2. Rheumatic Disease and HIV Infection
Dr M Jokar

3. اهداف هدف کلی: آشنایی با انواع علائم روماتیسمی در جریان HIV
اهداف جزئی:
آشنایی با Painful articular syndrome
آشنایی با HIV–associated arthritis
آشنایی با آرتریت پسوریاتیک در مبتلایان به عفونت HIV
آشنایی با DILS
آشنایی با درگیری عضلات در جریان HIV

4. HIV Myriad of clinical manifestations affecting every organ system
Rheumatic manifestations can occur in late stages or be the first presenting symptom
Frequency 1-60% – varies with ethnicity, geography, HIV stage, antiretroviral treatment

5. Articular considerations in HIV
Unique to HIV
Altered by HIV
Possibly ameliorated by HIV
Painful articular syndrome
HIV–associated arthritis
DILS
Polymyositis
Zidovudine- associated myopathy
Reactive Arthritis
Psoriatic arthritis
Undifferentiated spondyloarthropathy
Vasculitis
Infectious arthritis (bacterial, fungal)
Rheumatoid Arthritis
SLE

6. PAINFUL ARTICULAR SYNDROME
Severe bone and joint pain
Self-limited syndrome
Lasting less than 24 hours
Few objective clinical findings
Late stages of HIV infection
Knee, elbow, shoulders

7. HIV ASSOCIATED ARTHRITIS
Oligoarthritis
Lower extremities
Self-limited
Lasting less than 6 weeks
Knees, ankles, metatarsophalangeal joints, wrists , elbows, metacarpophalangeal , interphalangeal joints

8. REACTIVE ARTHRITIS

9. PSORIATIC ARTHRITIS Psoriatic rash can be extensive
Arthritis is predominantly polyarticular, lower limb, and progressive

10. Diffuse infiltrative lymphocytosis syndrome (DILS)
Sjogren’s-like disease
Significant, painless parotid gland enlargement
Sicca symptoms – xerostomia
Anti-SSA, Anti-SSB negative
CD8 inflammatory infiltrate
Prominent extraglandular symptoms including RTA, PM, lymphocytic hepatitis, lymphoma, VII nerve palsy

12. Myopathies Myalgias – associated with viremia, FMS
PM – with signs/symptoms similar to HIV negative patient but ? milder; with/without skin disease
Zidovudine- associated myopathy

13. خلاصه
در مبتلایان به عفونت HIV سندرمهای روماتیسمی مختلفی دیده می شود که مهمترین آنها عبارتند از:
Painful articular syndrome
HIV–associated arthritis
DILS
Polymyositis

14. Common Rheumatologic Tests: Evaluation and Interpretation
Dr M. Jokar

15. اهداف
هدف کلی: آشنانی با تفسیر تست های آزمایشگاهی در بیماریهای روماتیسمی
اهداف جزئی:
آشنایی با تفسیر CBC در بیماریهای روماتیسمی
آشنایی با تفسیر پروتئین های فاز حاد در بیماریهای روماتیسمی
آشنایی با تفسیر اتوآنتی بادیها در بیماریهای روماتیسمی
آشنایی با تجزیه مایع مفصلی در بیماریهای روماتیسمی

16. indication for a test Screen for a particular disease
Help confirm a specific diagnosis
Evaluate disease activity
Assess for target organ involvement
Monitor for drug toxicity

17. Before ……. Interpret a test result Sensitivity Specificity
positive and negative
predictive values

18. Sensitivity Specificity
Proportion of patients with a disease who have a positive test result
Specificity
Proportion of persons without a disease who have a negative test result

19. Predictive value
likelihood or lack of the disease based on a positive or negative test result
Negative predictive value (NPV)
True negative/(true negative + false negative)
Positive predictive value (PPV)
True positive/(true positive + false positive)
Positive test result on test with high pos predictive value indicates pt probably has disease---neg test result on test with high neg predictive value means pt prob doesn’t have disease

20. CBC
Leukocytosis
Leukopenia
Lymphocytosis
Lymphopenia

21. CBC Anemia Anemia of chronic di. Hemolytic anemia Iron de.
Megaloblastic anemia

22. CBC
Thrombocytosis
Thrombocytopenia

23. Acute phase reactants
Heterogeneous group of proteins synthesized in liver in response to inflammation
Fibrinogen
Serum Amyloid A
Haptoglobin
C-reactive protein
Alpha-1-antitrypsin
IL-6 is inflammatory cytokine, important mediator that stimulates production of acute-phase reactants

24. Acute phase protein response
Typical plasma acute-phase protein (APP) changes after a Moderate
inflammatory stimulus. Several patterns of response are seen: Major APP increase up to 100-fold (e.g., C-reactive protein and serum amyloid A); moderate APP increase twofold to fourfold (e.g., fibrinogen, haptoglobin); minor APP increase 50 to 100 percent (e.g., complement C3); and negative APP decrease (e.g., albumin, transferrin).
Adapted from Gitlin JD, Colten HR in Pick E, Landy M [eds]: Lymphokines.14;123,1987.

25. Common markers of inflammation
ESR
Indirect measure of changes in acute-phase reactants and quantitative Igs
Westergren method uses a 200 mm tube, and has a dilution step that corrects for the effect of anemia (PREFERRED) Wintrobe uses 100mm tube s dilution step; only Westergren can detect ESR>50-60 mm/hr (b/c longer tube)

26. Mechanism of elevated ESR
If higher concentration of asymmetrically charged acute-phase protein or hypergammaglobulinemia occurs, dielectric constant of plasma increases and dissipates inter-RBC repulsive forces, leads to closer aggregation of RBCs, so they fall faster, and cause ESR elevation
Proteins such as fibrinogen dissipate inter-RBC repulsive forces , Rouleaux formation follows

27. Noninflammatory conditions with elevated ESR
Aging
Female sex
Obesity
Pregnancy

28. Rule of thumb Age-adjusted upper limit normal for ESR Male: age/2
Female: (age + 10)/2

29. Causes of markedly elevated ESR
Infection, bacterial
CTD (GCA, PMR, SLE, vasculitides
Malignancy: lymphomas, myeloma, etc
Other causes

30. Causes of extremely low ESR
ESR ~ 0mm/hr
Agammaglobulinemia
Afibrinogenemia/dysfibrinogemia
Extreme polycythemia (Hematocrit >65%)
Increased plasma viscosity

31. C-reactive protein (CRP)
Acute phase reactant produced by liver
Response to IL-6, other cytokines
Rises and falls quickly
Elevation within 4 hr of tissue injury
Peak at hr
Half-life ~18 hr
Pearl- levels >10 often associated with bacterial infection, systemic vasculitis, or metastatic cancer

32. Rule of thumb CRP <0.2 mg/dL: normal
CRP mg/dL: indeterminate (may be seen in smoking, DM)
CRP >1.0 mg/dL: inflammatory
Levels > 10mg/dL suggest bacterial infection (up to 85%), or possibly systemic vasculitis, metastatic cancer

33. Antinuclear antibodies (ANA)

34. Current ANA measurement
Fluorescence microscopy
HEp-2 cells (derived from human epithelial tumor cell line) incubated with pt’s serum
Fluoresceinated Ab added, binds to pt’s Abs bound to nucleus

35. ANA High sensitivity in SLE, but poor specificity
Positive ANA has predictive value of only 11%
ANA found in 5-10% of pts without CTD
Healthy pts, chronic infections (e.g., Hep C), multiple meds, etc.

36. ANA Condition % ANA-positive SLE Drug induced lupus MCTD
Autoimmune liver dz
Sjogren’s syndrome
Polymyositis RA
% ANA-positive
99%
95-100%
60-100%
75-90%
30-80%
30-50%

37. ANA Condition % ANA-positive Multiple sclerosis
Pts with silicone breast implants
Healthy relatives of pts with SLE
Neoplasms
Normal elderly (>70 yrs)
% ANA-positive
25%
15-25%
20%

38. ANA Is the ANA a good screening test for SLE?
If entire population was screened, more normal individuals would be detected with positive ANA than SLE pts. by ~50:1

39. ANA
Clinical value of ordering an ANA test can be dramatically enhanced when there is a reasonable pre-test probability of an autoimmune disease

40. ANA patterns Homogeneous (diffuse)
SLE, drug-induced SLE, other diseases
Most common- whole nucleus is evenly stained

41. ANA patterns
Rim (peripheral)
SLE, autoimmune hepatitis

42. ANA patterns Speckled SLE, MCTD, Sjogren’s, Scleroderma, other dz
Nuclear staining is speckled

43. ANA patterns Nucleolar Scleroderma, hepatocellular carcinoma
Nucleoli show up as two or three green blobs within nucleus

44. ANA profile
If screening ANA is positive and additional info needed to further delineate type of autoimmune disease
In extremely rare instances, ANA may be negative but SS-A antibodies may be detected in pts. with an SS-A associated disease

45. ANA Profile dsDNA RNP Sm SS-A SS-B CENTROMERE SLE 60% 30% 15% Rare RA
(-)
MCTD
>95%
Scleroderma
Low titer
10-15%
CREST
60-90%
Sjogren’s
70%
dsDNA highly specific for SLE, correlates c nephritis, disease activity; RNP with MCTD, Centromere Ab c limited scleroderma, SSA, SSB c Sjogrens

46. Antiphospholipid antibodies
Heterogeneous group of Ab that bind to plasma proteins, have affinity for phospholipid surfaces
Anticardiolipin Ab (ACL)
Lupus anticoagulant (LAC)
Beta 2-glycoprotein I

47. Antiphospholipid antibodies
ACL measured by ELISA assay for IgG, IgM, and IgA isotypes
LAC measured by phospholipid-dependent screening test, if prolonged, add 1:1 mix with normal plasma - if no correction, LAC present
Beta 2-glycoprotein I measured by ELISA
If factor deficiency, will correct, but if inhibitor like LAC, no correction

48. Antiphospholipid antibodies
Conditions with positive aPL
~8% normal population
chronic infections e.g., HIV, Hep C
Medications e.g., phenothiazines, hydralazine, phenytoin, procainamide, quinidine
~20% pts. with systemic vasculitis
~15% pts. with recurrent miscarriage
~50% pts. with SLE
60-80% HIV positive have aPL; aPL associated with infections not associated with increased thrombotic risk b/c not directed against B2glycoprotein I

49. Antiphospholipid antibodies
~50% pts. with SLE and aPL will develop a thrombotic event
~3-7% pts. per year who have aPL will experience a new thrombotic event
Overall positive predictive value of an aPL for future CVA, venous thrombosis, or recurrent MC is between 10-25%

50. Anticytoplasmic Antibodies
Often more helpful in diagnosis than antibodies against nuclear antigens
Seen with multiple autoimmune diseases and several forms of vasculitis

51. Anticytoplasmic antibodies
Disease
Cytoplasmic
Antigen
Frequency
Polymyositis
tRNA synthetase (anti-Jo-1, etc)
20-30%
SLE
Ribosomal P
5-10%
Wegener’s granulomatosis
Serine proteinase-3
(in neutrophils)
90%
Microscopic polyarteritis
Myeloperoxidase
70%
Primary biliary cirrhosis
Mitochondria
80%

52. Anti-neutrophil cytoplasmic Antibodies (ANCA)
C-ANCA
Most commonly seen in Wegener’s granulomatosis, microscopic polyarteritis, rarely Churg-Strauss vasculitis
C-ANCA is a diffuse, granular cytoplasmic staining, with Ab to neutrophil specific antigens, namely proteinase-3

53. ANCA P-ANCA seen in multiple diseases as well as vasculitis
Perinuclear staining with or without nuclear involvement, most often associated with neutrophil specific antigen, myeloperoxidase (MPO) Drug-induced syndromes from hydralazine, PTU, penicillamine, minocycline

54. P-ANCA MPO positive MPO negative Microscopic polyarteritis
Pauci-immune GN
Churg-Strauss vasculitis
Drug-induced syndromes
MPO negative
Ulcerative colitis
Autoimmune disease
HIV
Chronic infections or neoplasms (rare)
Drug-induced syndromes such as hydralazine, PTU, penicillamine, minocycline; autoimmune disease such as liver disease, RA, SLE

55. ANCA
If pt. tests positive to ANCA, evaluation of specific antigen testing for MPO and PR3 should be undertaken
If C-ANCA is not against PR3 or P-ANCA is not against MPO, must consider causes other than vasculitis

56. Rheumatoid factor (RF)
Autoantibody directed against the Fc (constant) region of an IgG molecule
Multiple isotypes, including IgM, IgG, IgA, and IgE
IgM RF is routinely measured using latex agglutination titers, nephelometry, and ELISA
RF is essentially a misnomer b/c not that high of specificity for RA

58. Rheumatoid factor
Very low levels normal, but higher production secondary to chronic immune stimulation
RF positive in ~80% of patients with RA
Multiple other causes of positive RF

59. Conditions associated with a positive RF
Rheumatologic diseases
RA (80-85%)
Sjogren’s (75-95%)
MCTD (50-60%)
Scleroderma (20-30%)
Sarcoidosis (15%)
Polymyositis (5-10%)
Non-rheumatologic conditions
Chronic hepatitis
Pulmonary disease
Neoplasms
Aging
Cryoglobulinemia
(40-100%)
Infections
AIDS, Mono, TB, syphilis, parasites, endocarditis
Pulm disease- sarcoidosis, interstitial fibrosis, silicosis, asbestosis; neoplasms, esp leukemia, colon ca

60. Frequency of RF positivity in normal population
AGE
20-60 years
60-70 years
>70 years
Frequency of +RF
2-4% 5%
10-25%

61. Anti-CCP antibodies
High specificity and moderate sensitivity for RA

62. Anti-CCP antibodies Sensitivity 68% for RA Specificity 98% for RA
Can be seen in active TB, other CTD
Clinical implications
Predictive of more aggressive disease with more progressive joint damage
Levels >40 seen in 32% active TB in one study, and lower titers seen in SLE, sjogrens, myositis, scleroderma---lower sens but higher spec than IgM RF---progressive radiographic changes in multiple studies vs RF+ or seroneg

63. Complement
Cascade of proteins activated by many agents, including immune or antigen-antibody complexes
May be decreased due to
Increased consumption (proteolysis)
Increased levels of circulating immune complexes activate classical pathway
Decreased production
Hereditary deficiency or liver disease

64. Hereditary complement deficiencies
May see SLE-like disease with deficiencies in C1-C4
Terminal complement (C5-9) deficiencies lead to recurrent infections
Deficiency in C1 INH leads to angioedema (hereditary or acquired)
Gonococci and meningococci

65. Diseases associated with low complement levels
Rheumatic diseases
SLE, systemic vasculitis, cryoglobulinemia,
RA (rare)
Glomerulonephritis
Post streptococcal and membranoproliferative
Infectious diseases
Bacterial sepsis, SBE, Hepatitis B, other viremias, parasitemias
RA with extraarticular findings

66. Complement level assessment
C3 and C4 generally decreased with increased disease activity in SLE
Decreased levels may predict impending disease flares
C4 lowers before C3 and remains lower longer
CH50 not useful as disease activity marker
Total hemolytic complement good screen for complement deficiency (if unmeasurable, but variable otherwise), mention dsDNA

67. HLA-B27 Sensitivity ~95% for AS ~80% for Reactive Arthritis
~70% for SpA associated with psoriasis
~50% for SpA associated with IBD
~70-84% for uSpA

68. HLA-B27
Specificity
Low given prevalence is ~8% in Caucasian population
In patients with inflammatory back pain, HLA-B27 positivity yields
20-fold increased risk of SpA

69. Synovial fluid analysis
Studies to perform
Gram stain and culture
Total leukocyte count with differential
Polarized microscopy
Glucose, total protein, LDH unlikely to yield helpful info routinely

70. Synovial fluid analysis
Fluid type
Appearance
Total WBC
Count/mm3
%PMNs
Normal
Clear, viscous
0-200
<10%
Non-inflammatory
Clear to sl. turbid
<20%
Inflammatory
Slightly turbid
,000
20-70%
Septic
Turbid
>50,000
>70%

71. )String testنخي شكل شدن (

73. Synovial fluid analysis
Noninflammatory joint effusions
OA, joint trauma, mechanical derangement, AVN
Inflammatory synovial fluid
Multiple rheumatic disorders
Infectious arthritis
Septic
Joint sepsis
Pseudosepsis in gout, reactive arthritis or RA
Infectious includes viral (HIV, Hep. B, Fungal, Mycobacterial etc)

74. Polarized light microscopy
Gout
Pseudogout
Crystal
Monosodium urate (MSU)
Calcium pyrophosphate dihydrate (CPPD)
Shape
Needle
Rhomboid or rectangular
Birefringence
Negative
Positive
Crystal color parallel to axis
Yellow
Blue

75. CPPD and MSU crystals

76. خلاصه
تست های آزمایشگاهی در تشخیص و پیگیری بیماران روماتیسمی از اهمیت زیادی برخودارند بهر حال علائم آزمایشگاهی همیشه در کنار علائم بالینی باید تفسیر شوند