Reactive arthritis

1. REACTIVE ARTHRITIS

2. Reactive Arthritis
• ReA refers to acute nonpurulent arthritis complicating an infection
elsewhere in the body.
• 60–85% of patients who developed ReA triggered by Shigella,
Yersinia, or Chlamydia were HLA-B27-positive.
• ReA as a clinical syndrome triggered by specific etiologic agents in a
genetically susceptible host. A characteristic spectrum of clinical
manifestations can be triggered by enteric infection with certain
Shigella, Salmonella, Yersinia, and Campylobacter species, by genital
infection with Chlamydia trachomatis, and by many other agents as
well, apparently in some cases via nasopharyngeal infection with
Chlamydia pneumoniae or other agents

3. • The most common age range is 18–40 years, but ReA can occur in
children and older adults.

4. Pathology of ReA
• Synovial histology is similar to that of other SpAs.
• Enthesitis shows increased vascularity and macrophage infiltration of
fibrocartilage.
• Microscopic histopathologic evidence of inflammation mimicking IBD
has routinely been demonstrated in the colon and ileum of patients
with postenteric ReA and less commonly in postvenereal ReA.
• The skin lesions of keratoderma blennorrhagica, associated mainly
with venereally acquired ReA, are histologically indistinguishable from
pustular psoriasis.

5. ETIOLOGY AND PATHOGENESIS
• Definite bacterial triggers of ReA include several Salmonella spp.,
Shigella spp., Yersinia enterocolitica, Yersinia pseudotuberculosis,
Campylobacter jejuni, and Chlamydia trachomatis.
• These are all gram-negative bacteria containing lipopolysaccharide
(LPS).
• All Shigella species have been implicated in cases of ReA, with S.
flexneri and S. sonnei being the most common.
• The ocular serovars of C. trachomatis appear to be particularly,
perhaps uniquely, arthritogenic.

6. • There is also evidence implicating Clostridium difficile, Campylobacter
coli, certain toxigenic Escherichia coli, Ureaplasma urealyticum, and
Mycoplasma genitalium as potential triggers of ReA.
• Many of the established triggers share a capacity to attack mucosal
surfaces, to invade host cells, and to survive intracellularly.
• Antigens from Chlamydia, Yersinia, Salmonella, and Shigella have
been found in synovium and/ or synovial fluid leukocytes of patients
with ReA for long periods following the acute attack.

7. Clinical Features
• Male preponderance of 15:1
• Constitutional symptoms: fatigue, malaise, fever, and weight loss.
• Musculoskeletal symptoms are usually acute in onset. Arthritis is usually
asymmetric and additive, with involvement of new joints occurring over a
few days to 1–2 weeks.
• The joints of the lower extremities, especially the knee, ankle, subtalar,
metatarsophalangeal, and toe interphalangeal joints, are most commonly
involved, but the wrist and fingers may be involved.
• Dactylitis, or “sausage digit,” a diffuse swelling of a solitary finger or toe, is
a distinctive feature of ReA and PsA, but can be seen in polyarticular gout
and sarcoidosis.

8. • Tendinitis and fasciitis are particularly characteristic lesions,
producing pain at multiple entheses, especially the Achilles insertion,
the plantar fascia, and sites along the axial skeleton. Back and buttock
pain are quite common and may be caused by insertional
inflammation, muscle spasm, acute sacroiliitis.
• In men, urethritis may be marked or relatively asymptomatic and may
be either an accompaniment of the triggering infection or a result of
the reactive phase of the disease. Prostatitis is common.
• In women, cervicitis or salpingitis may be caused either by the
infectious trigger or by the sterile reactive process.
• Ocular disease is common, asymptomatic conjunctivitis to an
aggressive anterior uveitis and acute iritis.

9. • The characteristic skin lesion, keratoderma blennorrhagica, consists of
vesicles and/or pustules that become hyperkeratotic, ultimately
forming a crust before disappearing. They are most common on the
palms and soles but may occur elsewhere as well.
• Lesions on the glans penis, termed circinate balanitis, consist of
vesicles that quickly rupture to form painless superficial erosions,
which in circumcised individuals can form crusts similar to those of
keratoderma blennorrhagica. Nail changes are common and consist of
onycholysis, distal yellowish discoloration, and/or heaped-up
hyperkeratosis.
• Less frequent or rare manifestations of ReA include cardiac
conduction defects, aortic insufficiency, central or peripheral nervous
system lesions, and pleuropulmonary infiltrates.

10. LABORATORY AND RADIOGRAPHIC FINDINGS
• ESR and acute-phase reactants are usually elevated during the acute phase
of the disease
• GBP: Mild anemia and polymorphonuclear leucocytosis
• Synivial fluid: leukocyte-Rich ( >2000 wbc/mL with predominance of
neutrophils) and may contain multinucleated macrophages (Reiter’s cells)
• Polymerase chain reaction (PCR) for chlamydial DNA in first-voided urine
specimens may have high sensitivity in the acute stage but is less useful
with chronic disease
• Serum tests for rheumatoid factor and antinuclear antibodies: negative
• HLA B27: positive in more than 75 % of cases

11. • In early or mild disease, radiographic changes may be absent or
confined to juxtaarticular osteoporosis
• With long-standing disease, radiographic features share those of PsA;
marginal erosions and loss of joint space can be seen in affected
joints. Periostitis with reactive new bone formation is characteristic,
as in all the SpAs. Spurs at the insertion of the plantar fascia are
common. Sacroiliitis and spondylitis may be seen as late sequelae.

12. Diagnosis
• Evaluation should include thorough but tactful questioning regarding
possible triggering events.
• On physical examination, attention must be paid to the distribution of
the joint and tendon involvement and to possible sites of
extraarticular involvement, including the eyes, mucous membranes,
skin, nails, and genitalia.
• Synovial fluid analysis is usually necessary to exclude septic or crystal-
induced arthritis.
• Culture, serology, or molecular methods may help identify a triggering
infection

13. Treatment
• High-dose NSAIDs and Analgesics. Indomethacin
• Antibiotics for infections
• Sulfasalazine, azathioprine and methotrexate useful in patients with
disabiling relapsing and remitting.
• DMARDs: for patient with persistent marked symptoms, recurrent
arthritis or severe keratoderm blennorrhagica
• TNF alpha blocking agents for severe and persistent diseases
• Tendinitis and other enthesitic lesions may benefit from intralesional
glucocorticoids.

14. PSORIATIC ARTHRITIS
• Psoriatic arthritis refers to an inflammatory musculoskeletal disease
that has both autoimmune and autoinflammatory features
characteristically occurring in individuals with psoriasis.
• 30% of patients with psoriasis develop PsA
• In white populations, psoriasis is estimated to have a prevalence of
1–3%
• 30% have an affected first-degree relative. In monozygotic twins, the
reported concordance for psoriasis varies from 35–72%, and for PsA
from 10–30%

15. • HLA-C6 is directly associated with psoriasis, particularly familial
juvenile-onset (type I) psoriasis. HLA-B27 is associated with psoriatic
spondylitis (see below).
• HLA-DR7, -DQ3, and -B57 are associated with PsA because of linkage
disequilibrium with C6.

16. • PsA presumably shares immunopathogenic mechanisms with psoriasis.
• PsA synovium is characterized by lining layer hyperplasia; diffuse
infiltrationwithTcells, B cells, macrophages, and NKreceptor–expressing
cells, with upregulation of leukocyte homing receptors; and neutrophil
proliferation with angiogenesis.
• Clonally expanded T-cell subpopulations are frequent and have been
demonstrated both in the synovium and the skin.
• Plasmacytoid dendritic cells are thought to play a key role in psoriasis, and
there is some evidence for their participation in PsA.
• Interferon γ, TNF, and IL-1β, 2, 6, 8, 10, 12, 13, 15, and 17A, and myeloid-
related protein (S100A8/A9) are found in PsA synovium or synovial fluid.

17. • IL-23/17 pathway cytokines are critical drivers of PsA pathogenesis.
Both TH17 cells and type 3 innate lymphocytes (ILC3) have been
identified in dermal extracts of psoriatic lesions and in synovial fluid
of PsA patients.
• Consistent with the extensive bone remodeling in PsA, patients with
PsA have been found to have a marked increase in osteoclastic
precursors in peripheral blood and upregulation of receptor activator
of nuclear factor κB ligand (RANKL) in the synovial lining layer.
• Increased serum levels of TNF, RANKL, leptin, and omentin positively
correlate with these osteoclastic precursors.

18. CLINICAL FEATURES
• 70% of cases, psoriasis precedes joint disease.
• 15% of cases, the two manifestations appear within 1 year of each
other.
• In about 15% of cases, the arthritis precedes the onset of psoriasis
and can present a diagnostic challenge.
• frequency in men and women is almost equal
• The disease can begin in childhood or late in life but typically begins
in the fourth or fifth decade, at an average age of 37 years

19. • Pattern of PsA
(1) arthritis of the DIP joints;
(2) asymmetric oligoarthritis;
(3) symmetric polyarthritis similar to RA;
(4) axial involvement (spine and sacroiliac joints); and
(5) arthritis mutilans (a highly destructive form of the disease.)
• A simpler scheme in recent use contains three patterns: oligoarthritis,
polyarthritis, and axial arthritis.

20. • Nail changes in the fingers or toes occur in most patients with PsA
• Dactylitis and enthesitis are common in PsA
• Shortening of digits because of underlying osteolysis is particularly
characteristic of PsA, and there is a much greater tendency than in RA
for both fibrous and bony ankylosis of small joints.
• Arthropathy confined to the DIP joints occurs in ~5% of cases.
• 30% of patients have asymmetric oligoarthritis
• Symmetric polyarthritis occurs in about 40% of PsA patients at
presentation
• Six patterns of nail involvement are identified: pitting, horizontal
ridging, onycholysis, yellowish discoloration of the nail margins,
dystrophic hyperkeratosis, and combinations of these findings.

21. • Extraarticular and extradermal manifestations are common.
• Eye involvement, either conjunctivitis or uveitis, is reported in 7–33%
of PsA patients.

22. LABORATORY AND RADIOGRAPHIC FINDINGS
• There are no laboratory tests diagnostic of PsA.
• ESR and CRP are elevated in only 30% of patients.
• Serum tests for rheumatoid factor and antinuclear antibodies:
negative
• About 10% of patients have anti-CCP antibodies.
• HLA-B27 is found in 50–70% of patients with axial disease but in ≤20%
of patients with only peripheral joint involvement.

23. Radiographic Features
• Characteristics of peripheral PsA include DIP involvement, including the
classic “pencil-in-cup” deformity; marginal erosions with adjacent bony
proliferation (“whiskering”); small-joint ankylosis; osteolysis of phalangeal
and metacarpal bone, with telescoping of digits; periostitis and
proliferative new bone at sites of enthesitis; and a “ray” distribution of
lesions.
• Characteristics of axial PsA that differ from idiopathic AS include
asymmetric sacroiliitis; less facet joint arthritis; nonmarginal, bulky,
“comma”-shaped syndesmophytes that tend to be fewer, less symmetric,
and less delicate than the marginal syndesmophytes of AS; fluffy
hyperperiostosis on anterior vertebral bodies; severe cervical spine
involvement, with a tendency to atlantoaxial subluxation but relative
sparing of the thoracolumbar spine; and paravertebral ossification.

24. DIAGNOSIS
The CASPAR (Classification Criteria for Psoriatic Arthritis) Criteria
To meet the CASPAR criteria, a patient must have inflammatory
articular disease (joint, spine, or entheseal) with ≥3 points from any of
the following five categories:
1. Evidence of current psoriasis, a personal history of psoriasis, or a
family history of psoriasis
2. Typical psoriatic nail dystrophy observed on current physical
examination
3. A negative test result for rheumatoid factor

25. 4. Either current dactylitisf or a history of dactylitis recorded by a
rheumatologist
5. Radiographic evidence of juxtaarticular new bone formationg in the
hand or foot
• Specificity of 99% and sensitivity of 91%.
• Current psoriasis is assigned 2 points; all other features are assigned 1
point

26. Treatment
• NSAIDs and Analgesics
• Secukinumab and ixekizumab, monoclonal antibodies to IL-17A; and
ustekinumab, a monoclonal antibody to the shared IL-23/IL-12p40
subunit.
• Three monoclonal antibodies to IL-23 (p19 subunit) that are approved
for plaque psoriasis—guselkumab, risankizumab, and tildrakizumab—
showed efficacy in PsA in clinical trials
• Apremilast, an oral phosphodiesterase-4 inhibitor, is approved for
both psoriasis and PsA.
• The oral JAK inhibitor, tofacitinib, is approved for treatment of PsA.
When directly compared, its efficacy was comparable to the anti-TNF
agent adalimumab

27. • Older treatments for PsA have been based on drugsthat have efficacy
in RA and/or in psoriasis. Methotrexate in doses of 15–25 mg/week
has moderate efficacy for psoriasis, and expert opinion favors its use
in PsA not requiring biologics.
• Agents with efficacy in psoriasis reported to benefit PsA are
cyclosporine, retinoic acid derivatives, and psoralens plus ultraviolet A
light (PUVA).
• The pyrimidine synthetase inhibitor leflunomide has been shown to
be beneficial in PsA, with modest benefit for psoriasis.