Ankylosing Spondylitis

1

• Ankylosing Spondylitis

2
Case

• 52 yo wm c 25 yr hx of AS. Recurrent iritis and
  persistent bilateral knee synovitis treated with
  indomethacin and local steroid injections.

3

• In 2006 increasing knee pain with failure of
  cortisone injections led to consideration of TKR.
  Low grade fever by hx, weight loss, anemia,
  malaise and an increase of creatinine to 2.0 led
  to dc of indocin.
• On Clinoril or Diclofenac creatinine 1.8.
  Chronic kidney stones. Sed rate 120 CRP 18.
  SPEP IgM lambda monoclonal spike
• 0.2 gm/dl Ig G 2500 IgA and IgM normal. Bone
  marrow normal. Upper and lower endoscopies
  negative.

4

• Lab hgb 9.4 , wbc 9900, plt 792,000 sed 112
• crp 18.1 urinalysis hematuria, no protein.
  Renal consult saw and found an negative ANA, but
  a positive ANCA with PR3 of 97 (20). Nephrologist
  thought he saw one red cell cast.
• Lung and ENT CTs and eval neg for Wegeners.
  Kidney biopsy showed no glomerulonephritis, very
  minimal interstitial inflammation.

5
Attempted right TKR, but surgeon closed the
procedure thinking tissues looked infected.
Extensive evaluation of the knee tissues and for
SBE for infection were negative.
6

• Temporal artery biopsy was negative. PPD neg pt
  was started on Enbrel and left off an NSAID.
  Three weeks later ESR was 50 crp 3, pt had
  gained 5 lbs had continued neck pain. Scheduled
  for TKR again.

7

• False positive PR3
• Perioperative use of antiinflammatories and
  immunosuppressants.
• 3. Effects of above meds on bone fusion
  surgeries.

8
C-ANCA Pattern

• Demonstration of cytoplasmic antineutrophil
  cytoplasmic antibodies (C-ANCA) by indirect
  immunofluorescence with normal neutrophils. There
  is heavy staining in the cytoplasm while the
  multilobulated nuclei (clear zones) are
  nonreactive. These antibodies are usually
  directed against proteinase 3 and most patients
  have Wegener's granulomatosis. Courtesy of Helmut
  Rennke, MD. , 2007 UpToDate

9
P-ANCA Pattern

• Demonstration of perinuclear antineutrophil
  cytoplasmic antibodies (P-ANCA) by indirect
  immunofluorescence with normal neutrophils.
  Staining is limited to the perinuclear region and
  the cytoplasm is nonreactive. Among patients with
  vasculitis, the antibodies are usually directed
  against myeloperoxidase. However, a P-ANCA
  pattern can also be seen with autoantibodies
  against a number of other antigens including
  lactoferrin and elastase. Non-MPO P-ANCA can
  be seen in a variety of nonvasculitic disorders.
  Courtesy of Helmut Rennke, MD. , 2007 UpToDate

10
PR3

• Subacute bacterial endocarditis with positive
  cytoplasmic antineutrophil cytoplasmic antibodies
  and anti-proteinase 3 antibodies.
• AU
• Choi HK Lamprecht P Niles JL Gross WL Merkel
  PA
• SO
• Arthritis Rheum 2000 Jan43(1)226-31.

11

• OBJECTIVE To report a potentially important
  limitation of antineutrophil cytoplasmic antibody
  (ANCA) testing positive results in patients with
  subacute bacterial endocarditis (SBE).
• METHODS We describe 3 patients with SBE who
  presented with features mimicking ANCA-associated
  vasculitis (AAV) and positive findings on tests
  for cytoplasmic ANCA (cANCA) by indirect
  immunofluorescence and for anti-proteinase 3
  (anti-PR3)antibodies by antigen-specific
  enzyme-linked immunosorbent assay (ELISA).

12

• RESULTS We are now aware of a total of 7 cases
  of SBE with positive cANCA and anti-PR3
  antibodies. We are not aware of any cases of SBE
  associated with antimyeloperoxidase/perinuclear
  ANCA.
• Clinical manifestations mimicking AAV included
  glomerulonephritis, purpura, epistaxis, or sinus
  symptoms in 6 of the patients.
• Streptococcal species were identified in 5
  patients, and cardiac valvular abnormalities were
  demonstrated in 6.
• All patients except 1, who died of a complication
  of SBE, recovered with antibiotic therapy.

13

• CONCLUSION Findings of tests for anti-PR3/cANCA
  antibodies may be positive in patients with SBE.
• When encountering ANCA positivity in patients
  suspected of having systemic vasculitis,
  physicians should take appropriate steps to rule
  out infectious diseases, including SBE, before
  committing the patient to long-term, aggressive
  immunosuppressive therapy.

14
PR3

• Antineutrophil cytoplasmic antibodies reacting
  with human neutrophil elastase as a diagnostic
  marker for cocaine-induced midline destructive
  lesions but not autoimmune vasculitis.
• AU
• Wiesner O Russell KA Lee AS Jenne DE
  Trimarchi M Gregorini G Specks U
• Arthritis Rheum 2004 Sep50(9)2954-65.

15

• OBJECTIVE Human neutrophil elastase (HNE) and
  proteinase 3 (PR3) are structurally and
  functionally related. PR3 is the prominent target
  antigen for antineutrophil cytoplasmic antibodies
  (ANCAs) in Wegener's granulomatosis (WG).
  Reported frequencies of HNE ANCAs in WG and other
  autoimmune diseases range from 0 to 20.

16

• HNE ANCA reactivity in 25 patients with CIMDL was
  characterized and compared with that in a control
  cohort of 604 consecutive patients (64 with WG,
  14 with microscopic polyangiitis MPA, and 526
  others) and 45 healthy volunteers

17

• Among patients with CIMDL, HNE ANCAs were
  detectable by 1 assay in 84, by 2 assays in 68,
  and by all 3 assays in 36. Fifty-seven percent
  of HNE ANCA-positive CIMDL sera were also PR3
  ANCA-positive by at least 1 assay.

18

• In contrast, only 8 (1.3) of 604 control sera
  reacted with HNE in at least 1 assay, 3 (0.5)
  reacted in 2 assays, and only 1 serum sample
  (0.16) reacted in all 3 assays.
• Sera obtained from patients with WG or MPA were
  universally HNE ANCA-negative, as were sera
  obtained from healthy controls. CONCLUSION
  Optimal sensitivity for HNE ANCA requires
  multimodality testing.

19
PR3

• Clinical interpretation of antineutrophil
  cytoplasmic antibodies parvovirus B19 infection
  as a pitfall.
• AU
• Hermann J Demel U Stunzner D Daghofer E Tilz
  G Graninger W
• SO
• Ann Rheum Dis 2005 Apr64(4)641-3. Epub 2004 Oct
  14.

20

• OBJECTIVE To investigate whether positive ANCA
  test results may be a common feature of acute
  parvovirus B19 infection.
• METHODS Sera were analysed from 1242 patients
  from a rheumatology outpatient clinic for
  reactivity with parvovirus B19 and EBV
  antibodies. They were tested for the presence of
  PR3-ANCA and MPO-ANCA

21

• ANCA were found in 10 (5/50) of the sera
  positive for IgM antibodies to parvovirus and in
  3/51 sera containing IgM antibodies to EBV.
• Three of six patients with arthritis and
  concomitant parvovirus infection were found
  positive for PR3-ANCA and two were found positive
  for MPO-ANCA. All six patients tested negative
  for ANCA after six months of follow up.

22

• CONCLUSIONS PR3-ANCA and MPO-ANCA may occur
  transiently in patients with acute B19 infection
  or infectious mononucleosis, highlighting the
  importance of repeated antibody tests in
  oligosymptomatic clinical conditions in which
  systemic autoimmune disease is suspected.
• Department of Medicine, Johns Hopkins University
  Vasculitis Center, 1830 E. Monument Street,
  Suite 7500, Baltimore, MD 21205, USA.

23
PR3

• Prevalence of antineutrophil cytoplasmic
  antibodies in patients with various pulmonary
  diseases or multiorgan dysfunction.
• The Henry Dunant Hospital, Athens, Greece.
• OBJECTIVE To determine the prevalence of
  antineutrophil cytoplasmic antibodies (ANCA) in
  patients with diseases that may mimic systemic
  vasculitides, such as severe multiorgan
  dysfunction (MOD) and parenchymal pulmonary
  disorders.

24

• METHODS We conducted a prospective study of
  patients with MOD admitted to the medical
  intensive care unit and patients with various
  lung diseases seen at the outpatient pulmonary
  clinic of a tertiary care hospital. Patients
  with a documented diagnosis of Wegener's
  granulomatosis (WG) served as positive controls.
• RESULTS Ninety-nine patients with MOD, 29
  outpatients with various lung disorders, and 18
  patients with WG were included in the study.
  ANCA were detected by IIF alone in 16 (15/96) of
  patients with nonvasculitic MOD and 17 (5/29)
  of outpatients with various pulmonary disorders.
  The majority of the positive IIF specimens from
  each group displayed an atypical IIF pattern
  (73 and 80, respectively). Only 1 specimen
  from patients with nonvasculitic disorders was
  positive for anti-MPO

25

• CONCLUSION Detection of ANCA by the combination
  of IIF and antigen-specific assays for
  proteinase 3 and myeloperoxidase in diseases that
  mimic systemic vasculitides is highly specific
  for WG, microscopic polyangiitis, and
  Churg-Strauss syndrome.

26
Periop Management-UpToDate

• Only limited data have been published to guide
  perioperative management. A randomized trial in
  orthopedic patients found no increased rate of
  infection in patients who continued weekly
  methotrexate compared with those who discontinued
  methotrexate two weeks before surgery 89. There
  are no available human data regarding other
  DMARDs in the perioperative period. Many DMARDs
  are renally excreted, and thus impaired kidney
  function can lead to buildup of DMARDs or their
  metabolites this may lead to bone marrow
  suppression.

27

• We recommend that in patients with normal renal
  function, methotrexate can be continued in the
  perioperative period. In patients with renal
  insufficiency, methotrexate should be held for
  two weeks. Sulfasalazine and azathioprine should
  be held for a week prior to surgery and resumed
  after surgery. Leflunamide should be held for two
  weeks before surgery and resumed after surgery.
  Hydroxychloroquine has few potential side effects
  and can be continued without interruption, if the
  patient can take oral medications. The biologic
  response modifiers should be stopped one to two
  weeks prior to surgery and resumed one to two
  weeks after surgery.
• UpToDate

28

• High dose nonsteroidal anti-inflammatory drugs
  compromise spinal fusion.
• Acute Pain Service, Baystate Medical Center and
  Tufts University School of Medicine, 759 Chestnut
  Street, Springfield, Massachusetts 01199, USA.
  scott.reuben_at_bhs.org
• The goal of this retrospective study was to
  assess the incidence of non-union following the
  perioperative administration of ketorolac,
  celecoxib, or rofecoxib. METHODS We
  retrospectively analyzed the data of 434 patients
  receiving perioperative ketorolac
• 20-240 mg day(-1), celecoxib 200-600 mg
  day(-1), rofecoxib 50 mg day(-1), or no NSAIDs
  in the five days following spinal fusion surgery.

29

• RESULTS There were no significant differences in
  the incidence of non-union among the groups that
  received no NSAIDs (11/130 8.5), celecoxib
  5/60 8.3), or rofecoxib (9/124 7.3).
• In contrast, 23/120 of patients (19.2) that
  received ketorolac had a higher incidence
• (P lt 0.001) of non-union compared to non-NSAID
  users. However, only 3/50 patients (6) receiving
  low-dose ketorolac lt or 110 mg day(-1)
  resulted in non-union which was not significantly
  different from non-NSAID users.
• Patients administered higher doses of ketorolac
  120-240 mg day(-1) resulted in a higher
  incidence (P lt 0.0001) of non-union (20/70 29)
  compared to non-NSAID users.

30

• CONCLUSIONS This study revealed that the
  short-term perioperative administration of
  celecoxib, rofecoxib, or low-dose ketorolac lt or
  110 mg day(-1) had no significant deleterious
  effect on non-union.
• In contrast, higher doses of ketorolac
  120-240 mg day (-1), history of smoking, and
  two level vertebral fusions resulted in a
  significant increase in the incidence of
  non-union following spinal fusion surgery.

31

• The effect of cyclooxygenase-2 inhibition on
  analgesia and spinal fusion.
• Baystate Medical Center and Tufts University
  School of Medicine, 759 Chestnut Street,
  Springfield, MA 01199, USA. scott.reuben_at_bhs.org
• METHODS Eighty patients who were scheduled to
  undergo spinal fusion received either celecoxib
  or placebo one hour before the induction of
  anesthesia and every twelve hours after surgery
  for the first five postoperative days.

32

• RESULTS There were no differences in demographic
  data or blood loss between the two groups. Pain
  scores were lower in the celecoxib group at one,
  four, eight, sixteen, and twenty hours
  postoperatively. There were no differences
  between the two groups with regard to the pain
  scores at twelve and twenty-four hours
  postoperatively.
• CONCLUSIONS The perioperative administration of
  celecoxib resulted in a significant reduction in
  postoperative pain and opioid use following
  spinal fusion surgery. In addition, the
  short-term administration of this COX-2-specific
  non-steroidal anti-inflammatory drug had no
  apparent effect on the rate of nonunion at the
  time of the one-year follow-up.

33

• Time-dependent inhibitory effects of
  indomethacin on spinal fusion.
• Department of Orthopaedic Surgery, Barnes-Jewish
  Hospital at Washington University, St. Louis,
  Missouri 63110, USA. riewd_at_msnotes.wustl.edu
• METHODS Seventy New Zealand White rabbits
  underwent posterior intertransverse process
  arthrodesis at L5-L6 with use of iliac
  autograft. Rabbits randomly received indomethacin
  (10 mg/kg orally) starting at two weeks after
  surgery (twenty-four animals), indomethacin
  starting at four weeks postoperatively
  (twenty-three), or saline starting at two weeks
  postoperatively (twenty-three) (the control
  group).

34

• RESULTS Sixty-five percent (fifteen) of the
  twenty-three spines in the control group and 48
  (eleven) of the twenty-three in the four-week
  group fused. However, only 21 (five) of the
  twenty-four spines in the two-week group fused.
  The difference between the two-week and control
  groups was significant (p lt 0.002), as was
  the difference between the two and four-week
  groups (p 0.05).
• CONCLUSIONS The earlier that indomethacin was
  resumed postoperatively, the greater was its
  negative effect on fusion. Indomethacin appears
  to play a significant inhibitory role in the
  early phase of healing. Initiating indomethacin
  treatment in the latter phase of healing does not
  appear to significantly affect fusion rates,
  although there was a nonsignificant trend toward
  inhibition.

35

• Infectious and healing complications after
  elective orthopaedic foot and ankle surgery
  during tumor necrosis factor-alpha inhibition
  therapy.
• Department of Orthopaedic Surgery, Marshfield
  Clinic, WI 54449, USA. bibbo.christopher_at_marshfie
  ldclinic.org
• METHODS Patients with rheumatoid arthritis
  undergoing elective foot and ankle surgery over a
  12-month period were prospectively followed for
  the development of complications in the
  postoperative period. All patients continued
  their antirheumatic medication schedule
  unaltered in the perioperative period
• Patients were then stratified into two groups
  based on the use of immunomodulation via
  TNF-alpha inhibition (group 1) versus patients
  who did not receive TNF-alpha inhibition therapy
  (group 2). Groups 1 and 2 were followed and
  compared for the development of
  infectious/healing complications.

36

• RESULTS Thirty-one patients were enrolled in the
  study. Group 1 (n 16) and group 2 (n 15)
  patients were comparable for sex distribution,
  number of orthopaedic procedures performed, and
  use of steroids, methotrexate, leflunamide, and
  nonsteroidal anti-inflammatory drugs. Group 1
  contained six times the number of smokers in
  group 2. At mean follow-up of 10.6 months
  (group 1) and 9.7 months (group 2), healing or
  infectious complications were similar in both
  groups. However, when total complications
  (healing infection) were analyzed, group 1
  (TNF-alpha inhibition, "higher risk") patients
  demonstrated a lower complication rate (p
  .033).
• CONCLUSIONS The data suggest that in patients
  with rheumatoid arthritis undergoing elective
  foot and ankle surgery, the use of TNF-alpha
  inhibition agents may be safely undertaken in the
  perioperative period without increasing the risk
  of healing or infectious complications.

37

• Methotrexate and early postoperative
  complications in patients with rheumatoid
  arthritis undergoing elective orthopaedic
  surgery.
• Wrightington Hospital NHS Trust, Hall Lane,
  Appley Bridge, Wigan WN6 9EP, UK.
• OBJECTIVES To determine whether continued
  methotrexate treatment increases the risk of
  postoperative infections or of surgical
  complications in patients with rheumatoid
  arthritis (RA) within one year of elective
  orthopaedic surgery. DESIGN A prospective
  randomized study of postoperative infection or
  surgical complications occurring within one year
  of surgery in patients with RA who underwent
  elective orthopaedic surgery.
• SUBJECTS 388 patients with RA who were to
  undergo elective orthopaedic surgery. Patients
  who were receiving methotrexate were randomly
  allocated to groups who either continued
  methotrexate (group A) or who discontinued
  methotrexate from two weeks before surgery until
  two weeks after surgery (group B). Their
  complication rates were compared with
  complications occurring in 228 patients with RA
  (group C) who were not receiving methotrexate and
  who also underwent elective orthopaedic surgery.
  

38

• RESULTS Signs of infection or surgical
  complications occurred in two of 88 procedures
  in group A (2), 11 of 72 procedures in group B
  (15), and 24 of 228 (10.5) procedures in group
  C. The surgical complication or infection
  frequency in group A was less than that in either
  group B (plt0.003) or group C (p0.026).
• At six weeks after surgery there were no flares
  in group A, six flares in group B (8), and six
  flares in group C (2.6). Logistic regression
  analysis of the overall surgical complication
  rate in all the patients with RA studied showed
  that methotrexate, whether continued or
  discontinued before surgery, did not increase the
  early complication rate in the patients with RA
  who underwent elective orthopaedic surgery.
• CONCLUSION Continuation of methotrexate
  treatment does not increase the risk of either
  infections or of surgical complications occurring
  in patients with RA within one year of elective
  orthopaedic surgery. Thus methotrexate treatment
  should not be stopped in patients whose disease
  is controlled by the drug before elective
  orthopaedic surgery.