RHEUMATOLOGY MAY 9, 2018

CLINICAL PRESENTATION OF OTHER CONNECTIVE TISSUE DISEASES (part2) & VASCULITIS

DR.LUGUE-LIZARDO
MIXED CONNECTIVE TISSUE DISEASE MTCD present if serologic criterion accompanied by 3 or more clinical criteria
 Autoimmune condition affecting almost every major organ in the body –one of which must include synovitis or myositis
just like in lupus
 First discovered in 1972 by SHARP et al MANAGEMENT:
 Combination of two or more other autoimmune diseases  NONDRUG
 AKA overlap syndrome  All patient should be given advice on smoking cessation if
 Overlapping features of five major connective tissue applicable and also avoiding cold exposure, especially to the
 SLE hands and feet
 Scleroderma  Patient should be encourage to keep active and mobile but to
 Polymyositis avoid over excretion
 Dermatomyositis  DRUGS
 Rheumatoid arthritis  For patient with mild disease , the initial treatment is NON
 Serology: ANTIBODY AGAINST RIBONUCLEOPROTEIN ANTIGEN(RNP) STREOIDAL ANTI INFLAMMATORY AGENTS such as ibuprofen to
treat the pain and inflammation
EPIDEMIOLOGY  Mild disease may also benefit from the anti-malarial agent
 Prevalence:3-4 per 100,000 population HYDROXYCHLOROQUINE(DMARD)
 Peak onset: 15-25 years old  In more severe cases, or when there is secondary organ
 High female predominance (80%) with 3:1 ratio involvement, SYSTEMIC CORTICOSTEROIDS are used
 Present in all races  Adjuvant therapy with steroid- sparing agents such as
 Majority of patients symptoms progress in different disease CYCLOPHOSPHAMIDE and CYCLOSPORIN may be used when
prolonged treatment with highdose steroid is required
episodes rather than present all at once on initial clinical evaluation
 CALCIUM- CHANNE BLOCKING AGENTS such as nifedipine may be
used for the treatment of the Raynaud’s phenomenon
PATHOPHYSIOLOGY
 Esophageal dysfunction may require treatment with PROTON
 Autoantigen modification
PUMP INHIBITORS
 Innate immune activation
 Symptoms of pulmonary hypertension and Raynaud’s
 B lymphocytes phenomenon can also be helped by PHOSPHODIESTERASE
 T lymphocytes INHIBITRS such as sildenafil can be seen in 2d echo, the
pulmonary artery pressure going up more than 25 mmhg so we
CLASSIFICATION give phosphodiesterase inhibitor that resolve to vasodilatation
 Early clinical features are non-specific  Endothelin receptor antagonist such as ambrisentan can help to
 General malaise reduce the symptoms of pulmonary hypertension and improve
 Arthralgia exercise tolerance
 Myalgia
 Lower grade fever
 Kung ano ung condition ung patient like lupus plus scleroderma VASCULITIS
basically un din ung mga sign and symptoms  Clinicopathologic process characterized by inflammation of and
 Positive antinuclear antibody(ANA) in association with Raynaud’s damage to blood vessels
phenomenon  Vessel lumen is usually compromised and associated with ischemia
 Almost all organ systems are involved of the tissues because decrease in blood flow
 Four clinical features that suggest the presence of MTCD rather than  Most are assumed to be mediated by immunopathologic
other connective tissue disease mechanism in response to certain antigenic stimuli
1. Raynaud’s phenomenon and swollen hands or puffy fingers  Classified first by the size of the blood vessel involved
2. Absence of severe renal and central nervous system disease  Small(capillaries and post capillary venules)
3. More severe arthritis and insidious onset of pulmonary  Medium(muscular arteries and arterioles)
hypertension  Large(aorta and its major branches)
4. Autoantibodies whose fine specificity is anti-U1RNP, especially  Consideration in classification include patient demographics, organ
antibodies to the 68kd protein tropisim, presence or absence of granulation inflammation,
participation(or not) of immune complexes, finding of
ALARCON-SEGOVIA DIAGNOSTIC CRITERIA autoantibodies, and detection of infections associated with some
vasculitides

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 VASCULITIS

 Chronic inflammation of the vessel wall leads to aneurysm formation

,stenosis or thrombosis

CLASSIFICATION CRITERIA
 onset before the age of 40years
 Limb claudication Must meet 3
 Decreased brachial artery pulse out of 6
 Unequal arm blood pressure (>10mmhg) criteria
 Subclavian or aortic bruit
 Angiographic evidence of narrowing or occlusion of aorta or primary
branches

PATHOPHYSIOLOGY AND PATHOGENESIS

EPIDEMIOLOGY

CLINICAL MANIFESTATION
LARGE MEDIUM SMALL
Limb claudication Cutaneous nodules Purpura Impairment of your function of T lymphocytes and can activate or trigger
Asymmetric blood - Ulcers Vasiculobullous lesion yourself reactive CD4 T cells and leads to the production of B cells and
pressures Livedo reticularis Uticaria
eventually produce antibodies against your vascular antigens , triggers t
Absence of pulses Digital gangrene Glomerulonephritis
cell driven IgG switching , expansion of your macrophages and formation of
Bruits Mononeuritis multiplex Alveolar hemorrhage
Aortic dilatation Microaneurysms Cutaneous langhans multinucleated giant cell
Renovascular HPN Renovascular HPN extravascular - On other hand can also trigger your cytotoxic t cell or your cd8 t cell leading
necrotizing granulomas to cell death mediated by your perforin and fas/fas-lall of these processes
Splinter hemorrhages will leads to recruitment and activation of your fibroblast leading of
Uveitis/episcleritis/scler deposition in tissues of collagen and matrix protein leading to pulseless
itis disease
Constitutional symptoms of fever, weight loss, malaise, arthralgia/arthritis CLINICAL FEATURES
common to vasculitides of all vessel sizes Feature At presentation Ever present
(%) (%)
PATHOPHYSIOLOGY AND PATHOGENESIS Vascular 50 100
Potential mechanism of vessel damage in vasculitis syndromes Bruit 80
1. Pathogenic immune complex formation and/or deposition Claudication (upper extremities) 30 62
2. Production of antineutrophilic cytoplasmic antibodies (ANCA) Claudication (lower extremities) 15 32
3. Pathogenic T lymphocytes response and granuloma formation Hypertension 20 33
Unequal arm blood pressure 15 50
Carotidynia 15 32
LARGE BLOOD VESSEL
Aortic regurgitation 20
TAKAYASU’S ARTERITIS
Central nervous system 30 57
 Most commonly affected is your aorta
Lightheadedness 20 35
 Even your blood vessel arising to your aorta is affected just like your
Visual abnormalities 10 30
carotid, subclavian, coronary artery , abdominal aorta and renal
Stroke 5 10
artery
Musculoskeletal 20 53
 Occurs most commonly in japan , china, india and southeast asia Chest wall pain 10 30
 Cause is unknown thought to result from an autoimmune process Joint pain 10 30
that targets large elastic containing arteries Myalgia 5 15
 Affecting women 8 times more frequent than men ,median age of Constitutional 33 43
onset is 25years old Malaise 20 30
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FEVER 20 25  Immune deposits are minimal or absent

Wt. loss 15 20  ANCA are typically negative
Cardiac 15 38  Can occur at any age, Peak is at 5 th or 6th decades
Aortic regurgitation 8 20
 Propensity for aneurysm formation especially in the mesenteric
Angina 2 12
circulation
CHF 2 10

LABORATORY FINDINGS AND IMAGING STUDIES POLYARTERITIS NODOSA AS A REFERENCE POINT

 At presentation, ESR is more frequently elevated (80%) than CRP(50%)
 Mild anemia and hypergammaglobulinemia are common
 Wbc count is usually normal or slightly elevated. Platelet count is usually
elevated in 1/3 of patients (may exceed 500,00) may be mistaken as
infection
 Vascular abnormalities can be imaged by conventional angiography
(gold standard), MRI, MRA, CT angiography
MEDICAL TREATMENT
 Other forms of vasculitis can be differentiated from PAN through the
following characteristics:
 General confinement to medium-sized vessels
 Exclusive involvement of arteries, sparing of veins
 Tendency to form microaeurysms
 Absence of lung involvement
 Lack of granulomatous inflammation
 Absence of associated antibodies (ANCA, anti-GBM, RF)
 Association of some cases with Hepatitis B virus

 Corticosteroids are the CORNERSTONE OF TREATMENT OF ACTIVE TA. PATHOPHYSIOLOGY AND PATHOGENESIS VASCULITIS
Prednisone, at a dose 0.5-1mg/kg/day Pathogenic immune complex formation and/or deposition
 Acttive TA:  Antigen-antibody complexes are formed in antigen excess and
 Fever or other systematic features (in the absence of other deposited in vessel wall
cause) Permeability has been
 Elevated ESR increase by vasoactive
 Symptoms or sign of vascular ischemia or inflammation amines (histamine,
 Typical angiographic lesions bradykinin, leukotrienes)
 Initial dose is continued for 4-12 weeks before commencing a gradual released from platelets or
taper maintain dose up to 3 months from mast cell as a result of
 Relapses can be treated by increasing the prednisone dose or adding IgE-triggered mechanism
an immunosuppresive agent:
 Methotrexate (gradually increased to 25mg/wk)
 Azathioprine (2mg/kg/day)
 Mycophenolate mofetil (2g/day)  Activation of complement components (c5a) which is strongly
 Cyclophospgamide (2mg/kg/day) chemotactic for neutrophils
SURGICAL TREAMENT
 Treating stenotic or aneurysmal lesions may require bypaass surgery,
aortic value replacement, or percutaneous transluminal angioplasty  Infiltrates the vessel wall phagocytose the immune complexes
 The mere presence of stenosis does not necessitate intervention Release of intracytoplasmic enzymes
 Surgical intervention should be deferred until TA is in remission,
procedures done in active disease produce disappointing results
 Bypass surgery yields better results than angioplasty
 Autologous vessels give better results than synthetic grafts  Damage

OUTCOME AND PROGNOSIS CLINICAL MANIFESTATION

 20% of TA patients gave self-limited disease, the rest have a relapsing-
remitting or progressive course
 Survival is 92.9% at 5 years, 87.2% at 10 years and 73.5% at 20 years
 Congestive heart failure and renal failure are the most common causes
of death
 Pregnancy appears to be relatively well tolerated
MEDIUM BLOOD VESSEL
POLYARTERITIS NODOSA(PAN)
 It is a pathological condition in which the medium and small sized
arteries in the body become swollen and are significantly damaged
when attacked by immunes cells
 Necrotizing vasculitis of small and medium-sized muscular arteries
 Involvement of renal and visceral arteries is characteristic
NMCastro
 Cutaneous Manifestations in PAN
 Purpura- red or purple discolorations that do not blanch upon
applying pressure; caused by bleeding underneath the skin
 Livedo Recularis-red or purplish discoloration ,net like pattern
especially patient expose to cold and stress
 Subtaneous nodules in PAN- can ulcerate and have necrotizing
vasculitis within the walls of medium- sized arteries, usually located
in the deep dermis and subcutaneous fat
 Musculoskeletal system
 arthritis, arthralgia or myalgia
 Cardiac
 cardiomegaly pericarditis
 coronary artery involvement leading to ischemia and infraction
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 Renal system Methotrexate 15-25 mg orally Less effective but often used
 Most commonly involved weekly after 1-2 yr of therapy with
 Hypertension more potent agents
 Renal insufficiency Plasmapheresis No proven benefit
Intravenous Proven benefit in vasculitis
 Rupture of renal arterial aneurysms –> parirenal hematomas/
caused by parvovirus B19
hemorrhage(can form microaneurysm) may benefits others
 Neurologic Involvement Monocional Limited expenence
 Peripheral nervous system antibody
o Mononeurits multiplex (eg, radial, ulnar, peroneal) Interferon alfa Used in vasculitis secondary
o Distal symmetric polyneuropathy to Hepatitis B
 Central nervous system
o Transient monocular blindness
SMALL BLOOD VESSELS
o Cerebral arteritis, arterial thrombosis, cerebral ischemia or
ANCA-ASSOCIATED VASCULITIDES
intraparenchymal or subarachnoid hemorrhage  Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA),
o Acute or subacute
and Churg Strauss syndrome (CSS)
o Myelopathy with paraparesis
 Can be considered together in view of a number of shared
 Gastrointestinal Tract
pathologic; clinical and laboratory features:
 abdominal pain nausea vomiting bleeding
 Preferentially involve small vessels (arterioles, capillaries,
 bowel infraction and perforation venules)
 hepatic infraction  Similar glomerular lesions (crescents, focal necrosis, pauci-
 pancreatic infraction immune)
 Orchitis  Propensity to present as lung-renal syndromes
 testicular pain  Varying prevalence of ANCA positivity
 Ischemic retinopathy
 with hemorrhages, retinal detachment DEFECTION OF ANCA
 ANCAs were originally describe based on the immunofluorescence
ACR 1990 CRITERIA FOR THE CLASSIFICATION OF POLYARTERITIS NODOSA patterns
 Weight loss of> 4kg since beginning of illness  cytoplasmic (c-ANCA() and perinuclear(p-ANCA)
 Livedo reticularis  The antigens responsible for these patterns have also been
 Testicular pain or tenderness identified
 Myalgias, weakens, or leg tenderness  proteinase 3(PR3) for c-ANCA
 Mononueropathy or polyneuropathy  myeloperoxidase (MPO) for p-ANCA
 Presence of hepatitis B surface antigen or antibody
In serum
 Development of hypertension
 Elevated BUN or creatinine unrelated to dehydration or obstruction
 Arteriogram demonstrating aneurysms or occlusions of the visceral
arteries
 Biopsy of small or medium-sized artery containing granulocytes
***3/10 required to make a diagnosis of PAN

TREATMENT OF POLYARTERITIS NODOSA

Drug Dose Comment

Oral prednisone 1mg/kg/day Mainstay of therapy
Methylprednisolone 1 g/day for 3-5 Used in Fulminant Disease
days
Cyclophosphamide 2-4 mg/kg/day Used with major organ
orally involvement or inability to
withdraw
Cyclophosphamide 10-15 mg/kg/mo Alternative to oral therapy,
intraventously less toxic
Chlorambucil 0.1 mg/kg/day Alternative to
cyclophospharmide
Azathioprne 2-4 mg/kg/day Less toxic and possibly less
effective than
cyclophosphamide

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VASCULITIS

PATHOPHYSIOOLGY AND PATHOGENESIS  67% to 76% during the course of disease

 most patients experience only arhralgias, myaylgias and arthrits
1. Production antineutrophilic cytoplasmic antibodies (ANCA)  Neurologic
2. PR3 and MPO which are the antigen they are confine within the  Rare
granules of your neutrophils and monocytes once in inside they  Peripheral neuropathy is the most common single neurologic
cannot be interact with others manifestation
3. But once they are prime by your IL-1 and TNF- alpha  -Mononeuritis multiplex is the most frequent clinical pattern
4. PR3 and MPO Translocate to extracellular area or your cell  Gastrointestinal
membrane your ANCA that are located outside the cell can now  asymptomatic and may be unrecognized
 Abdominal pain, diarrhea and bleeding are the most frequently
interact with the antigen
reported symptoms and they relate to the presence of
5. Then they Degranulate your monocytes and neutrophils which
ulcerations in the small intestines, large intestines, or both
form your ROS causing damage
 Genitourinary
 Case reports: ureteral obstruction, hemorrhagic cystitits
WEGENER’S GRANULOMATOSIS

Cardiac
 Granulomatous necrotizing vasculitis with a predilection to affect
 Pericarditis is the most frequently reported
the upper and lower respiratory tracts and, in most cases, the
 Necrotizing vasculitis and granuloma formation may involve the
kidneys
pericardium in a focal or diffuse pattern
 Cause is unknown  -Other: coronary vasculitis, myocarditis, endocarditis, and …
 Higher prevalence of HLA-DR1 and HLA-DQw7 has been reported
 Upper airway disease is the most common presenting feature, DIAGNOSIS
occurring in more than 70% at onset and ultimately developing in  leukocytosis, normocytic normochromic anemia,
more than 90% thrombocytosis, and elevated ESR
 Pulmonary manifestation occur in 45% of cases at presentation and  The sensitivity of PR3 –ANCA is about 90% in active WG and 40%
in 87% during the course of disease when the disease is in remission
 The most common radiographic findings include  The specificity of PR3-ANCA in the diagnosis of WG exceeds 95%
 Pulmonary infiltrates (67%)  Inflammatory lesions in WG typically include necrosis,
 nodules (58%) granulomatous changes, and vasculitis
 Pulmonary nodules in WG are usually multiple and bilateral and  The diagnostic yield of a biopsy varies with the size of the
often cavitate (50%) specimen
 Less common pulmonary manifestations of WG include pleural TREATMENT
effusions, diffuse pulmonary hemorrhage, and mediastinal or hilar
lymph node enlargement or mass
 Renal
 The presence of absence of renal disease defines the subset of
generalized(more on) and limited WG
 Defined by pathologic findings on kidney biopsy or the
presence of an active urinary sediment and functional
abnormalities
 11% to 18% of patients at presentation
 77%to 85% during the course of disease
 Early segmental fibrinoid necrosis and infiltration by
neutrophils
 Ocular
 28% to 58% of patients with WG
 8% to 16% of cases in the initial presentation
 Any compartment can be affected: Keratisis, conjunctivitis,
scleritis, episcleritis, nasolacrimal duct obstruction, uveitis, retro-
orbital pseudotumor with proptosism, retinal vessel occlusion,
and neuritis
 Cutaneous MICROSCOPIC POLYANGIITIS
 40% to 50% of patients with WG
 Initial presentation in 13% to 25%  A necrotizing vasculitis with few or no deposits affecting small
 ulcers, palpable purpura, subcutaneous nodules, papules and vessel
vesicles  Often associated with necortizing glomerulonephritis and
 Musculoskeletal pulmonary capillarits
 32% to 53% of patients at presentation  Affects males more frequently than females

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VASCULITIS

 Onset is generally in the 4th or 5th decade but can range from early 1990 ACR Classification Criteria for Churg-Strauss Syndrome (CSS)
childhood to old age
 Onset may be hyperacute, with rapidly progressive  Asthma Eosinophilia>10%
 Can be insidious with several years of intermittent constitutional  Neuropathy
symptoms, purpura mild renal disease and even periodic bouts of  Pulmonary infiltrates
hemoptysis  Paranasal sinus abnormality
CLINICAL FEATURES OF MICROSCOPIC POLYANGIITIS  Extravascular eosinophil infiltration on biopsy

The presence of at least four of the six criteria indicates that Churg-Strauss
Clinical feature Percentage*
syndrome is very like to be the differentiating factor to other disease
Constitutional Symptoms 76-79
Fever 50-72 CSS MANISFESTATION
Renal Disease 100
Arthralgia’s 28-65  Pulmonary
Purpura 40-44  Pulmonary infiltrates may occur in the prodromal phase, vasculitic
Pulmonary disease (hemorrhage, 50 phase; or both and is generally nonspecific
infiltrates, effusion)
 Radiographic appearance is variable, but lobar, interstitial and
Neurologic disease (central, peripheral) 28
nodular patterns
Far nose throat involvement 30
 Neurologic
DIAGNOSIS
 Mononeuritis multiplex or symmetric or asymmetric
 Diagnosis of MPA can sometimes be based on clinical and laboratory
polyneuropathy
findings, it is preferable to secure the diagnosis with histology
 CNS involvement is uncommon and tends to dominate in the
 Most accessible and rewarding tissues are:
latter stages of the illness
 skin,
 Renal
 Kidney
 CSS shares the same renal lesion (necrotizing crescentric pauci-
 lung
immune glomerulonephritis) with the other ANCA-associated
 MPO-ANCA is present in 60% to 80% of patients PR3-ANCA may be diseases)
positive
TREATMENT PROGNOSIS AND TREATMENT
 Treatment of MPA is based on the same therapeutic principles as  Overall, the 5-year survival rate for patients with CSS was 78.9%
those outlined for WG  Five factors were associated with poor outcome:
 Steroids and immunosuppressive agents  Azotemia (creatinine level > 1.58mg/dL)
 proteinuria (>1g/day)
CHURG STRAUSS SYNDROME OR ALLERGIC ANGIITIS  Cardiomyopathy
 Several problems like gastrointestinal bleeding, numbness and severe  CNS involvement
pain in feet and hands, high fever and rash may also occur in Churg  Therapeutic trial are limited, but have demonstrated that bot
Stauss syndrome glucocorticoid alone and glucocorticoid combined with
 Eosinophil-rich and granulomatous inflammation involving the cyclophosphamide are efficacious
respiratory tract and necrotizing vasculitis involving the medium-
sized vessels associated with asthma and eosinophilia
IMMUNE COMPLEX MEDIATED SMALL VESSEL
 70% of patients have a history of allergic rhinitis, often associated
 What is Hypersensitivity Vasculitis or Allergic Vasculitis?
with nasal polyposis
 It is one such acute type of vasculitis that is characterized by
 Eosinophilia at levels in excess of 1500 cells/mm3 often occurs in the redness or inflammation at the skin occurring after coming in
prodromal stages of CSS contact with an allergen or irritating substance
 Majority of patients tested have elevated IgE levels  Immune complex- mediated small vessel vasculitis that spares internal
 ANCA positivity is associated with a higher incidence organs and usually follows drug exposure or infection
 renal disease
 alveolar hemorrhage 1990 ACR Classification Criteria of Hypersensitivity Vasculitis
 mononueritis multiplex  Age> 16yr
 purpura  Use of a possible offending medication in temporal relation to
 ANCA-negative patients were more likely to suffer from symptoms
 Cardiomyopathy  Palpable purpura
 nonhemorrhagic pulmonary infiltrates  Maculopapular rash
 nasal polyposis  Biopsy of skin lesion showing neutrophils around an arteriole or
 eosinophilic gastritis or enteritis venule

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HENOCH-SCHONLEIN PURPURA
 Strongly associated with IgA deposition within blood vessels walls
 Hallmark is URTI followed by a syndrome characterized by purpuric
rash, arthralgias, abdominal pain, and renal disease
 Children are mostly affected than adults
 In mild case of HSP, no specific therapy is necessary
 Prudent to treat aggressive renal involvement with
 High dose steroid
 another immunosuppressive (cyclophosphamide,
azathioprine or MMF)

HENOCH SCHOLEIN PURPURA CRITERIA FOR DIAGNOSIS


American College of  EULAR/PRESS Criteria 2006
Rheumatology Criteria
1990
-2 or more of the ff: -Mandatory Criterion
 Age <20 years  Palpable purpura
 Palpable Purpura -Plus at least one of the ff:
 Bowel Angina  Diffuse abdominal pain
 Biopsy showing  IgA deposition in any biopsy
granulocytes in the  Arthritis/arthralgia
walls of small arterioles  Renal involvement
or venules (hematuria and/or
proteinuria)

VASCULITS CAUSED BY VIRAL INFECTIONS

 Hepatitis B vasculitis
 Manifestations vary: diffuse small vessel vasculitis to larger vessel
lesions typical of PAN
 Hepatitis C
 Patients with cryoglobulinemia almost always have concomitant
hepatitis C infection
 Parvovirus B19 vasculitis
 Usually in children
 May resemble PAN

Positive anca ,eosinophilia and asthma-css

Positive C-ANCA-WG

Positive P-ANCA-MPA

No anca but theres iga deposite –HPS(hallmark upper respiratory infection)

RECORDING (thank you DEN for the recordings)

POWERPOINT

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“An adventure too big for the real world”

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