10/29/2013

Oregon Health & Science University Wins the Knowledge Bowl ACR 2013: Go Portlandumabs!! REACTIVE IN 2013: WHAT HAVE WE LEARNT?

Atul Deodhar MD Professor of Medicine Division of Arthritis & Rheumatic Diseases Oregon Health & Science University Portland, OR

Disclosures Evidence-Based Medicine 1. Townes JM, Deodhar AA, Smith K, et al. Rheumatologic • Honoraria, Advisory Boards: Abbvie, MSD, Novartis, Sequelae of Enteric Bacterial Infection in Minnesota and Pfizer, UCB Oregon: A Population-based Study. Ann Rheum Dis. 2008;67:1689-96. • Research Grants: Abbvie, Amgen, Novartis, Pfizer, UCB 2. On the difficulties of establishing a consensus on the definition of and diagnostic investigations for . Results and discussion of a questionnaire prepared for the 4th International Workshop on Reactive Arthritis, , , July 3-6, 1999.Braun J. et al. J Rheumatol. 2000 Sep;27(9):2185-92. 3. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter's syndrome). A Department of Veterans Affairs Cooperative Study. Clegg DO. et al. Arthritis Rheum. 1996 Dec;39(12):2021- 7.

What is Reactive Arthritis? Reactive Arthritis

• “Arthritis associated with demonstrable infection at a distant site without traditional evidence of sepsis at the affected joint(s)” Andrew Keat, Adv Exp Med Biol 1999;455:201-6 • Classical Pathogens : Chlamydia trachomatis, Yersinia, Salmonella, Shigella & Campylobacter (perhaps Clostridium difficile, Chlamydia pneumoniae & BCG instillation in bladder) • Interval between preceding infection and onset of arthritis — Urethritis Oligoarthritis Chlamydia Minimum of several days & maximum of several weeks Enthesopathies Dysentery • Typical arthritis pattern — asymmetrical mono- or oligo- Rash: Keratoderma Blenorrhagica, nail changes, Campylobacter arthritis, predominantly of the lower extremities Salmonella Psoriasis, Circinate Balanitis Yersinia Eye: uveitis, conjunctivitis • Reactive arthritis of more than six months duration is Shigella Mucosal: oral ulcers, urethritis, cervicitis regarded as being “chronic” instead of “acute” ReA is part of Spondyloarthritis

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ReA is part of Peripheral Spondyloarthritis (ASAS Classification Criteria) Spectrum of Spondyloarthritis (SpA)

Axial Peripheral spondyloarthritis Sensitivity 78% spondyloarthritis Specificity 82%

PsA

AS ReA

A of Non-radiographic IBD axSpA

What % of ‘undifferentiated’ peripheral SpA actually have Reactive Arthritis?

RudwaleitRudwaleit M M et et al. al. Ann Ann Rheum Rheum Dis Dis 2011;70:25 2011;70:25-31-31

Uncertainties in Reactive Arthritis The Tainted Legacy of Hans Reiter

• Several classification criteria with no • Supporter of & the Nazi regime agreement on their use • Wrote a book on the theory of “Racial Hygiene” • Confusion in use of terms: • Proposed killing mentally or physically handicapped, • Reiter’s syndrome ~ Reactive arthritis sterilizing carriers of hereditary defects to ‘purify the race’ • Incomplete Reiter’s syndrome • No rationale to preserve professional memory of • Post-infectious arthritis Reiter • Role of lab tests in the diagnosis: serology? • Reiter’s syndrome is part of Reactive Arthritis PCR? stool culture? • However, ICD-10-CM M02.30 is still “Reiter's disease, • Is arthritis essential for the diagnosis of ReA? unspecified site” (.33 is wrist, .34 is hand etc)

Panush RS. Sem Arthritis Rheum 2003;32:231-36

Reactive Arthritis Vs Post-infectious Arthritis Consensus on ReA 4th International Workshop on ReA, Berlin, July 1999 • Several bacteria are known to cause post-infectious arthritis: acute rheumatic fever, Meningococcus, • ReA: Only if clinical picture & microbes are HLA- Mycoplasma genitalium, Ureaplasma urealyticum, B27 & SpA related Chlamydia pneumoniae, Neisseria gonorrhea, some live • vaccines, beta-hemolytic Streptococci, and Yersinia, Campy, Salmonella, Shigella, Chlamydia Propionibacterium acnes • H/O preceding infection is most relevant for • But these should not be described as ReA since the diagnosis clinical pattern is not like a spondyloarthritis • Minimal interval between infection & arthritis: 1-7 • “Reactive Arthritis” term should be restricted to an acute days, maximum: 4 weeks spondyloarthritis that is linked to acute genitourinary or gastrointestinal infection • Asymmetric, LL>UL, other SpA symptoms • Infection related arthritis: All arthritides associated with infections except septic arthritis Braun J. et al. J Rheumatol. 2000 Sep;27(9):2185-92.

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(Lack of) Consensus on ReA Uncertainties in Reactive Arthritis 4th International Workshop on ReA, Berlin, July 1999 Inflammatory musculoskeletal disease (joint, spine or entheseal) is essential for the diagnosis of ReA • No consensus reached on: • Is arthritis essential for the diagnosis of ReA? . Spectrum of ReA: • Is it oligoarthritis or any arthritis? . Asymmetric, oligoarticular arthritis . Enthesitis/tendonitis/bursitis • What is the role and value of serology or PCR investigation? . Dactylitis . Uveitis/conjunctivitis • Is the diagnostic sensitivity of microbiological tests for ReA increased by HLA-B27 . Inflammatory back pain/sacroiliitis determination? . Erythema nodosum . Circinate balanitis . Keratoderma blenorrhagica Braun J. et al. J Rheumatol. 2000 Sep;27(9):2185-92.

ReA Has Two Presentations Epidemic ReA • June 2nd 1962: USS Enterprise visited a port to celebrate ship’s anniversary • An Epidemic Form • Food prepared with ‘elaborate sanitary • In a Sporadic Form (in the community) precautions’ since the area was endemic for Shigella • An Acute form • Two cooks had contracted • A Chronic form dysentery but concealed it • 602/1276 developed Shigellosis over the next week • 257 were admitted, 174 in the ‘intensive care ward’ Noer HR. JAMA 1966;198:693-98

Epidemic ReA How common is Reactive Arthritis? • Prevalence 30-40/100,000 & annual incidence 5- 28/100,000 adults in Scandinavia • By one month, there # Signs/symptoms B27 were 10 cases of • Most cases occur sporadically and in outbreaks 1 Symptom free - ReA (9 with urethritis, following single source infections 0-21% develop ReA 2 Poly/spondy, balanitis, 8 conjunctivitis) + • Spanish national registry of spondyloarthropathies uveitis, urethritis • 2/10 became (REGISPONSER): 1-year recruitment period disabled: ‘invalidated’ 3 Oligoarthritis, urethritis, + uveitis, conjunctivitis Diagnosis # of Patients (1385, 68% men) % of Patients out of Navy AS 842 61% 4 Blind in one eye uveitis, • 10 years later, 5 were + PsA 290 21% poly/urethritis/balanitis traced, re-interviewed USpA 205 15% & re-examined 5 Oligo/spondy, balanitis, + ReA 16 1.2% urethritis, uveitis IBD arthritis 13 0.9%

Calin A. Ann Int Med 1976;84:564-66 Colantes E. et al. Rheumatology (Oxford). 2007 Aug;46(8):1309-15.

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How common is Reactive Arthritis? The Oregon Study on Reactive Arthritis

• Population-based study in OR & MN (2002-04) • ReA after culture-proven bacterial infection (Shigella • HLA B27 prevalence was not different between Salmonella, Campylobacter &Yersinia) of the GI tract cases and controls • All patients with new onset of joint/tendon/back • This may indicate that the “Community acquired” discomfort > 3 days within 8 weeks of culture included ReA may be different from the “epidemic” type ReA • 13% (575) of 6379 culture-confirmed infections where presence of HLA B27 leads to increased risk developed ‘possible’ ReA for development of ReA • Only 82 could be examined and 66% (56) were • Use of antibiotics during acute diarrheal illness did confirmed ReA not affect development of, or severity of ReA • The estimated incidence of ReA in Oregon is 0.6-3.1 per 100,000 population Townes JM, Deodhar AA, Laine ES et al. Ann Rheum Dis. 2008 Dec;67(12):1689-96 Townes JM, Deodhar AA, Laine ES et al. Ann Rheum Dis. 2008 Dec;67(12):1689-96

Is Reactive Arthritis Under Reported? Pathogenesis of ReA

• Chlamydia tr (Ct) is the most common trigger of ReA • ReA: Genetically predisposed host, known • CDC estimates new Ct genital infections to be 3 million/yr bacterial infections, relatively short period of with 4-6 million active cases at any given time time • 5% get ReA after Ct infection in prospective studies • Despite this, the pathophysiology is unclear • 150,000 cases of acute Chlamydia-induced ReA would occur in the US each year compared to 125,000 new cases • Several uncertainties exist: of RA per year (incidence of RA: 44.6/100,000) • What is the role of HLA-B27? • The above figure does not include ‘GI induced ReA’ • What is the role of bacteria in the pathogenesis of • Is ReA more common than RA?? Reactive Arthritis? • (However, only 4%–19% of patients go on to develop a • Is the arthritis Septic or Aseptic? protracted course of ReA lasting more than 1 year*) • Should long-term antibiotics be used?

*Leirisalo-Ripo M. Rheum Dis Clin N Am 1998;24:737-51

Pathogenesis of ReA What is the role of HLA-B27* in pathogenesis? What is the role of genetic factors? Homodimer 2 Protein misfolding, formation due to • In rats & mice transgenic for resulting in pro- Cys67 residue on α-1 human HLA-B27 + 2 inflammatory chain (unique to HLA- Unfolded Protein B27)resulting in microglobulin, spontaneous Response recognition by NK arthritis develops only when 3 cells receptors the animals are outside a germ-free zone 1 HLA B27 may Altered intracellular 5 4 killing in certain Binding of a unique • Arthritogenic peptide theory: influence the human infections, antigenic (self) suggesting that HLA-B27 groove binds peptide microbiome. ‘special’ peptides infection or immune Change in response may act • Molecular mimicry theory: microbiome as a trigger Homology between HLA-B27 predisposes to AS structure & bacterial antigens *most of the work is done in AS Reveille J, Arnett F. Am J Med. 2005;118:592-603. Khare SD. J Exp Med 1995;182:1153-58 Reveille J. Curr Rheumatol Rep. 2009;11:340-348. Rosenbaum J, Davey M. Arthritis Rheum 2011;63:3195-98

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What is the role of infection in ReA? Clinical Manifestations of ReA

• Pathogenesis of post-Chlamydia & post-enteric ReA may be different even though the phenotype is very similar • Post-Chlamydia ReA is “aseptic” but may not be “sterile” • Bacteria/bacterial products shown by PCR in synovium & skin lesions in post-Chlamydia, but not consistently in post-enteric ReA Asymmetric oligoarthritis • Chlamydia are in morphologically aberrant (gene Enthesitis expression attenuated) but metabolically active form • Bacteria/bacterial products also shown in OA, RA synovium, but the prevalence is much lower • Conclusion: Bacteria trigger an autoimmune response & participate in perpetuating the disease

Carter J. Best Pr & Res Clin Rheum 2010;24:701-714 Dactylitis Spondylitis

Clinical Manifestations of ReA Investigations in ReA Keratoderma Blenorrhagica • Synovial fluid examination • HLA-B27 (<50%) • Nonspecific tests for Acute phase reactants: • ESR, CRP • Imaging: X-rays, US/MRI for enthesitis • Infection-related tests: Positive in 50% • Stool Cultures (unclear in the absence of GI symptoms) Circinate Balanitis • Chlamydia trachomatis urine test (is specific based on DNA amplification, send even in asymptomatic individuals) • Serological (antibody) tests for Yersinia, Salmonella Acute Anterior Uveitis Campylobacter – no consensus Conjunctivitis

Are long-term antibiotics beneficial in ReA? Treatment of ReA • 12 months RDBPC trial: 71 pts with ReA randomized to . 50% of patients recover from ReA within the initial Ciprofloxacin 500 mg or placebo BID X 3 months 6 months, only 4%–19% of patients go on to develop a protracted course of ReA lasting more • Outcome measures: #swollen joints, ESR, PtGA than 1 year • Both groups improved with no statistical difference . No treatment recommendations exist for ReA • Conclusion: No advantage of Ciprofloxacin X 3mths . Current treatment choices: . All 71 patients re-invited 4-7 years later, 53 agreed . NSAIDs . Significantly more from placebo group (41% vs 8% . Antibiotics p<0.006), had developed chronic rheumatic disease, 2 . DMARDs: Sulfasalazine, Methotrexate on placebo had AS, 3 had recurrent anterior uveitis . Anti-TNF agents . Conclusion: 3 mths of Ciprofloxacin may be beneficial! Yli-Kerttula T et al. Ann Rheum Dis 2000 Jul;59(7):565-70 Leirisalo-Ripo M. Rheum Dis Clin N Am 1998;24:737-51 Morris D. et al. Curr Rheumatol Rep (2012) 14:390–394 Yli-Kerttula T et al. Ann Rheum Dis 2003 Sep;62(9):880-4

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Are long-term antibiotics beneficial in ReA? Long-term Antibiotics in Chlamydia Induced ReA “The EULAR trial” • 9-mth, prospective DBPCT on Swollen Joint Count • DBRPC trial on 186 patients with ReA from 12 Chlamydia +ve pts by PCR countries • Doxy+Rifam (n=12), 6 • All received Azithromycin 1 g, then randomized to Azithro+Rifamp (n=15) or Pl (n=15) 5 weekly Azithromycin or Placebo for 24 months • 10 endpoint: 20% improvement in 4 • 152 completed the trial, mean age 34, mean CRP 4/6 parameters without worsening 3 in the remaining Combi- 4.8/dl, 50% were HLA-B27 +ve 2 Antibio • Results: 10 endpoint 63% vs 20%, • No statistical difference between the groups in 1 Placebo number of swollen/tender joints, joint/back/heel pain, remission 22% vs 0%, 70% –ve for Chlamydia by PCR in AB group 0 physician & patient GA, CRP • Conclusion: 6-mth Rx of

• Conclusion: Prolonged treatment with antibiotics is combination antibiotic useful for

Baseline

month month 6

Month Month 1 Month 3 Month Month 9 ineffective in ReA Chlamydia induced chronic ReA

Kvien TK et al. Ann Rheum Dis. 2004 Sep;63(9):1113-9 Carter JD et al. Arthritis & Rheum 2010;62:1298–1307

Antibiotics for treatment of ReA: ReA Treatment: Sulfasalazine Systematic Review & Meta-analysis • VA cooperative study: 134 patients • Inclusion criteria: RCTs of antibiotics for treatment of ReA, with ReA unresponsive to NSAIDs Response in % Pts reporting remission, joint counts, pain or patient global • DBRPC 36-wk study: 70 62.3 • 12 included, 10 provided data for meta-analysis SSZ (2 grams/day) or Placebo 60 47.7 • Results: No significant benefit of antibiotic treatment on • Definition of treatment response: 50 remission (7 trials, n=375, pooled RR of failure to achieve 40 remission 0.74, 95% CI 0.49-1.10) Joint pain/tenderness & swelling scores plus physician & patient 30 • Treatment effect did not differ significantly by type of 20 global assessments organism, use of mono Vs combination antibiotics 10 • Limitations: Definition of ReA loose (arthritis/arthralgia • Results: 0 post-skin infection & URTI included), only 1 trial used SSZ group did better than placebo SSZ Placebo rifampicin (62.3% vs 47.7% P = 0.02), • Bottom-line: “Heterogeneous results, antibiotics efficacy ESR declined more with SSZ than still uncertain” placebo (P < 0.0001) Clegg DO. et al. Arthritis Rheum. 1996 Dec;39(12):2021-7. Barber CE. et al. J Rheumatol. 2013 Jun;40(6):916-28.

Adalimumab in Peripheral SpA (ABILITY 2) TNF Inhibitors use in ReA • Peripheral SpA patients 45 *P=0.006; NRI • No guidelines for aggressive treatment, if initial Rx fails (ASAS criteria, n=165) 40 without PsO randomized • No RCT on TNFi in ReA 35 to ADA 40 mg qow or • 30 Anecdotal experience is positive PBO for 12 weeks *P=0.001; Observed data 25 • 1° endpoint: Peripheral 20 SpA Response Criteria Placebo 15 (PSpARC) 40: ≥40% Adalimumab improvement in PGA, 10 PGA-pain, SJC/TJC, 5 enthesitis count, dactylitis 0 count

Morris D. et al. Curr Rheumatol Rep (2012) 14:390–394 Mease P, et al. EULAR 2012, Berlin, THU0280

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Summary • Several uncertainties remain in the diagnosis and treatment of Reactive Arthritis • ReA is a subset of SpA, & the term is limited to arthritis after Salmonella, Shigella, Yersinia, Campylobacter & Chlamydia infections Thank you • With high prevalence of chlamydial plus enteric infections, ReA may be significantly under-recognized (?“uSpA”) with a significant physical and economic burden • Commonest presentation oligoarticular inflammatory arthritis, tendonitis, enthesitis, eye and skin involvement • Long-term combination antibiotics (including rifampicin) may be useful in chronic Chlamydia induced ReA • Sulfasalazine & anti-TNF useful in difficult cases

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