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An old paradigm revisited:The case of a 29 year old woman with

painful, blue digits

Gordon Lam, M.D.

Rheumatology Rounds

March 2, 2007

Disclosures

None

Objectives

1. To discuss an illustrative case of an interesting rheumatic condition

2. To review a familiar mechanism of immunology and its postulated role in autoimmune diseases

3. To propose a conceptual link between this mechanism and the pathogenesis of this particular disease

Case Report

• 29 year old African American female from NYC• History significant for Crohn’s disease• Treated with Remicade via implanted catheter• Presented to UMd on 2/11/05 with fevers, chills• Blood cultures on admission grew Staphylococcus

epidermidis and Candida albicans• Catheter was removed• IV antibiotic/antifungal agents initiated• Discharged to rehabilitation facility on 3/2/05

Case Report cont’d

• 3/15/05:– Acute erythema, edema, and pain in right hand and

left foot– Right 5th fingertip, Left 4th toe:

red blue dark blue


• 3/17/05:– Presented to Harbor Hospital– Echocardiogram showed ?Right atrial thrombus– Diagnosed with endocarditis with embolic phenomena– Transferred to JHH CCU for further management


• JHH CCU course:– Transesophageal echocardiogram:

No thrombus or spontaneous echocontrast

No vegetations; all valves pristine

Intact interatrial septum; no patent foramen ovale

No shunt physiology by doppler or bubble studies

No aortic root or aortic arch abnormalities

Trace pericardial effusion noted

– Rheumatology consulted: ? vasculitis?


• Past Medical History:1. Crohn’s disease

– Apparently diagnosed at Columbia Presbyterian Hospital in NYC years ago

– Treated previously with prednisone, hydrocortisone enemas and mesalamine

– Now treated with Remicade (dose not known)

– Status post hemicolectomy 2003

– Extraintestinal manifestations: mucocutaneous ulcerations

2. Status post cholecystectomy 2003


• Medications on Admission:Vancomycin (Day #27/42)

Fluconazole (Day #22/42)

Hydrocortisone enemas twice daily

Ciprofloxacin (Day #26/42)

Metronidazole (Day #26/42)

Lovenox 30 mg

Protonix


• Allergies:sulfa, morphine nausea, vomiting

• Social History:Resident of New York City

Single, no children

Unemployed

Denied tobacco, alcohol, or illicit drug use

No history of STDs, high risk behaviors

• Family HistoryNo rheumatic diseases


• Review of Systems:+ Ø

30 lb unintentional wt loss Rash/malar rash

Fatigue Arthritis

Malaise Dry eyes/mouth

Decreased energy Nasal discharge

Sun sensitivity Ocular inflammation

Oral ulcerations Urinary changes

Post-prandial abdominal pain Seizures

2 prior miscarriages (19,9 wks) Hearing loss

Myalgias

Focal weaknesses

Physical Examination

• Vitals: T: 36.6 BP: 146/93 P: 91 R: 14• HEENT: no conjunctival lesions, no Roth’s spots,

no oral ulcerations, no bloody/crusting nasal lesions, no septal perforation, no saddle

nose deformity, no LAD• Lungs: clear• CV: no murmurs or rubs• Abd: soft, RUQ/RLQ tenderness to palpation• Ext: edematous right hand,

left foot, ischemic right 5th finger and left 4th toe

Physical Examination

• Vitals: T: 36.6 BP: 146/93 P: 91 R: 14• HEENT: no conjunctival lesions, no Roth’s spots, no

oral ulcerations, no bloody/crusting nasal lesions, no septal perforation, no saddle nose deformity, no LAD

• Lungs: clear• CV: no murmurs or rubs• Abd: soft, RUQ/RLQ tenderness to palpation• Ext: ischemic right 5th finger

and left 4th toe, 2+ radial pulses, dopplerable DP pulse, no Osler nodes or Janeway lesions

•

Laboratory findings

• WBC 14.0 (N85 L5 M6 E3)

• Hgb/Hct 9.8/31 (MCV 84, RDW 18.6, Coomb’s negative)

• Plt 264

• BUN/Cr 13/2.1 mg/dL

• UA trace protein, trace hgb, 5-10 RBCs/hpf

• Spot urine protein:creatinine = 28/46 = .600

• ESR 93 mm/hr

• CRP 44.7 mg/dL

• aPTT 98.0s; PT 48.1s

• D-dimer: 16.00 mg/L; fibrinogen: 563

Laboratory findings

• ANA negative

• dsDNA negative

• RNP/Sm negative

• Ro/La negative

• C3/C4 144/30

• ANCA negative

• RF negative

• RPR non-reactive

• HBsAg negative

• HCV negative

• Tox screen negative

Radiographic findings

• CXR: no airspace disease, no cardiomegaly

• Jt plain films: diffuse soft tissue swelling of the right hand and left foot; no fractures, no joint space narrowing, no erosions

• CT extremities: diffuse subcutaneous edema, no abscess, osteomyelitis,

subcutaneous gas, or joint effusion

Patient Summary

• 29 yo AAF presents with acute ischemic digits

• h/o 2 prior spontaneous abortions at 19 and 9 weeks gestation

• h/o Crohn’s disease treated with Remicade

• Recent septicemia ~1 month prior

• ROS: constitutional sx, 30 lb weight loss, post-prandial abdominal pain, oral ulcerations

Patient Summary

• Report of RA thrombus TEE at JHH showed trace pericardial effusion only

• Workup notable for HTN, leukocytosis, anemia, renal insufficiency, elevated inflammatory markers, elevated D-dimer, and abnormal coags

• Serologies to date negative

Thoughts?

Differential diagnosis

1. Antiphospholipid syndrome– embolic phenomena, abnormal coags, h/o miscarriages

2. SLE– oral ulcerations, pericardial effusion, renal insufficiency

3. Vasculitis– weight loss, HTN, ischemic digits, post-prandial abdominal

pain, renal insufficiency, oral ulcerations

4. Coagulopathy– protein C, protein S, antithrombin III deficiency

5. Thromboembolic phenomenon

6. Vascular insufficiency

Further workup

• Blood, urine cultures negative• HIV negative• HBsAb, HBcAb negative• Cryoglobulins negative• Factor V activity normal• Factor VIII level normal• Protein C/S normal• Heparin inhibitor negative• Opthalmology examno ocular manifestations

of rheumatic disease• CTA head, neck, no vascular abnormalities, no chest,

abd, pelvis evidence of vasculitis

Further workup

• Anti-cardiolipin ab negative• Anti-β2 glycoprotein I ab negative• Lupus anticoagulant:

PT 44.7s (9.5 – 11.7)

1:1 mix 13.1s

aPTT 74.9s (23.5 – 34.0)

1:1 mix 44.5s

dRVVT 103.5s (27.0 – 45.0)

1:1 mix 48.8s

confirm ratio 1.5

Diagnosis

• Antiphospholipid Syndrome (APS)– ACR classification criteria1. Clinical criteria:

– Vascular thrombosis (arterial, venous, small vessel)– Pregnancy complications

2. Laboratory criteria:– Anti-cardiolipin abs positive 2 or more times, 6 weeks apart– Lupus anticoagulant positive 2 or more times, 6 weeks

apart

Definite APS is considered to be present if at least one of the clinical and one of the laboratory criteria are met

√

Antiphospholipid antibodies (aPL) and Infections

• Many infections are accompanied by aPL elevations and APS manifestations

aPL and Infections

Blank M et al. J Clin Immunol 2004;13-14.

Molecular mimicry

A postulated mechanism of autoimmunity in which antigens from infectious microbes cross-react with self antigens, triggering immune responses to self-tissues

Relationship of infection and autoimmunity

Hochberg et al (eds)

Molecular mimicry

Albert LJ and Inman RD, New Eng J Med 1999;341:2069

Molecular mimicry

Hochberg et al (eds)

Molecular mimicry proposed in autoimmune diseases

Animal

Disease Self antigen Pathogen X-reactivity model

Rheumatic fever cardiac myosin M protein of ?T and B cells? —

Grp A Strep

Lyme disease LFA-1 OspA of Borrelia ?T cells? —

Multiple sclerosis MBP Multiple viruses T cell LCMV mouse

SpA HLA-B27 Multiple GN B cell —

bacterial proteins

Grave’s disease Thyrotropin Yersinia B cell —

receptor enterocoliticia

Molecular mimicry proposed in autoimmune diseases

Animal

Disease Self antigen Pathogen X-reactivity model

RA Heat-shock M.tuberculosis T and B cells Adjuvant

protein 60 heat-shock arthritis (rat)

protein 65

HLA-DRB1*0401 E.coli dnaJ (heat T and B cells —

shock protein 65)

Type 1 DM GAD65 Coxsackievirus T cell —

P2-C

Pancreatic LCMV T cell LCMV-NP

β cell mouse

Myocarditis M7Aα Chlamydia T cell —

Molecular mimicry in APS

• Blank et al. Proc Natl Acad Sci 1999;96:5164

1. Created monoclonal antibodies (mAbs) to β2-GPI from patients with APS

2. Introduced these mAbs to a hexapeptide phage display library containing 2x108 clones

3. Identified 3 hexapeptides as target epitopes for α-β2-GPI Abs:

LKTPRV, TLRVYK, KDKATF

Location of the β2-glycoprotein I hexapeptides identified by the phage

display library


4. All 3 hexpeptides inhibited activation of endothelial cells in vitro


5. Employing a protein database, homologies were found between the 3 hexapeptides and various bacteria, viruses, and yeast that were associated with aPL


6. Immunized mice with microbial pathogens that shared homologies with the β2GPI and induced pathogenic antibodies to β2GPI, which were then infused into naïve mice. APS was recapitulated.


Conclusions:

• Bacteria homologous to β2GPI can induce the generation of anti-β2GPI antibodies

• These antibodies can generate manifestations of APS in naïve mice

• A mechanism of molecular mimicry is established

Hence: Molecular mimicry between β2GPI and microbial products is one aspect of the infectious origins of APS

Unresolved issues of molecular mimicry as a mechanism of

autoimmunity

• Infection is common; autoimmunity is not

• Prevalence of infection has decreased with industrialization, yet that of autoimmune diseases has increased

Inverse relationship between incidence of infections and immune diseases

Bach, New Engl J Med 2002

Unresolved issues of molecular mimicry as a mechanism of

autoimmunity

• Infection is common; autoimmunity is not• Prevalence of infection has decreased with industrialization,

yet that of autoimmune diseases has increased• Lack of treatments of proven efficacy• Effects of vaccination• Genetic factors

Appeal of molecular mimicry

Physiologic response

(i.e. defense against infection)

Pathologic process

(i.e. autoimmunity)

Molecular mimicry, revisited

Acknowledgements

• Antony Rosen

• Helina Kassahun

• Steven Schulman

• Sanjay Desai

• Martin Britos-Bray

References

1. Abbas AK et al. Cellular and Molecular Immunology 4th ed. WB Saunders Co:Philadelphia. 2000,487.

2. Albert LJ and Inman RD. New Engl J Med 1999;341:2068-74.

3. Amital H et al. Ann Rheum Dis 2004;63:1004-1006.

4. Asherson RA and Cervera R. Ann Rheum Dis 2003;62:388-393.

5. Asherson RA and Shoenfeld Y. J Rheum 2000;12-14.

6. Bach JF. New Engl J Med 2002;347:911-919.

7. Blank M, et al. Proc Natl Acad Sci 1999;96:5164-5168.

8. Blank M et al. J Clin Invest 2002;109:797-804.

9. Blank M et al. J Clin Invest 2004;24:12-20.

10. Cervera R et al. Ann Rheum Dis 2004;63:1312.

11. Elbeialy A, et al. Clin Exp Rheum 2000;18:492.

12. Hochberg et al. In Rheumatology 3th ed. Mosby:New York. 2003, 846 & 1048.

13. Janeway et al.In: Immunobiology 6th ed.Garland Science Publishing: New York. 2005, 586-587.

14. Leder AN et al. Lupus 2001;10:370-374.

15. Ramos-Casals M, et al. Clin Infect Dis 2004;38:1009-16.

16. Shoenfeld Y, Blank M, and Krause I. Clin Exp Rheum 2000;18:431-432.

17. Shoenfeld Y. La revue de medecine interne 2004;25:S10-S11.

18. Shoenfeld Y et al. Ann Rheum Dis 2006;65:2-6.

19. Sorice M et al. Clin Exp Immunol 2000;120:301-306.

20. Uthman IW and Gharavi AE. Sem Arthritis Rheum 2002;31:256-263.

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