, our physical examination was unremarkable.
There was no evidence of synovitis. She had no restrictions of movement,
effusions overlying any of her joints, or evidence of any structural
defects. Skin examination revealed no evidence of nodules, rashes, or tophi.
Laboratory evaluation was completely unremarkable, with the exception of her
level of anti-cyclic citrullinated peptide (anti-CCP) antibodies, which was
markedly elevated at over 100 units. A repeat rheumatoid factor was
negative.
Thus, in
summary, our patient was a 48-year-old female with no relevant family
history who presented with reports of an episodic, migratory mono-arthritis
for 2½ years that was not associated with any constitutional symptoms,
morning stiffness, or physical examination findings during disease-free
intervals. The only laboratory abnormality was a markedly elevated anti-CCP.
A phenomenon
similar to what our patient experienced was first described in 1944 by
Edward Rosenberg and Philip Hench, who incidentally was awarded the Nobel
Prize in medicine in 1954 for his discovery of cortisone. Rosenberg saw his
first patient with palindromic rheumatism in 1928. In 1944, they published a
paper in the Archives of Internal Medicine, entitled "Palindromic
Rheumatism," which coined the phrase that is still used today. They reported
34 cases of this phenomenon, collected between 1928 and 1939 and all from
the Mayo Clinic. After describing each case in great clinical detail with
follow-up data of many years, they concluded that palindromic rheumatism
represented a new, distinct clinical entity.
However, it
wasn’t until approximately 15 years later that this condition was revisited
by Ansell and Bywaters, who published a case series on 28 patients with
palindromic rheumatism. They noted that the majority of their patients
eventually developed rheumatoid arthritis. So, in stark contrast to Hench
and Rosenberg, who postulated that this was a distinct immunologic entity,
Ansel and Bywaters concluded that palindromic rheumatism was merely a
variant of rheumatoid arthritis. This started a controversy as to exactly
what palindromic rheumatism is and what its pathophysiology represents.
Since then, a multitude of papers over the next 18 years by Mattingly,
Williams, Wajed, Bregeon, and Hannonen reported various patients with
syndromes similar to that originally described by Rosenberg and Hench. In
these reports, a third to a half of all cases eventually evolved into
rheumatoid arthritis. Yet, none of them found a clinical, immunologic, or
genetic factor that could reliably predict who would develop rheumatoid
arthritis and who would maintain a course of palindromic rheumatism.
In 1986,
Pasero and Barbieri proposed five criteria required for diagnosis of
palindromic rheumatism:
- Six-month history of brief, sudden onset and recurrent episodes of
mono-arthritis or polyarthritis;
- Direct observation by a physician of at least one attack;
- Involvement of three or more joints, although they could be involved
at different times;
- Complete absence of radiographic findings; and
- Exclusion of all other arthritides.
This set of
criteria was never adopted by the American Rheumatism Association or by the
American College of Rheumatology, but it did add fuel to the controversy of
palindromic rheumatism. By proposing diagnostic criteria, Pasero and
Barbieri imposed that this, in fact, represented a distinct clinical entity,
separate from rheumatoid arthritis.
The
difficulty in characterizing palindromic rheumatism is simply that this is
an extremely rare disease. Depending on which report you read, it has a
prevalence of approximately 1/8 to 1/20 that of rheumatoid arthritis. Unlike
rheumatoid arthritis, which affects mostly women, men are equally affected
by palindromic rheumatism, and their age range can span from the 20s to the
70s. There is no known ethnic predisposition to the disease. Clinical
features have very sudden onset and progressive intensity, which usually
peaks within a few hours. Attacks can last from two hours to more than two
weeks, but most episodes last two days on average. Constitutional symptoms
and morning stiffness are rare. Different joints can be affected with each
attack, and any joint in the body is susceptible, although the hands,
particularly the metacarpophalangeal and the proximal interphalangeal
joints, are the most commonly involved. The spine and the jaw are rarely
affected. Interval periods are symptom free.
|
Joint
|
Mean %
of Patients
|
Range
of % of patients
|
|
MCP/PIP
|
91
|
74-100
|
|
Wrists
|
78
|
54-82
|
|
Knees
|
64
|
41-94
|
|
Shoulders
|
65
|
33-75
|
|
Ankles
|
50
|
10-67
|
|
Feet
|
43
|
15-73
|
|
Elbows
|
38
|
13-60
|
|
Hips
|
17
|
0-40
|
Palindromic
rheumatism also has associated cutaneous manifestations. Although
subcutaneous nodules may form, they are different from those commonly seen
in rheumatoid arthritis--they are transient, smaller, found mainly in the
hands, and nodules lack any central fibrinoid necrosis or palisading
mononuclear cells. A second cutaneous manifestation, seen in the slide
below, is neutrophilic dermatitis, characterized by well demarcated,
violaceous papules and plaques that are edematous.
They are usually symmetric and occur on extensor surfaces. Although rare,
they are commonly seen in the hand.
In terms of
objective findings, inflammatory markers usually are not elevated during the
symptom-free intervals, but they may be elevated during flares of the
disease. Radiographs are always normal. Erosions, joint space narrowing, and
periarticular osteopenia are absent.
The
differential diagnosis of palindromic rheumatism is broad and includes
rheumatoid arthritis, crystalline arthropathies, gout, seronegative
spondyloarthropathies such as reactive arthritis or inflammatory bowel
disease-related arthritis, Whipple’s disease, Behcet’s syndrome, relapsing
polychondritis, intermittent hydrarthrosis, and familial Mediterranean
fever.
The
association of rheumatoid factor and anti-CCP in patients with palindromic
rheumatism is perhaps the most fascinating aspect of this condition.
Rheumatoid factor is found in 40 – 65% of these patients according to some
studies, and its presence has been associated with a more severe form of
disease as well as a higher probability of eventually developing classic
rheumatoid arthritis.
|
Reference
|
PR(%)
|
Pr->RA(%)
|
F/U
|
| Hannonen
et al. |
11/25(44)
|
29/35(83)
|
5 yrs
|
| Bregeon
et al. |
3/16(19)
|
16/25(64)
|
10 yrs
|
| Wajed
et al. |
2/22(9)
|
16/17(94)
|
10 yrs
|
For example,
in Hannonen's study, 83% (29 of 35) of patients with palindromic rheumatism
who were rheumatoid factor positive eventually developed rheumatoid
arthritis, compared with only 44% of patients (11 of 25) who maintained
palindromic rheumatism.
Anti-CCP was
examined in only one paper by Salvador (Rheumatology, 2003). In it, anti-CCP
was present in 56 percent of 32 patients with palindromic rheumatism;
rheumatoid-factor was found in 15 of the 32 (46%). Rheumatoid factor and
anti-CCP were highly correlated: in 18 patients who were anti-CCP positive,
10 of them were also rheumatoid factor positive. The authors concluded that
because anti-CCP is specific for rheumatoid arthritis and because rheumatoid
factor is correlated with rheumatoid arthritis, palindromic rheumatism is,
therefore, on the same spectrum of disease. They reasoned that palindromic
rheumatism may be considered an abortive form of rheumatoid arthritis.
When Hench
and his colleagues first described palindromic rheumatism in patients, they
postulated that genetics played a role, though they had no proof of family
incidence. To this day, good data on the genetics of palindromic rheumatism
is still lacking. At this point, the best conclusion one can draw is that
there is an absence of a striking association with HLA-DR4, which suggests
that palindromic rheumatism is not simply a variant of rheumatoid arthritis,
and perhaps not in the same spectrum of disease.
In terms of
treatment, there have been no randomized, controlled trials investigating
treatment of palindromic rheumatism. People have tried all of the
conventional therapies for rheumatoid arthritis, with reported response
rates from 3 – 68% effectiveness. Even anti-malarials have been used, with
15 – 80% response; sulfasalazine appeared effective in half of all trials;
gold injections produced responses in 20 – 68%; and colchicines reportedly
induced remission in four of five patients. But because the total number of
patients treated is so small, no statistical significance can be ascertained
from these data. In our patient, we initially prescribed non-steroidal
anti-inflammatory drugs for her acute attacks, although they had little, if
any, clinical benefit. We discussed using prednisone during acute attacks,
but our patient opted to avoid this agent. Surprisingly, there is little in
the literature about using corticosteroids for this condition.
With regard
to the natural history of palindromic rheumatism, three patterns have
emerged:
- Clinical remission of attacks;
- Recurrent attacks without persistent joint involvement; and
- Evolution into a more chronic disease, such as rheumatoid arthritis.
So, in returning to the age-old controversy, the question remains: Is
palindromic rheumatism a form of rheumatoid arthritis, or is it a distinct
entity?
Points that argue for it being withing same spectrum of disease include
these facts:
- Up to 50 percent of patients with palindromic rheumatism eventually
progress to rheumatoid arthritis
- There is a high prevalence of rheumatoid-factor and anti-CCP in
patients with palindromic rheumatism.
- Cutaneous nodules, which is a manifestation of rheumatoid arthritis,
are also present in palindromic rheumatism (although the histopathology is
different).
- There is some response to common treatments of rheumatoid arthritis,
such as NSAIDS, anti-malarial agents, gold injections, and sulfasalazine.
However, the responses are variable and not as effective as in rheumatoid
arthritis.
On the opposite end of the argument, there are equally compelling data
that suggests that palindromic rheumatism is a distinct clinical entity:
- The pattern of inflammation differs, with frequent remissions
separated by symptom-free intervals and no apparent accumulation of
disease.
- There is no bone or joint destruction.
- Constitutional symptoms are absent or rare.
- There is no strong HLA association.
- The demographics of palindromic rheumatism differs from that of
rheumatoid arthritis, specifically, it affects men and women equally
(whereas rheumatoid arthritis favors women).
In conclusion, palindromic rheumatism is an idiopathic, periodic
arthritis marked by multiple and recurrent attacks affecting one to a few
joints, with tissue inflammation around or adjacent to them. Episodes
usually last from a few hours to several days, and then the attack
disappears just as peculiarly as its onset. There are no residual effects,
such as bony abnormalities or impairments to the patient’s overall
functioning status. The etiology of palindromic rheumatism is unknown,
similar to that of rheumatoid arthritis, although anti-CCP is associated
with it. Approximately 1/3 to a 1/2 of patients eventually evolve to a more
classic form of rheumatoid arthritis. Risk factors to this appear to be
rheumatoid factor positivity, female sex, and involvement of the hands.
There is no genetic association known, and no clinical trials for treatment
have been performed.
In the future directions for this field of palindromic rheumatis include:
1) the need for long-term follow-up in larger cohorts of patients; 2)
recognition of associations with other diseases; 3) development of a
standardized set of diagnostic criteria; and 4) systematic studies of
traditional and novel therapies, such as methotrexate, leflunomide, and
anti-TNF agents. |
