Reactive Arthritis John D. Reveille, M.D.
Reactive Arthritis-Definition • An arthritis that arises following an infection, although the pathogens cannot be cultured from the affected joints. • It is generally regarded as a form of spondyloarthritis.
Spondyloarthropathies (SpA), Psoriasis, Inflammatory Bowel Disease, and Uveitis Uveitis Ankylosing spondylitis (AS)
Undifferentiated SpA Arthritis associated with ulcerative colitis Crohn disease
Psoriatic arthritis (PsA)
Reactive arthritis (ReA)
Inflammatory bowel disease
Adapted from Khan MA.
Reactive Arthritis-History • 1600-Thomas Sydenham • 1776-Stoll describes a soldier in the Continental Army with arthritis following dysentery • 1818-Benjamin Brodie (1783-1862) describes a case of sexually acquired reactive arthritis in a 45 yo man presenting with urethritis, conjunctivitis and arthritis at St. George’s hospital • 1916-Reiter describes urethritis, conjunctivitis and arthritis in a German soldier • 1916-Fiessenger and Leroy (France)
Urethritis Epidemiology • Chlamydia is the most commonly reported bacterial infection in the United States • Gonorrhea is the second most commonly reported communicable disease in the United States • An estimated 2.86 million cases of chlamydia and 820,000 cases of gonorrhea occur annually in the United States • Some epidemiologic surveys have shown a chlamydia coinfection rate of up to 46% percent among men and women with gonorrhea
It is thought that less than 50% of these infections are detected and reported to the CDC
ReA epididemiology • Reactive arthritis is said to be a very uncommon disease • Much of the data on the prevalence and annual incidence of reactive arthritis in populations come from the Scandinavian countries – The prevalence is estimated to be 30 to 40 per 100,000 adults, and the annual incidence is from 0.6 to 27 per 100,000
• Among patients with any of the spondyloarthritis variants seen by rheumatologists, those with reactive arthritis are a small minority – Spanish study showed 1.2 to 1.4% of all patients with SpA had been diagnosed with ReA
• This typically occurs in young adults, affecting both men and women – The postdysentery form of ReA affects men and women with the same frequency, whereas the postvenereal form occurs at a male-to-female ratio of 9:1
DGI Epidemiology • Neisseria gonorrhoeae is the most common STI causing infective arthritis • During the 1970s and 1980s, it was also the most common cause of infective arthritis in the United States • DGI occurs in 0.5 to 3% of patients infected with N. gonorrhoeae – Calculates to 4100 to 24600 cases estimated per year in US
• Most are younger than 40 years of age, although DGI can occur in any age group • DGI historically occurred more frequently in women than men – However, a more recent study from France suggested that in some western countries DGI may now be more common in men than women
What is the cause of Reactive Arthritis?
Genes such as HLA-B27 can make you Susceptible
New Bone Formation
•Infection •Toxins •Biomechanical Forces
HLA-B27 and the Seronegative Spondyloarthritides HLA-B27 Disorder frequency (%) Ankylosing spondylitis 90% Reactive arthritis 70% Psoriatic arthritis 25% Psoriatic spondylitis 60% Enteropathic arthritis 7% Enteropathic Spondylitis 70% ---------------------------------------------------------------------Normal Caucasians 7.5%
HLA-B27 in ReA • The risk of ReA in HLA-B27-positive patients has been reported in another study to be up to 50 times higher after the exposure of a triggering infection compared to HLA-B27negative patients in hospital-based studies . However, this number is possibly (partly) biased due to inclusion of the most severe cases in hospital based studies.
How does HLA-B27 predispose to AS? Protein misfolding, resulting in pro-inflammatory Unfolded Protein Response
Homodimer formation due to Cys67 residue on a-1 chain (unique to HLA-B27) resulting in recognition by NK cell receptors Altered intracellular killing in certain infections, suggesting that infection or immune response may act as a trigger
Binding of a unique antigenic (self) peptide
HLA B27 may influence the human microbiome. Change in microbiome predisposes to AS
Reveille J Am J Med. 2005;118:592-603 Rosenbaum JT et al. A&R 2011;63:3195-98
Anatomy of the Microbiome
Lee YK et al. Science 2010:;330:1768
Microbiome and genome interactions contribute to inflammation
Lee YK et al. Science 2010:;330:1768
HLA-B27 and human β2-microglobulin affect the gut microbiota of transgenic rats
Lin et al, PLoS One. 2014 Aug 20;9(8):e105684. doi: 10.1371/journal.pone.0105684
MICA-Function • T cells with variable region V-delta-1 gamma / delta T cell receptor (TCRG, 186,970; TCRD, 186,810) are distributed across the human intestinal epithelium and may function as sentinels that respond to self antigens. MICA expression coincides with this location. • Groh et al. (1998) found that the MICA and the closely related MICB were recognized by intestinal epithelial T cells expressing different V-delta-1 gamma / delta TCR. These interactions involving domains alpha-1/alpha-2 MICA and MICB but were independent of antigen processing. • With intestinal epithelial cell lines, the expression and recognition of MICA and MICB could be stress induced. • Therefore, these molecules in general can regulate the response to protect the V-Delta-1 gamma / delta T cells in the epithelium of the intestinal tract.
ReA Pathogenesis •
• • • • • •
Recent evidence of elevated levels of IL-10 and TGF b-secreting cells in the synovial membrane of patients with Chlamydia ReA compared with RA also indicates ineffective elimination of the microbes in the joint, permitting the prolongation of arthritis An imbalance in the production of proinflammatory cytokines by peripheral blood mononuclear cells during acute arthritis (low production of TNF) has been observed After invasion via the mucosal route, the microbes persist either in the epithelium or within associated lymphoid tissues, liver, and spleen The viable organisms or bacterial antigens are disseminated to the joint, causing a local inflammatory response A CD4+ T-cell response to the invading microorganism drives, and probably supports, the arthritis A poor T helper 2 cytokine response may favor the persistence of the microbes or antigens and contribute to the poor elimination of the antigens in the host The persistence of microbial structures in the host could be explained by an impaired elimination of the microbes by deficient cytokine reaction or defective function of HLA-B27
Conditional analysis of HLA-B27 negative subjects for MICA allele associations with AS, and MICA alleles for HLA-B27 association with AS. AS patients
MICA*007:01 (+) US cohort -MICA*007:01 (-)
US cohort - HLA-B27 (-)
Chinese cohort - HLA-B27 (-) MICA*007:01 (+)
MICA*007:01 or *019 (+) Chinese cohort -MICA*007:01 (-)
HLA-B27 (+) Chinese cohort-MICA*019 (-)
Chinese cohort - MICA*007:01 and *019 (-) HLA-B27 (+)
Zhou X, et al .Ann Rheum Dis. 2013 Jun 1. [Epub ahead of print]
ERAP in AS
Haroon N, Inman RD. Nat Rev Rheum 6:462, 2010
HLA Class I, ERAP1, ERAP2, NPEPPS
HLA Class I, ERAP1, ERAP2
HLA Class I, ERAP1
Parkes et al Nat Rev Genet in press
New Loci Established In AS Susceptibility Genomic Inflation factor 1.047
Novel Associations and Implicated Genes/Pathways • IL-17 mediated immunity • IL23R, TYK2, IL6R, IL7R?, IL7?, IL1R2/IL1R1, IL12B
• CD8 T cell function • RUNX3, EOMES, IL7R?
• Peptide Presentation • MHC, ERAP1, UBE2E3, UBE2L3, NPEPPS
• Microbial sensing • CARD9, NOS2
• Other • ZMIZ1, FCGR2A, KIF21B, SH2B3, TNFRSF1A, GPR65, SULT1A1, GPR35, BACH2, ICOSLG, NKX2-3
IL-23 Signalling Gene
AS, IBD, PS
AS, IBD, PS, MS
IBD, PS, MS
AS, IBD, PS, MS, RA, T1D, PBC Parkes et al Nat Rev Genet in press
Bacteria Associated with Reactive Arthritis • Chlamydia trachomatis (endemic) • Salmonella (various) • Shigella, especially Shigella flexneri, but also Shigella dysenteriae and sonnei • Yersinia, including Yersinia enterocolitica 0:3 and 0:9 and Yersinia pseudotuberculosis • Campylobacter, especially Campylobacter jejuni • Clostridium difficile
ReA Pathogenesis • The classical bacteria capable of triggering the arthritis are gram-negative obligate or facultative intracellular aerobic bacteria with a lipopolysaccharide-containing outer membrane • They are invasive and cause primary infection of gastrointestinal mucosa or urogenital mucosa • The invasiveness of the bacteria is probably not attributed to genetic factors (HLA- B27), but more likely an impaired elimination of the microbes in the infected host • In patients with ReA, bacterial antigens seem to disseminate in the body, and Chlamydia, Yersinia, Salmonella, and Shigella antigens have been detected in the synovial fluid or in synovial tissue
Impaired IL23 Production in ReA • PBMNs and macrophages from healthy subjects with previous ReA show normal inflammasome activation and low TNF-α and IL-23 production. This low cytokine production may impair bacterial elimination and thereby contribute to the triggering of ReA. Välimäki et al. Scand J Rheumatol. 2013;42(4):294-8
Enteric pathogens and reactive arthritis: a systematic review of Campylobacter, salmonella and Shigellaassociated reactive arthritis • A systematic literature review to establish the global incidence of ReA for each of the three most commonlyassociated enteric pathogens: Campylobacter, Salmonella, and Shigella. • The weighted mean incidence of reactive arthritis was 9, 12, and 12 cases per 1,000 cases of Campylobacter, Salmonella and Shigella infections respectively • Ajene et al, Health Popul Nutr. 2013 Sep;31(3):299-307.
ReA Epidemiology • However, data indicate that about 5% of patients develop objective features consistent with ReA after a Ct infection • With an attack rate at 5%, as many as 150,000 cases of acute chlamydia-induced ReA would occur in the US each year – 3 million x 0.05 – This is a low estimate representing half or fewer of the total cases, because does not include cases from postdysentary organisms
Clinical Manifestations • an asymmetric oligoarthritis, usually one to four weeks following the inciting infection • In at least half of patients, all symptoms resolve in less than six months; in most patients, symptoms resolve within one year. The several types of clinical manifestations of reactive arthritis include: ]. •
Musculoskeletal signs and symptoms – Arthritis — Usually see acute onset asymmetric oligoarthritis, often affecting the lower extremities • About 50% have arthritis in the upper extremities and some have polyarthritis in the small joints • Less often axial arthritis can occur involving the spine at any level and the SI joints • If symptoms continue for more than six months, this is considered chronic ReA
Enthesisis in Reactive Arthritis Enthesitis — Inflammation at the site of insertion of ligaments, tendons, joint capsule, or fascia to bone Swelling at the heels is among the most characteristic symptom of enthesitis Common sites of heel involvement are at the insertions of the Achilles tendon and of the plantar fascia on the calcaneus. Pain, swelling, and local tenderness are suggestive clinical features Estimates of the frequency of enthesitis in patients with reactive arthritis have ranged from 20 to 90% and may be more common than arthritis
Dactylitis – Dactylitis — Some patients also develop sausage digits • The frequency is not reported in ReA, but probably less than in psoriatic arthritis
Extraarticular signs/symptoms • • • • • • • • •
• • •
Conjunctivitis and, less frequently, anterior uveitis . Episcleritis and corneal ulcers are also occasionally seen. Genitourinary tract symptoms, such as dysuria, pelvic pain, urethritis, cervicitis, prostatitis, salpingo-oophoritis, or cystitis Oral lesions, including mucosal ulcers Constitutional symptoms, such as fever, malaise, headache, and weight loss, which may occur during the acute phase of illness and then generally resolve Rashes such as keratoderma blennorrhagica (hyperkeratotic skin lesions on soles and palms) and erythema nodosum Nail changes that resemble those seen in psoriasis, although pitting of the nails, which is often present in psoriasis, is typically absent in reactive arthritis Genital lesions such as circinate balanitis Cardiac manifestations, which are uncommon but include pericarditis during the acute illness and valve disease, such as aortic insufficiency, with greater chronicity of illness None of these manifestations is specific for reactive arthritis. Balanitis, for example, may result from any of numerous causes other than reactive arthritis.
Septic arthritis Gout Diarrhea and arthritis –
Enteroviral infection-associated arthritis may represent a substantial number of cases of nonspecific, selflimited inflammatory joint disease; although arthritis is an uncommon manifestation of enterovirus infection, viral gastroenteritis is relatively common. Additional symptoms suggestive of a viral etiology include the presence of myalgias, an evanescent rash, and constitutional symptoms such as fever. Both large and small joints may be involved. Sore throat, pleuritic pain, and myocarditis are other features suggestive of enteroviral infection.
Inflammatory bowel diseases (eg, Crohn’s disease and ulcerative colitis), Behçet’s disease, celiac (sprue) disease, Whipple’s disease, parasitic infections, and intestinal bypass surgery may cause diarrhea and arthritis Genitourinary symptoms/disorders and arthritis — – –
Disseminated gonococcal infection (DGI) is the primary cause to consider when urethral, uterine, cervical, or tuboovarian inflammation occurs in a patient with arthritis. The presence of a rash and tenosynovitis are suggestive Arthritis and arthralgias are a rare complication of intravesical Bacillus Calmette-Guerin (BCG) treatment for bladder cancer.
Poststreptococcal arthritis — Arthritis is a common manifestation in patients with acute rheumatic fever (ARF) following streptococcal pharyngitis. These patients typically lack features common to the spondyloarthritides (eg, enthesitis), and this condition is generally not considered to be a form of reactive arthritis. Other clinical and laboratory manifestations of rheumatic fever and evidence of recent streptococcal infection distinguish these patients from those with reactive arthritis. A “poststreptococcal reactive arthritis” has been described, but most consider such patients to have ARF. These issues are discussed elsewhere.
ReA vs. DGI
HIV-Associated Reactive Arthritis • The higher frequencies reported in patients from the U.S. have been attributed to behaviours also associated with HIV infection, however this is contradicted by recent data from Africa in the HIV epidemic. • HLA-B27 is positive in the majority of whites and Hispanics, but is virtually absent in Africans.
CONTRASTING FEATURES OF HIV-ASSOCIATED ARTHRITIS AND REACTIVE ARTHRITIS
HIV-Assoc Reactive Arthritis
Synovial Fluid WBC
Organisms in synovium
ReA Diagosis • The diagnosis of ReA is clinical without a single definitive diagnostic test or validated diagnostic criteria • The diagnosis can generally be made in patients with all three of the following: – Characteristic musculoskeletal findings - oligoarthritis of peripheral joints, usually asymmetric involvement of the lower extremity, enthesitis, dactylitis, or inflammatory back pain – Evidence of preceding extraarticular infection – urethritis or diarrhea – Lack of evidence for another more likely cause of oligoarthritis, monoarthritis, or enthesitis
LABORATORY AND IMAGING FINDINGS • Serologic or other evidence of antecedent or concomitant infection • Elevated acute phase reactants • HLA-B27 testing • Inflammatory synovitis • Imaging abnormalities consistent with enthesitis or arthritis
ReA Diagnosis – The findings in synovial fluid are nonspecific and are characteristic of inflammatory arthritis, with elevated leukocyte counts, predominantly neutrophils • WBC counts are typically between 2000 and 64,000 WBC per mm
– Synovial cultures should be negative – As discussed earlier, synovial tissue biopsy may show +Ct PCR, however this is not routinely done for diagnosis
ReA Diagnosis • In a patient with a typical arthritis presentation, in whom other diagnoses have been excluded, plus a history of proven symptomatic preceding infection by Chlamydia trachomatis, the probability of reactive arthritis is very high (increased to about 90%)
ReA Diagnosis • Other supporting diagnostics may include: • Elevated acute phase reactants – elevations in acute phase reactants were found in less than half of patients diagnosed with reactive arthritis in one study – nonspecific
• Positive testing for HLA-B27 – The prevalence of HLA-B27 is generally estimated at 30 to 50% in patients with reactive arthritis, although values range widely – In hospital-based studies with more severely affected patients, frequencies as high as 60 to 80% have been reported – May be helpful in patients with intermediate probability of ReA
• Inflammatory synovitis • Imaging abnormalities consistent with enthesitis or arthritis
The Role of Serologic Examination in the Diagnosis of Reactive Arthritis Serology for Yersinia Infections • An indirect hemagglutination test (IHA) was among the first serological tests • Using Immunoblot IgA antibodies to a 36-kDa protein were present in 18/19 ReA compared to 8/17 with unclear • an issue for scientific debate. • The most important are invasin (Inv), YadA (Yersinia adhesion A, previously known as Yop1), which is the major adhesin, and Ail. These antibodies were more prevalent in patients with gastroenteritis compared to ReA patients ( Serology for Campylobacter Infections • Campylobacter serology is highly variable. • In the early 1980s, EIA-based techniques emerged • IgM and IgG-class antibodies were positive in only 73 and 52%, respectively in culture confirmed hospitalized patients . The seroprevalence to this antigen in healthy blood donors increases with age, reaching 60, 42, and 21% for the age group of 56–65years for IgG, IgA, and IgM, respectively ( • It is evident that, IgM-class antibodies may persist, making an assumption of acute infection on the basis of a single serum specimen imprecise. • Secondly, diagnostic serology is more informative in younger subjects. Serology for Salmonella Infections • IHA utilizes erythrocytes sensitized with the Salmonella O-antigen. • The sensitivity is only 62% and specificity 98.2% with positive and negative predictive values of 66.7 and 96.7%, respectively • Demonstration of antibodies to LPS of salmonellae other than S. typhi is common practice, especially in S. typhimurium or S. enteriditis infections, the two predominant serogroups responsible for the majority of gastroenteritis in Europe. In patients who had salmonellosis the LPS antibodies were equally detected with antigens prepared from phenolic or trichloro acid extraction; however, in the control group these antibodies were also highly prevalent. Serology for Shigella Infections • Lumixex™ technology allowed simultaneous detection of specific antibodies to recombinant invasin plasmid antigens Ipa B, C, and D as wells as to LPS from Shigella sonnei, flexneri 2a, and dysenteriae • Although promising, this technology has not yet been widely evaluated to support ReA diagnosis. Serology for Chlamydia trachomatis • A huge body of seroepidemiological studies on Chlamydia using in-house and commercial MIF has been published. • In the 1990s EIA-based techniques emerged. • However, the evidence of specific antibodies does not prove casualty. • In our and other’s opinion whatever serology for C. trachomatis is used, it is of a limited value for ReA.
Treatment of Reactive Arthritis Treatment of the infection Antibiotics are not used to treat the arthritis specifically but may be indicated for treatment of the underlying infection if there is evidence of ongoing genitourinary infection or carriage of potentially pathogenic organisms. A role for antibiotic therapy in the treatment of chronic arthritis has not been established. Enteric infection — In general, antibiotics are not indicated for uncomplicated enteric infections, but some patients with active enteric infections may require treatment, depending upon theircomorbidities and upon the specific organism. For example, therapy may be indicated in patients with severe gastrointestinal disease, in older adults, or in immunocompromised hosts. Treatment of enteric infections is discussed separately. Genitourinary tract infection — In contrast with most patients with enteritis, patients with acute Chlamydia trachomatis infection of the genitourinary tract and their sexual partners should receive antimicrobial treatment. Treatment regimens are presented elsewhere
Antibiotics and Reactive Arthritis • Routine use of long-term antibiotics to treat established reactive arthritis not established • One study has suggested that combination antibiotics might be useful in the subset of patients with PCR-proven Chlamydia-induced arthritis (Carter JD et al. Arthritis Rheum. 2010;62:1298-307), • A more recent study of 56 patients with recent onset ReA found that three-month treatment with the combination of ofloxacin and roxithromycin had no advantage over placebo in patients with recent-onset ReA (Kuuliala et al. Rheumatol Int. 2013 Jun 20. [Epub ahead of print]) • A recent meta-analysis of 10 randomized controlled trials of antibiotics for treatment of ReA concluded “Trials of antibiotic treatment for ReA have produced heterogeneous results that may be related to differences in study design. The efficacy of antibiotics is uncertain.” Barber et al, J Rheumatol.2013 Jun;40(6):916-28
Treatment of Acute Reactive Arthritis •
Nonsteroidal anti-inflammatory drugs — NSAIDs in full anti-inflammatory doses for symptomatic therapy for most patients, unless contraindicated (eg, due to allergy, cardiovascular, or renal status. Intraarticular glucocorticoids — In patients who do not respond adequately to NSAIDs, we suggest injection of major affected joints with intraarticular glucocorticoids. Systemic glucocorticoids — In patients who do not respond adequately to NSAIDs and intraarticular glucocorticoid injections or in those with a large number of involved joints, we suggest low to moderate doses of oral glucocorticoids (eg, a starting dose of prednisone 20 mg daily), which should be reduced gradually to the lowest dose required to control symptoms. Resistant to NSAIDs and glucocorticoids — Treatment with a DMARD is indicated in patients who do not respond adequately to initial therapies. The duration prior to beginning DMARDs depends upon the degree of disease activity and upon the relative risks and benefits of NSAIDs and glucocorticoids in a given patient, given the comorbidities that are present and the dose of glucocorticoids required to control symptoms. We generally use DMARDs in patients who have not responded adequately to at least two different NSAIDs over a total of four weeks and who require ongoing therapy with more than 7.5 mg of prednisone or equivalent for more than three to six months.
Treatment of Chronic Reactive Arthritis •
DMARD s – Sulfasalazine. • initiate treatment with 500 mg once daily and increase the daily dose stepwise (in increments of 500 mg each week) to 1000 mg twice daily. • The dose can be increased to a maximum of 3000 mg/day (taken in two or three divided doses) if required.
– Methotrexate — • Methotrexate (MTX) may be used as an alternative nonbiologic DMARD for patients who may be allergic to or intolerant of SSZ or who do not respond to SSZ treatment. • MTX has not been formally studied in patients with reactive arthritis
– Duration of therapy • DMARDs can be continued for at least four months (SSZ) or three months (MTX) at the maximally tolerated therapeutic dose (up to 3 g/day SSZ or up to 25 mg/week MTX) to determine if there is a response to therapy and are then discontinued three to six months after the patients have entered into remission, with resolution of clinical signs and symptoms of disease activity.
Anti-TNF Agents – For patients who have reactive arthritis that is refractory to NSAIDs and glucocorticoids and who do not respond to or have a contraindication to the use of sulfasalazine and methotrexate, an anti-tumor necrosis factor (TNF) agent may be indicated. – In patients who do not respond to an initial trial of one agent after three months of therapy, another TNF inhibitor can be tried instead. – An effort can be made to discontinue therapy in patients who have been in remission induced by a TNF inhibitor for at least three months, but treatment should be resumed with the medication if disease then recurs. – The use of TNF inhibitors in patients with reactive arthritis is directly supported only by case reports and by small case series. – There are no studies of patients with reactive arthritis refractory to the above therapies,
Treatment of HIV-Associated Reactive Arthritis • NSAIDs – Indomethacin has been observed to inhibit the replication of HIV in vitro \
• Sulfasalazine – Effective in some studies at doss of 1.5 to 2 gm/day. – One study suggested an ameliorative effect on HIV infection.
• Methotrexate – Initially thought to be contraindicated, but now safe as long as guidelines followed
• TNF blockers
Use of anti-TNF agents in ReA Author, Year No. patients Rx