?מתי ומה לשלוח, למי -בירור ראומטולוגי

1-מקרה

ללא מחלות רקע, שנים 15אורלי בת •

כאבים מפושטים במפרקים מזה חודשיים •

ברכיים, מרפקים, אצבעות? איפה כואב•

בכל שעות היום? מתי כואב•

8/10? כמה כואב•

לא? האם מעיר משינה•

לא? האם יש קישיון בוקר•

לא? האם יש נפיחות במפרקים•

אין? האם יש סימפטומים אחרים•

לופוס לדודה, דלקת מפרקים לסבתא -הסטוריה משפחתית•

כאבי שלד בילדים

2-52%שכיחות כאבי שלד בילדים •

עולה בהדרגה עם הגיל מהילדות לגיל ההתבגרות•

מהפניות לרופא הראשוני עקב כאבי שלד הסיבה אינה דלקתית 97%ב •

הסיבה הכי שכיחה היא טראומה•

transient synovitisיש 2.5%מאלה . מהמקרים הסיבה היא דלקתית 3.3%רק ב •

תהיה דלקת מפרקים כרונית 0.8%וב

:בדיקה גופנית

.סימנים חיוניים תקינים, במצב כללי טוב•

ללא אפטות -לוע•

ללא אלופציה, ללא פריחה -עור•

ללא הגדלה -בלוטות לימפה•

.דפקים פריפרים תקינים וסימטרים, תקין -לב•

ללא קריפיטציות או צפצופים, צ"כניסת אויר תקינה דו -ריאות•

ללא אורגנומגליה, לא רגישה, רכה -בטן•

ללא . רגישות או הגבלה בתנועה, חום מקומי, נפיחות, אין נוזל -ללא סימני ארטריטיס -מפרקים•.רגישות ניכרת במישוש

.סימטרי תקין -כח גס•

תקינה -נוירולוגית•

? איזה בירור לשלוח

:רשימת בעיות

ארטרלגיה מזה חודשיים. 1

דלקת מפרקים, לופוס -הסטוריה משפחתית אוטואימונית. 2

:מעבדה

ספירת דם•

וחומצה אורית LDHכולל -כימיה מלאה•

שקיעה•

•CRP

•ANA?

•RF?

? שתן•

שקיעת דם

שקיעת דם

: שקיעה גבוהה ללא דלקת

זיקנה-

נשים-

השמנה-

הריון-

אנמיה-

:(mm/hr 0)שקיעה נמוכה

אגמגלובונמיה-

(HCT > 65)פוליציטמיה -

עליה בצמיגיות הפלסמה-

CRP

• Seen in sera of patients with pneumococcal pneumonia in 1930- reacted with the somatic 'C' carbohydrate antigen of pneumococc

• Acute-phase reactant produced by the liver in response to IL-6 and other cytokines

• CRP binds to lysophosphatydilcholine expressed on the surface of dead/dying cells and some types of bacteria in order to activate the complement system promoting phagocytosis by macrophages

• Can bind to and modulate the behavior of phagocytic cells in both pro and anti-inflammatory ways

• Rises within two hours, up to a 50,000-fold, peaks at 48 hours

• Its half-life of 18 hours

• Quicker rise and fall than ESR

• Sensitive but not diagnostic of any particular condition

• Interferon alpha inhibits CRP production, may explain the relatively low levels of CRP during viral infections compared to bacterial infections

• “CRP rises with infection and ESR rises with CTD’s….” (not always true!!!)

Other acute phase reactants

• Polyclonal Immunoglobulins

• Fibrinogen

• Haptoglobin

• Serum amyloid A

• Platelet count

• Ferritin

• Decreased albumin (“negative” APR)

ANA?

ANA- Anti Nuclear Antibody

• Autoantibodies that bind to contents of the cell nucleus

• ANA- first discovered by Friou in 1957

• Gold standard: Indirect immunofluorescent antibody using HEp-2 cell line.

• Subjective interpretative assay

ANA

• Positive ANA in as many as 18% of healthy children

• At dilution of 1:40 : PPV for any rheumatic disease is only 33%

• Even high titer have poor ability to determine whether a child has an inflammatory rheumatic disease

• Cabral et al. followed 24 children with no clinical inflammatory disease but positive ANA�no patient developed an overt inflammatory disease during a follow-up period of 61 months

ANA

•ANA לאבחנות שגויות ואפילו לטיפול שגוי, חיובי יכול להוביל לבדיקות מיותרות

עלויות גבוהות•

כבדיקת סקר ANAנא לא לשלוח

:ANAשתי אינדיקציות ל

חשד ללופוס על פי האנמנזה או הבדיקה הגופנית 1.

להעריך סיכון לאובאיטיס JIAחולה עם 2.

Choosing wisely

• In 2011, the ABIM (American Board of Internal Medicine) Foundation launched the Choosing Wisely campaign, encouraging medical societies to identify sources of unnecessary spending

• Partnering societies were charged with developing a Top 5 list of tests, treatments, or services commonly used by that specialty that have high aggregate costs and are unnecessary or potentially harmful.

• 51 medical societies have participated in the Choosing Wisely campaign

• In March 2013, the ACR published it’s Top 5 list

Specific ANA’s

Anti ds-DNA

• Nearly 100% specific for SLE

• Correlates well with disease activity

• Probably pathogenic

• Moderate Sensitivity

Specific ANA’s

Anti Smith (Sm)

• RNA/protein complex involved in processing messenger RNA

• More severe disease

• Speckled ANA

• Higher prevalence in AA & Asians

• Moderate sensitivity (30%)

• Highly specific for SLE

Specific ANA’s

Anti RNP (U1 RNP)

• Ribonucleoprotein

• Speckled ANA

• Diagnostic of MCTD if:

• High titer

• Features of SLE, PM, RA, and PSS

• RF (+)

Anti HISTONE

• High sensitivity and low specificity

• Drug induced lupus gives anti-histone alone

• SLE gives anti-histone along with ds-DNA

• Also seen in RA

Specific ANA’s

Anti Ro/SS-A

• Protein-RNA complex found in both nucleus and cytoplasm

• Sjogren’s and lupus

• The rare ANA-neg lupus

• Subacute cutaneous lupus (a very photosensitive lupus)

• Neonatal SLE and congenital heart block

Anti La/SS-B

• Protein-RNA complex found in both nucleus and cytoplasm

• Sjogren’s and lupus

• The rare ANA-neg lupus

• May protect against renal disease

• Usually also have antibodies to

Ro/SS-A

Specific ANA’s

Anti SCL-70

• Anti-topoisomerase I

• Found in 20% of patients with PSS

• VERY specific

• NOT sensitive

• Lung disease

• Associated with nucleolar ANA pattern

Anti Jo-1

• Anti-histidyl tRNA synthetase

• A cytoplasmic protein

• Found in 30% of PM/DM patients – often with lung involvement/ILD

• Highly specific

ENA- Extractable Nuclear Antigens

• The second-level testing for antibodies to intracellular specific antigens

חיובי וחשד למחלה ראומטית ANAאלא אם יש ENAנא לא לשלוח

בדיקה גופנית

תקינה לחלוטין

:בדיקות מעבדה

ספירה תקינה ללא ציטופניה -

CPK, חומצה אורית, LDHכימיה מלאה תקינה כולל -

תקינים CRPשקיעה ו -

:רשימת בעיות -1מקרה

ארטרלגיה מזה חודשיים. 1

דלקת מפרקים, לופוס -הסטוריה משפחתית אוטואימונית. 2

ANAאין צורך לשלוח

2מקרה

כ"בריאה בד, בת שנתיים•

מזה כארבעה שבועות נפיחות של הברך וצליעה•

אין הסטוריה של טראומה•

ללא חום•

ללא פריחה•

מתנהגת כרגיל, לא נראית כאובה•

יש קישיון בוקר של כשעה•

לא מעיר משינה•

בדיקה גופנית

מדדים חיוניים תקינים, במצב כללי מצוין•

בלוטות לימפה ללא הגדלה•

ללא פריחה -עור•

תקין -ריאות, לב•

ללא הפטוספלנומגליה -בטן•

ריבוי נוזל . בתנועהעם ריבוי ניכר של נוזל והגבלה , נפוחה, ימין חמה ברך -מפרקים•ייתר המפרקים . שני מימין ושלישי משמאל PIP, גם בשורש כף יד ימיןוהגבלה בפלקציה

.תקינים

. אורך רגליים שווה•

.ללא אטרופיה של שרירים -כח גס תקין•

:רשימת בעיות

)אוליגו(מפרקים 4ארתריטיס של

?איזה בירור לקחת

ספירה ומשטח•

וחומצה אורית LDHכימיה כולל •

פרבו, EBV, הפטיטיס -סרולוגיה•

•ANA?

•RF?

Rheumatoid Factor- RF

• RFs are immunoglobulins that are reactive with the Fc fragment of the IgG molecule

• RFs are found in all Ig isotypes (IgA, IgG, IgD, IgE), but classically, IgM RFs have mainly been used to assess rheumatic disease

• Routine assays including latex agglutination and ELISA

• Important for the classification of JIA

Conditions associated with positive RF

• Rheumatologic diseases:

�RA (80-85%)

�Sjogren syndrome (75-95%)

�MCTD (50-60%)

�Scleroderma (20-30%)

� Sarcoidosis (15%)

�Polymyositis (5-10%)

�Cryoglobulinemia (>90%)

• Non Rheumatologic diseases:�Chronic hepatitis

�Pulmonary disease

�Neoplasms

�Aging

� Infections- HIV, TB, syphilis,

endocarditis..

Juvenile Idiopathic Arthritis

• Age of onset <16 years

• Arthritis of one or more joints

• Duration of disease > 6 weeks

• Other conditions which presents with arthritis must be excluded

RF

•RF מהילדים הבריאים 3%חיובי ב

כבדיקת סקר RFלא לשלוח נא

לצורך קלסיפיקציה RFנשלח JIAבילד עם אבחנה של

לצורך הערכת סיכון לאובאיטיס ANAונשלח

2002

• Rheumatology clinic at Children’s Hospital of Oklahoma between April 1998 and July 2001

• New referrals from pediatricians and orthopedics- without known rheumatology diagnosis

• 414 charts available for analysis

Musculoskeletal pain- 226 pt

• 111 Isolated pain� Only 1 had a rheumatic disease- ankylosing spondylitis

• 115 children presented with additional symptoms�11 diagnosed with JIA

• 76 children diagnosed with JIA during the study period, 64 did not include pain as a complaint.

• Thus, musculoskeletal pain, with or without other symptoms, had a strong NPV for JIA

• In 153 children laboratory test results were indicated as a reason for the referral.

• Test results included positive ANA (n 90) , IgM-RF (n 16) and/or elevated ESR (n

47).

• Positive RF- 3/16 (19%) had JIA.

• In all 3 patients, prominent synovial proliferation, morning stiffness, and fatigue would have established the diagnosis without a positive test.

• Children referred because of a positive RF test were no more likely to have JIA than children without RF testing (P 1.00).

• Positive ANA- 24/90 (27%) had a chronic inflammatory disease.

• In all of them the diagnosis could have been made by the basis of the history, physical examination, and other supportive laboratory studies.

• Elevated ESR- 18/47 (38%) were found to have JIA, 2 with SLE and 1 with uveitis.

• Children with Elevated ESR were significantly more likely to have JIA (P .009) than children in whom ESR results were not cited as a reason for referral.

• However, the PPV for JIA of an elevated ESR was small (0.38)

Abnormal laboratory test- 153 pt

Conclusions

• Musculoskeletal pain had a strong NPV for either JIA or other chronic inflammatory diseases

• Neither ANA nor RF tests had any discriminatory ability to identify patients with JIA

Hypergammaglobulinemia

• In adults Polyclonal hypergammaglobulinemia is most frequently related to liver disease, malignancy, autoimmune disease, or infection.

• In childrens?

• Boston Children’s Hospital

• IgG tests between January 1, 2000 and December 31, 2009

• 26,354 patients had a documented IgG level

• 1519 with IgG ≥ 2000 mg/dL belonging to 748 individual patients

• Excluded IVIG treated patients

• 442 patients

Conclusions

• Hypergammaglobulinemia >2000 in children is mostly due to autoimmune disease or chronic infections

• The risk for autoimmunity increases with female gender, leukopenia, anemia and normal CRP

Complement

• A system of interacting serum proteins that function sequentially as initiators, regulators, and effectors of cell lysis and inflammation

• Provide innate defense against microbes and a “complement” to humoral immunity

• Biologic cascade in which, by limited proteolysis, one component activates the next, causing rapid and robust amplification of the system

• Critical to normal processing of immune complexes

• Causes host tissue damage in antibody-mediated autoimmune syndromes

Routine complement testing

• C3 - useful screen for both classic and alternative pathways

• C4 - low with activation of classic pathway or in patients with angioneuroticedema

• CH 50

• Functional test- measure lysis of sheep erythrocytes that have been coated with anti-sheep erythrocyte antibodies.

• Reflects a functionally intact classic pathway; good screen for deficiency state

Diminished complement levels

• partial or complete inherited deficiency

• C1q inhibitor deficiency -> hereditary angioedema and low C4

• C2 or C4 deficiency -> SLE

• C3 deficiency -> recurrent infections (bacterial)

• C5-9 deficiency -> recurrent neisserial infxn

• immune complex consumption

Causes of hypocomplementemia

• Immune complex disease: 1. SLE- C3, C4 returns to normal with effective treatment

2. Idiopathic MPGN

3. Cryoglobulinemia

4. Chronic infections: chronic osteomyelitis, endocarditis, infected visceral abscess, hepatitis B, chronic parasitic/spirochetal infections.

5. Post-infectious glomerulonephritis: strep A, also strep pneumoniae and meningococcus. Usually C3 is low.

6. Hypocomplementemic vasculitis

7. Serum sickness

8. Hypersensitivity to drugs: sulfasalazine, potassium iodide, chlorpropamide

9. Chemotherapy for malignant disorders

10. Thyroid disorders: Graves' disease, radiation treatment, or thyroiditis

11. Jejunal ileal bypass: The mechanism is thought to be gastrointestinal absorption of antigens resulting in immunization and IC formation

12. B-cell lymphoproliferative disorders

Causes of hypocomplementemia

• Non immune complex disease:

In many instances it is the alternative pathway that is activated. Thus, typically, C3 levels are decreased but C4 levels are normal

1. HUS/TTP-The decreased C3 levels may be secondary to complement activation by toxins or microorganisms , plasminogen activation which can activate C3, or activation by damaged endothelium

2. Severe sepsis- especially with shock, serum C3 and C4 levels can be decreased markedly

3. Severe malnutrition

4. Hepatic failure-The hypocomplementemia in fulminant hepatic failure is probably the result of decreased synthesis of C3 and C4

5. Acute pancreatitis- Pancreatic proteases can convert complement components into their active forms

6. Inherited abnormalities of complement pathway components

7. Thermal burns- severe

8. Acute MI

9. Hemodialysis- activation of the alternative pathway by the dialysis membrane

Summary

• No lab test is as good as history taking and physical exam

• No lab test “screens” for connective tissue disease

• Disease pattern recognition is far more helpful than any serology or test

• Be aware of the PPV and NPV of lab tests for different diseases

Questions?