Palindromic rheumatrism
Ritasman Baisya

Discussion points
• Introduction
• Epidemiology
• Characteristics
• RA and PR – same disease process or not ?
• Differential diagnosis
• Treatment options
• Unmet need of research

What is Palindrome ?
• Palin- Again
• Dromos - Running
• So a palindrome runs both ways……

Definition
It is a clinical syndrome characterized by debilitating
flares of pain, swelling and erythema centred around
the joints that do not cause residual damage ……

Epidemiology
• First observed in 1928 by Hench & Rosenberg - 34 cases of PR in
1944….. PR as distinct entity … Hench syndrome
• Data from Canada - incidence of PR in a cohort of new
cases of arthritis seen in a 2 year period - 1 PR / 1.8 RA
• 10–15% of patients with RA begin with an episode of PR
• Data from Spain - presenting disease was PR in 17.5% of patients with
RA diagnosed between 2009 and 2010

Research continuing …..
Rheumatologist at University of
Leeds
Leeds, West Yorkshire, United
Kingdom
Most of the recent studies on
palindromic rheumatism and early
RA - contibuted by this young
scientist
Kulveer Mankia

Characteristics
• Multiple , sudden , irregularly recurring pain , swelling & erythema of
joints and adjacent structure …..
• Wrists, MCP & PIP joints are most commonly affected, followed by the
knees and shoulders .
• Flares are usually mono-articular & involves periarticular structure
• Flares usually last only a few days, but in some cases can persist up to 2
weeks

• In between flare , no symptoms and investigations are also
normal
• During attack – painful erythematous plaque , nodules may be
found
• No accepted case definitions or classification criteria for
palindromic rheumatism.
• Diagnosis is based on clinical judgement and can take several
months and multiple clinical encounters to reach.
Characteristics

A patient with anti-CCP positive palindromic rheumatism during a flare
affecting the left hand. Peri-articular swelling and skin erythema are typical
features in flares of PR ( K Mankia review )

Case definitions for palindromic
rheumatism
• The definition of palindromic rheumatism remains
controversial.
• The diagnosis of PR is essentially clinical …
• Diagnostic criteria have been described by Guerne, Pasero
and Barbieri, and Hannonen et al.

Pasero and Barbieri criteria … ( 1986)
1. A history of brief, sudden onset attacks of monoarthritis
2. Direct observation of one attack by a physician
3. More than five attacks in the previous 2 years; involvement of
three or more joints in different attacks
4. Negative radiographs, acute phase reactants and rheumatoid
factor
5. Exclusion of other recurrent forms of monoarthritis - gout,
chondrocalcinosis, intermittent hydrarthrosis and periodic diseases

Guerne and Weisman criteria ( 1992)
1. 6-month history of brief, sudden-onset and recurrent episodes of
monoarthritis or rarely , polyarthritis or of soft tissue inflammation
2. Direct observation of one attack by a physician
3. Involvement of at least three joints in different attacks
4. Absence of erosions on radiographs
5. Exclusion of other forms of arthritis.

Gonzalez-Lopez et al. case definition criteria- (1999 )
A history of brief , sudden-onset, recurrent episodes of mono
arthritis or oligo arthritis & two or more additional criteria -
1. Direct observation of one attack by a physician; more than five
attacks in the previous 2 years ;
2. Three or more joints involved in different attacks;
3. Normal radiographs
4. Reasonable exclusion of other recurrent forms of
monoarthritis ( gout, chondrocalcinosis or intermittent periodic
hydrarthrosis)

Is it forme fruste of RA ?
Answer may be yes

• Early clinical studies reported high rates of progression to RA in their
respective palindromic rheumatism cohorts
• First longitudinal study of PR in 1959 , progression to RA was
reported in 18 / 28 (64%) within 8 years of follow-up…. (1)
• In a UK cohort, 10 / 20 (50%) developed RA over 10 years of follow-
up …. (2)
Demographic study of disease progression
1.Ansell, B. M. & Bywaters, E. G. Palindromic rheumatism. Ann. Rheum. Dis. 18, 330 (1959).
2.Mattingly, S. Palindromic rheumatism. Ann. Rheum. Dis. 25, 307–317 (1966).

Demography of progression
• In another UK study , progression to RA was reported for
17/39 (44%) …… Wajed, M. A et al . Palindromic rheumatism. Clinical and serum
complement study. Ann. Rheum. Dis. 36, 56–61 (1977).
• In a Finnish cohort, progression to persistent arthritis was
described in 35 / 60 (58%) ……… Hannonen, P et al Palindromic rheumatism.
A clinical survey of sixty patients. Scand. J. Rheumatol. 16, 413–420 (1987)

Antibody profile ….
• A high prevalence of RF positivity was identified in early studies
conducted > 30 years ago
• Spanish palindromic rheumatism cohort, the frequency of anti-
CCP was similar in patients with PR to those with early RA ( 53%
and 55% ) ……… (1)
• A notable outlier is a Taiwanese cohort of 84 patients , in which
only 11 (13%) were anti-CCP-positive & 12 (14%) were RF -
positive……… (2)
1.Salvador, G. et al. Prevalence and clinical significance of ACPA and antikeratin antibodies in palindromic rheumatism.
Rheumatology 42, 972–975 (2003)
2. Chen, H. H. et al. Association of USfindings of synovitis with ACPA & RF in patients with PR during active episodes. J.
Ultrasound Med. 28, 1193–1199 (2009)

Genetic profile
• 2002 study reported an increased prevalence of HLA-DR shared epitope
(SE) alleles in patients with PR compared with a healthy individuals ( 1)
• This study found homozygosity of SE alleles to be predictive of progression
to chronic arthritis.
• The HLA-DRB1 SE alleles represent the strongest genetic risk factor
for RA and are associated with a threefold increased risk of RA.
1.Maksymowych, W. P. et al. HLA and cytokine gene polymorphisms in relation to occurrence of
palindromic rheumatism and its progression to rheumatoid arthritis. J. Rheumatol. 29, 2319–2326
(2002)

Palindromic rheumatism and the RA disease continuum

Is Palindromic rheumatism is forme fruste of RA ?
Answer may be no

Disease progression….
• A minority of patients develop other chronic diseases, such as
connective tissue disorders or vasculitis, and not necessarily RA
• Seronegative PR is more genetically and phenotypically
heterogeneous compared with seropositive PR
• Flares that define PR are not typical of an autoimmune
phenotype but seem to be more closely related to an
autoinflammatory process

Graphical network of the top 20 diseases related to Palindromic
Rheumatism:
https://www.malacards.org/card/palindromic_rheumatism

Disease progression
Palindromic rheumatism
progression
Hazard ratio 95% confidence interval
RA 118.76 89.81-157.04
SLE 51.56 32.96-80.66
SS 59.57 43.87-80.88
PM 57.38 6.90-476.83
SSC 13.42 3.79-47.55
A nationwide , population based , retrospective cohort study from the Taiwanese National
Health Insurance Research Database identified 4,421 cases of PR over a 5 year span
Chen HH, Chao WC, Liao TL, Lin CH, Chen DY. Risk of autoimmune rheumatic diseases in patients with
palindromic rheumatism: A nationwide, population-based, cohort study. PLoS One. 2018;13(7)

Genetics- difference
• Genetic studies support an inflammasome related disease
mechanism in PR
• Spanish cohort - a high frequency of mutations in the MEFV gene;
8 / 65 patients with PR ( 12.3%) carried at least one mutated
MEFV allele
• Mutations were more commonly found in ACPA-negative patients
with PR .
• HLA-DRB1*03 and *1302, were associated with PR . Importantly, no
associations have been reported for these alleles with RA
• An Italian study found a high frequency of HLAB16

Genetics ( contd )
• a Taiwanese study found a relationship between PR and
mutations in TNF-a receptor 1.
• TNFRSF1A +36 allele and TNFRSF1A +36 A/G genotype were
associated with persistent PR.
• A Japanese group reported that the frequency of homozygous
susceptibility of the PADI4 haplotype

Etiology- difference
• The possibility that PR attacks are related to a deficit of C1 esterase
inhibitor, or complement activation, has been studied without
success …
• Stress, excitement, vigorous exercise, cold and psychological factors,
such as anxiety can trigger attacks of PR …
• Elimination of food, such as cheese, fish, canned vegetables and
eggs may trigger attack ….
• Cases have also been related to the consumption of strawberries ,
grapefruit , mint and foods containing nitrate ,
• Most of these studies had few patients and were conducted many
years ago.

Clinical difference
• Painful inflammatory flares characterized by periarticular soft-
tissue inflammation and skin erythema
• Hench & Rosenberg chose the name ‘palindromic rheumatism’
rather than ‘palindromic arthritis’ on the basis of the striking
peri-arthritis and para-arthritis observed in some of their
patient
• Seems more similar to crystal-induced arthritis and other auto-
inflammatory diseases than to RA

Palindromic rheumatism: Part of or apart from the spectrum of rheumatoid
arthritis

Imaging difference
• Imaging study compared treatment-naive patients with
palindromic rheumatism vs early RA -
• PR flares had high frequency of extra-capsular inflammation
on US - 19 / 31 ( 63%) .
• 12 /19 cases (63%) there was no coexistent synovitis.
• Only 7 / 31 patients ( 23%) had evidence of synovitis on
ultrasound during a palindromic rheumatism flare
Mankia K., et al. Identification of a distinct imaging phenotype may improve the
management of palindromic rheumatism. Ann. Rheum. Dis. 2018.

Mankia K., et al. Identification of a distinct imaging phenotype may improve the
management of palindromic rheumatism. Ann. Rheum. Dis. 2018.
USG Difference

USG DIFFERENCE
Mankia K, D’Agostino M, Wakefield RJ, et al. Identification of a distinct imaging
phenotype may improve the management of palindromic rheumatism
Annals of the Rheumatic Diseases 2019;78:43-50.

(1) Peri-articular
inflammation shown at a
PIPJ in (a) LT and (b) TV.
Joint effusion is also
present.
(2) Peri-tendinous oedema
shown at (a) a PIPJ in LT
and (b) a MCPJ in TV.
(3) Subcutaneous oedema
shown at a MCPJ and
midfoot.
(4) Flexor tenosynovitis
shown in (a) LT and (b) TV.
Subcutaneous oedema is
also present.
(5) Synovitis shown at (a)
MCPJ and (b) wrist ICJ.
USG images

Imaging (contd)
1. Isolated extra-capsular inflammation appeared to distinguish
palindromic rheumatism from RA
2. Inflammation was rarely seen on ultrasound in absence of flare
3. Not characterised by relapsing–remitting synovitis, but instead
by a different pattern of inflammation that is focused on
periarticular rather than intra-articular structures

MRI study
• DMARD- naive palindromic
rheumatism. Leeds, UK -11
patients
• Synovitis - 7/11 (64%)
• Tenosynovitis - 5/11 (45%) ,
• Peritendinous oedema - 6/11
(55%)
• Periarticular inflammation 6/11
(55%),
• BME in ​1/11​(9%)
• ​No erosions​
Mankia K., et al. Identification of a distinct imaging
phenotype may improve the management of
palindromic rheumatism. Ann. Rheum. Dis. 2018.
Established, treated PR ,
Pavia, Italy ( 4 patients)
 ‘Mild’​synovitis​ in 3
 ​BME in 4
 Extra- capsular
inflammation was not
reported
Bugatti, S. et al. Ultrasonographic and MRI
characterisation of the palindromic phase
of rheumatoid arthritis. Ann. Rheum. Dis.
71, 625–626 (2012).

(1) Periarticular
inflammation (shown
for fourth PIPJ with
clinical photograph
insert).
(2) Peritendinous oedema
(shown for third
extensor tendon at MCPJ
level
(3) Synovitis (shown for
second and third
MCPJs).
(4) Tenosynovitis (shown for
second flexor tendon).
MRI images

Histopathology –
• Schumacher studied five patients with PR-
• synovial hyperplasia with neutrophilic infiltration
• Internal inspection of the joint during attacks revealed no cartilage
destruction, pannus formation or tendency to villous
proliferation of the synovial membrane.
• subcutaneous nodules is characteristic of nonspecific chronic
inflammation
Schumacher HR. Palindromic onset of rheumatoid arthritis. Clinical, synovial fluid,
and biopsy studies. Arthritis Rheum. 25(4), 361–369 (1982).

DIFFERENTIAL DIAGNOSIS

List of differential diagnosis

Pediatric PR
Butbul, Yonatan & Uziel et al . (2018). Is palindromic rheumatism amongst children a
benign disease?. Pediatric Rheumatology. 16.

Treatment options
• No controlled clinical trials
• In early PR study – gold was used but associated with side effects
• Grattan et al. found that NSAIDs improved symptoms during attacks
in 68% of patients, but other study shows not much role (only 3% )
• Glucocorticoids have also been used, with some improvement during
acute attacks ( case report )
• Polyarticular attacks require DMARD
• One small study of 14 patients reported that sulfasalazine was
effective in the treatment of PR

HCQS
• Response rate - 15-80%
• In a series of 71 patients treated with chloroquine, most
patients showed a decrease in the frequency, duration and
severity of the crisis, 22% of treated patients developed
persistent arthritis …….. (1 )
• Study on 113 patients – time to evolution in chronic disease
more in HCQS group ( 162 vs 56 month ) ……..(2)
1.Youssef W, Yan A, Russell AS. Palindromic rheumatism: a response to chloroquine. J. Rheumatol. 18(1), 35–37 (1991)
2.GonzalezLopez L et al . Decreased progression to rheumatoid arthritis or other CTD in patients with PR treated with
antimalarials. J. Rheumatol. 27(1), 41–46 (2000).

Others
• No published study for methotrexate , leflunomide ..
• One case report of MTX in PR with HOA
• A small study of five patients palindromic rheumatism seemed to
respond well to colchicine …… (1 )
• There are no reports as yet of IL-1 inhibition in palindromic rheumatism
• Recent report of Rituximab in csDMARD refractory PR ….recently
published ( n= 33 )
• Abatacept – study ongoing ( phase 4) – PALABA study
1. Schwartzberg, M. Prophylactic colchicine therapy in palindromic rheumatism. J. Rheumatol. 9,
341–343 (1982).
2.Raghavan, P., Sreenath, S., Cherian, S. et al. Efficacy of rituximab in resistant palindromic
rheumatism: first report in literature. Clin Rheumatol 38, 2399–2402 (2019).

Unmet need of research
1. Can consensus diagnostic or classification criteria for PR be
developed?
2. How prevalent are systemic autoinflammatory gene in PR ?
3. Geno and phenotype of ACPA (+) vs ACPA( -)PR differs or not ?
4. Role of HLA shared epitope in PR pathogenesis and progression ?
5. PR evolving to RA having different phenotype of auto-
inflammatory disease or not ?
6. Can flare of PR can be effectively treated with colchicine or IL1
therapy

Conclusion
• Palindromic rheumatism (PR) is a form of intermittent arthritis …….
• Its relationship with rheumatoid arthritis (RA) is controversial, although
some authors consider it to be an aborted or preclinical form of RA….
• PR shares serological markers with RA, including rheumatoid factor and,
especially, anticitrullinated peptide/protein antibodies….
• various diagnostic criteria for PR – nothing confirmatory ……
• The best treatment strategy for PR remains unclear. Antimalarial drugs have
shown clinical efficacy and may delay the evolution to RA……
• Area of unmet need for research ……

Nature reviews | Rheumatology
Published – October ,2019

References
1. Mankia K, Emery P, What can palindromic rheumatism tell us?, Best Practice & Research
Clinical Rheumatology (2017)
2. Mankia, K., Emery, P. Palindromic rheumatism as part of the rheumatoid arthritis
continuum. Nat Rev Rheumatol 15, 687–695 (2019)
3. Mankia, Kulveer et al. “Identification of a distinct imaging phenotype may improve the
management of palindromic rheumatism.” Annals of the Rheumatic Diseases 78 (2019):
43–50.
4. Sonia Cabrera-Villalba;Raimon Sanmartí; Palindromic rheumatism: a reappraisal .
International Journal of Clinical Rheumatology.2013. 8(5):569–577
5. Raul Castellanos-Moreira, Sebastian C.et al . Rheumatoid Arthritis Initiating as Palindromic
Rheumatism: A Distinct Clinical Phenotype? The Journal of Rheumatology August 2019
6. Williams MH, Sheldon PJ, Torrigiani G, Eisen V, Mattingly S. Palindromic rheumatism.
Clinical and immunological studies. Ann Rheum Dis. 1971;30(4):375–380