2. 49 y/o male presents with a complaint of chest
pain transferred from Lebanon for NSTEMI
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-Associated Symptoms
-Physical Exam Findings
-Past Medical & Surgical
History
-HPI
-Social History
-Investigations
-Diagnosis
-Management
3. Associated Presenting Symptoms
-Awoken from sleep with substernal and anterior CP,
spreading to bilateral ribs and over his shoulder to his back
-SOB
-Diaphoretic
4. Physical Examination
-NSR, S1 and S2 noted, no S2/S3, no murmurs, rubs
-Entire rib cage tenderness upon palpation, midline
sternotomy scar, well healed without evidence of infection
-Enlarged MCP joints, ulnar deviation of bilateral digitis 2-4
-Significant clubbing of fingernails bilaterally, minimal clubbing
in toenails
--Patient rolls eyes into backward similar to tick, bilateral
nystagmus
5. Past Medical History
-S/P recent 3 vessel CABG (3 total CABG procedures)
-Hypoxic Respiratory Failure
-Pulmonary Fibrosis
-COPD
-CHF w/ reduced EF
-Sick sinus Syndrome s/p AICD placement
-Long QT Syndrome
-Rheumatoid Arthritis
6. Social History
-Lives in Lebanon with dog ‘Lucy,’ used to work as CNA,
currently applying for disability
-2 packs/day for 30 years smoking Hx. Quit November 2014
-Unspecified history of drug abuse: methamphetamine,
marijuana, etc
-Poor record of attending outpatient appointments
7. Investigations
-CTA demonstrates no evidence of PE
-Initial troponin 0.05, repeat 0.10
-ECG reportedly showed anterior ischemic changes
-Coronary angiogram revealed total occlusion of all 3 of his grafts and a
75% stenosis of prox LAD -- DES placed here
-TT Echo demonstrated new wall motion abnormalities
-Bnp 573
-ESR
8. History of Present Illness
-Immediate coronary angiography performed upon arrival at GSRMC
-Angiogram demonstrated all 3 grafts were occluded (LIMA to LAD, saphenous
venous graft to RCA, and saphenous venous graft to obtuse marginal) and a 75%
stenosis of prox LAD)
-DES placed within the LAD lesion
-Intraoperatively he was noted to have pericarditis with extensive adhesions
11. Pathogenesis Overview
-RV is a secondary form of vasculitis and is characterized by a destructive,
inflammatory process centered on both medium and small BV walls
-RV leads to necrosis, BV occlusion and tissue ischemia -- often resembles other
forms of systemic vasculitis -- Polyarteritis Nodosa (medium BVs) and
Hypersenstitivity Vasculitis (small BVs)
-Precipitating factors for RV with severe RA is limited
-Occurs in Pt’s longstanding severe RA, leading to substantially higher mortality
than RA itself
13. History and Classification
-1951: 55 Pts with RV identified who demonstrated transmural inflammation of
large arterioles and small arteries. First elucidation of process distinct from other
vasculitic diseases
-In 1978 a published study placed RV as a subcategory of Hypersensitivity angiitis
associated with immune complex deposition in small venules (affecting primarily
the skin). It was eventually determined that this was a separate pathological
process.
-RV is a secondary form of vasculitis, in contrast to primary forms, such as Behcet
Dz, PAN, GPA, EGPA, Polymyalgia Rheumatica, Cutaneous Vasculitis, Giant Cell
Arteritis, Takayasu Arteritis, Microscopic Polyangiitis and Ig-Associated Vasculitis
15. Epidemiology
-Prevalence: Autopsy reports from 1960 - 1990 suggested that 25-31% of Pts w/
RA have RV. Symptomatic clinical presentation of RV is much less common. More
recent studies place the prevalence at much lower levels -- between 2% - 5.4%
are the latest estimates.
-Incidence: 1994 was the year that incidence of RA seems to have taken an
observable, significant downturn -- DMARDS therapy has been implicated in this
trend but no definitive evidence exists
-More common in males. High concentration of RF and anti-CCP antibodies in
blood, as well as Felty Syndrome are known non-exogenous risk factors for RV.
There is no known ethnic predominance.
17. Pathophysiology: Endothelial Cell Antibodies
-75% of RV Pts have ABs directed against surface of endothelial cells -- 15% in
RA alone
-Evidence suggests Antibody-dependent-cellular-cytotoxicity (ADCC) or Antibody-
dependent-cytotoxicity may be be mechanism of BV wall destruction
-This damage may be exacerbated by IgG RF (immune complex deposition),
which have an inverse relationship with levels of complement consumption.
-Data exists to support direct anti-endothelial ABs in RV, but thus far no targets
within the endothelium have been identified and investigations are ongoing.
19. Pathophysiology: Immune Complex Deposition
-Circulating immune-complexes, a relatively non-specific form of vascular damage
is often found in RV. Circulating IgG immune complexes with RF are a very
sensitive marker for RV.
-Immune complex deposition is frequently found in uninvolved areas of skin in Pts
with RV. This is indicative that additional pathogenic processes need to be
present, such as:
-C3 and C4 aggregated with circulating immune complexes
-Quantity and Quality of RF
-Increased IgA containing immune complexes -- activate alternative
pathway
21. Pathophysiology: Cell-Mediated Immunity
-Circulating T-cells w/ a unique phenotype are increased in RV but much less in
RA uncomplicated w/ RV. These T-cells are CD4+ but CD28-.
-These CD4+ CD28-null T cells function similarly to cytotoxic lymphocytes, natural
killer cells in that they release large amounts of interferon-gamma and are also
capable of lysing cells via cytolytic granule release
-The KIR2DS2 stimulatory receptor is found on the CD4+ CD28-null T cells and
has been identified as a risk factor for RV
22.
23. Pathophysiology: Cytokine & Free Radical
Mediated Endothelial Injury
-TNF-alpha and othe cytokines cause endothelial cells to express leukocyte
adhesion molecules. TNF-alpha induces increased vascular permeability and nitric
oxide synthase activity, which reacts with the ROS causing accelerated
endothelial damage. Elevated levels are seen in RV
-Elevated activation of sympathetic nervous system is seen in RV and may act to
protect the endothelium integrity via increased production of chromogranin A
(CgA)
-One study found higher levels of CgA in RV
25. Pathophysiology: Cigarette Smoking
-Cigarette smoking is the only environmental component shown to increase RV
risk. Smoking was ID’d as a risk factor for increased severity of RA prior to
recognition as risk factor for RA itself
27. Etiology
-Viral infections have been proposed but little supporting evidence exists. Chronic
HCV infections are associated w/ systemic vasculitis, however, the vast majority of
RV Pts are HCV negative
-Medications used in treatment of RA have been proposed as RV incitors, but
association is most likely circumstantial. Glucocorticoids, intramuscular gold, oral
penicillamine and azathioprine have been investigated with little evidence to
support their implication in RV
-Anti-TNF therapies have been linked to cutaneous vasculitis in a very small
minority of Pts, however these cases strongly resembled a hypersensitivity
vasculitis and resolved with medication cessation. There is little to no evidence
implicating anti-TNF therapies to RV
28. Clinical Presentation Overview
-BV inflammation is a central feature of RA and which is thought to be the primary
inciting event of rheumatoid nodule formation, however, this is a separate process
from RV, which is associated with a protean, destructive inflammatory process
centered on BV wall itself.
-This specific pattern associated with RV leads to necrosis, blood vessel occlusion
and tissue ischemia that can resemble other forms of systemic vasculitis
(especially Polyarteritis nodosa)
-In general, the progression of RA and its associated symptoms and signs are
progressed to the point of where the diagnosis of RA is obvious. One study had
13.6 years as the mean duration between RA Dx and onset of RV
-Multiple studies have shown that RV usually presents when maximal joint
damage has occurred. When this process “burns out” will RV Sxs present.
29. Constitutional Symptoms
As noted previously, RV development usually begins after a Pt’s joint disease has
decreased in intensity (“burned out”)
-RV Pts typically have substantial constitutional symptoms from debilitating RA
disease course, aspects associated with RV, such as increased fatigue may have
insidious onset and other signs such as myalgias may be confused for synovitis
flare-up.
-Weight loss occurs in many patients, and fever may be found in a smaller subset
of patients
30. Cutaneous Symptoms
-Skin vasculitis occurs in approx 90% of Pts with RV, and is the most common
manifestation
-Isolated cutaneous lesions in one or more nailfolds are common with RA and if
they occur alone, do not require therapy modification
-Classic RV skin lesions are deep ulcers on the lower extremities, often near or on
the medial or lateral malleoli
32. Neurological Symptoms
-Vasculitic neuropathy is a frequent component of RV, which results from
infarction of individual peripheral nerves by vasculitis in the vasa nervorum
-Full development of motor dysfunction of a nerve may occur within the same day
of onset, as there is generally maximal damage at time of presentation. Assuming
inflammatory process is treated and attenuated there may be a course of return to
function over the next weeks, months or years.
-Painful neuropathy is common during the recuperative process
-CNS involvement is rare in RV. Stroke, etc is in RA is seldom due to RV.
Historically, most CNS vasculitis associated with RV is from the 1940s to 1960s,
as less efficacious therapy was available
33. Ocular Symptoms
-There are 2 primary ocular RV manifestations: Episcleritis/scleritis and peripheral
ulcerative keratitis (PUK)
-Scleritis can occur in anterior or posterior locations. Anterior lesions are evident
from eye examination but also are associated with substantial pain. Posterior
scleritis usually is describes as a deep seated tenderness “behind the eye.”
-PUK is a process involving inflammatory cell infiltration into the peripheral
aspects of the cornea. Often coexists w/ necrotizing scleritis. PUK is characterized
by a crescent shaped ulceration found near the corneoscleral junction.
-Both of these disease processes require urgent therapy with high dose
immunosuppresive medications (both glucocorticoids and cyclophosphamide)
36. Aortitis associated with RV
-Aortitis is a rare complication of RV. It can develop into AV insufficiency,
aneurysm or rupture.
-It has been demonstrated that aortitis is a clinical extension of the systemic
inflammatory disease, and it is not demonstrable that the unique pathogenesis of
RV is driving aortitis
-Incidence of RA associated aortitis cases since biological DMARDS were
instituted suggest that this specific condition may be decreasing more than any
other RA or RV associated disease process
37. Pulmonary Symptoms
-While pulmonary disease is a relatively common extraarticular presentation of
RA, primary vasculitic involvement is uncommon. It has been shown to be difficult
to distinguish RV complication from interstitial lung disease.
-This may be due to the fact that while vasculitis is an inherent process of any
rheumatoid nodule (wherever they are found) it is not possible to elucidate the
distinct processes
-Patients will present with CP, SOB, cough and fever from pulmonary nodules
associated with RA and if there are RV processes occurring simultaneously,
presentation will be indistinguishable.
39. Renal, GI and Hepatobiliary Symptoms
-Renal involvement in RA is rare except for ATN associated with NSAID use, or
other secondary processes of chronic inflammation. Of note, there are
documented cases of circulating ANCA in Pts with RV associated
glomerulonephritis (which is rare), moreover the ANCAs found in these cases are
not against MPO or proteinase-3, as most other ANCA directed vasculitis
diseases.
-Older literature documented numerous cases of mesenteric vasculitis
40. Cardiac Symptoms
-Early RV literature focused on cardiac valves, but in general, valves are not
affected. An autopsy series of 72 RA patients describes arteritis of the coronary
arteries in various forms of subacute and healing processes, often with necrosis.
Thrombosis was not observed, and aneurysm formation was not seen. All layers
of the BV wall were involved, indicating that subclinical RV may have been
present.
-Pericarditis is often the first cardiac manifestation of RV, and pericarditis in a Pt
with RA should prompt further investigations into RV.
-True coronary vasculitis is rare in RV. However, known processes of accelerated
atherosclerosis in RA are also present in RV, no matter the extra-cardiac
manifestations of RV
42. Laboratory Findings Overview
-Lab testing in Pts w/ RV usually reveals nonspecific signs of underlying
inflammatory processes, such as:
-ESR
-CRP
-Thrombocytosis
-Hypoalbuminemia
-Anemia of chronic disease
43. Autoantibodies associated with RV
-Rheumatoid Factor: Higher in Pts with RV than RA alone. High titers are primary
predictor for RV development, and this is consistent with vasculitis being rare in
seronegative RA. As discussed before, IgA may be best predictor, and IgM (most
commonly measured) is a poor predictor.
-Anticyclic citrullinated peptide (CCP): Helpful in distinguishing RV from other
forms of small vessel vasculitis, as anti-CCP have a higher specificity for RA than
does RF. One study found 93% of Pts w/ RV were anti-CCP positive
-Antinuclear: ANA are present in majority of RV Pts, but are nonspecific and have
no correlation contribution to diagnosis or prognosis
-Antineutrophil Cytoplasmic: P-ANCA and A-ANCA are typical for RA and RV but
are usually one of the minor ANCA antigens, not Proteinase-3 or MPO, the 2
antigens most strongly associated with primary systemic vasculitis
44. Autoantibodies associated with RV Continued
-Anti-endothelial cell: Issues with consistency with assay quality has hampered
clinical implementation of these antibodies. No defined role as of yet in Dx or
prognosis
-Antibodies to glucose-6-phosphate isomerase: In mouse models this AB caused
erosive joint Dz indistinguishable from RV. Generally, this AB has been associated
with Felty Syndrome but ongoing work to elucidate role in RA/RV is ongoing
45. Hypocomplementemia
-Serum complement levels are often normal or elevated in RA, however,
hypocomplementemia seems to be more common in RV. There is no current data
to support following serum complement levels in clinical setting.
46. Diagnosis Overview
-RV should be suspected in any Pt w/ long standing history of RA, or Juvenile
Idiopathic Arthritis (JIA) who presents with worsening or new constitutional Sxs,
LE ulcers, digital infarctions, palpable purpura, new sensory or motor deficits, eye
redness (especially with pain), pericarditis and active urine sediment
48. Confirming Diagnosis
-Because the level of immunosuppression required to treat RV is substantially
toxic, whenever possible, RV should be confirmed with tissue biopsy if there are
non-obvious symptoms
-In biopsy of cutaneous ulceration, the optimal tissue sample is from the peripheral
aspect of the lesion
-There do exist situations where clinical manifestations of RV coupled with long
standing RA, such as LE ulcerations or ocular manifestations, can be treated
without performing biopsy. Often times these Pts are already suffering from
multiple systemic symptoms of RA which have the therapeutic drug levels already
significantly elevated
49. Differential Diagnosis of RV
-RV mimicry: Infection, thromboembolic diseases and malignancies
-Infective endocarditis: fever, skin lesions and renal Dz w/ active urine
sediment
-Cholesterol emboli: digital ischemia, leg ulcers, livedo reticularis
-Other vasulitides:
-Polyarteritis nodosa
-ANCA-associated vasculitides
-Hypersensitivity vasculitis
-Cryoglobulinemic vasculitis
51. Treatment and the Clinical Context
-Understanding the disease course of RA in the setting of RV is essential in
determining treatment going forward
-Treatment considerations are often complicated by comorbidities that RA has
inflicted: cytopenia, renal dysfunction, hepatic damage, GI ulceration and various
sequelae of long term high dose glucocorticoid administration
-Success in treating RV lies in balancing the need for stringent therapies coupled
with a typical Pt’s increased vulnerability to treatment complications -- this is
potentially very difficult
53. Treatment of Cutaneous RV
-Isolated Nailfold Infarctions: Treat symptomatically. Often, there is no correlation
between these lesions and full-blown RV
-Leg Ulceration: Wet-to-moist saline dressing, compression bandages/stokings,
Occlusive hydrocolloid dressings for exudative ulcers. Abx ointments are not
recommended.
54. Treatment of Systemic RV
-RV requires aggresive therapy, typically with high-dose glucocorticoids, with the
addition of rituximab or cyclophosphamide.
-Goals of Treatment: achieve remission, characterized by absence of active
vascular inflammation (ESR, CRP, etc) and clinical observation. Antibodies are
not reliable to measure remission status
-Alternatives to rituximab/cyclophosphamide: Azathioprine, TNF-Inhibitor,
Chlorambucil (last resort)
-MTX is not recommended for RV Tx, as it has been shown to precipitate RV in
Pts with RA
55. Maintenance Therapy
-Pts who have achieved remission with rituximab therapy should be kept on it, with
variable schedules depending on indivdualized needs
-Pts who have achieved remission with cyclophosphamide, typically they will be
transitioned to asathiprine for remission maintenance
56. Attenuation of Therapy Side Effects
-Preventing Pneumocystits pneumonia: TMP-SMX with varying schedules
-Preventing hemorrhagic cystitis and bladder cancer: Hydration and mesna
-Preventing osteoporosis: DEXA scan at time of Dx for baseline and subsequent
weight bearing exercises, calcium and vitamin D supplementation and
bisphosphonates
-Smoking cessation
-Skin care: avoiding undue pressure with properly fitting shoes, etc
57. Prognosis of RV
-In cohort of 86 Pts evaluated between 2000 and 2010, treated with various
immunosuppressive agents and DMARDs complete remission was seen after 6
months of therapy in 38%, and partial improvement in 52%, and 10%
demonstrated no improvement. At 5 years, relapse was at 36% and 26% had
died.
-Most common cause of death appears to be infection, while morbidity from
vasculitis is relatively rare. Infection is often due to immunosuppression, further
highlighting the need to individually titrate each therapy to lowest effective dose.
49 y/o male w PMHx of CAD s/p recent 3 vessel CABG, pulm fibrosis, COPD, CHF w/ reduced EF, sick sinus syndrome s/p AICD placement was transferred from Lebanon for acute NSTEMI. He was recently hospitalized for CP and SOB, culminating in a 3-vessel CABG aprox 5 weeks ago. Since D/C 3 weeks ago he has been experiencing persistent CP, diaphoresis and SOB. He was readmitted to hospital a day after initial D/C. CTA on that admission was negative for PE. Soon after he was again D/C’d with ibuprofen for his post thoracotomy CP.
Pt was awoken from sleep w/ substernal and anterior CP spreading to his back and the sides of his ribs, assoc w/ diaphoresis and SOB. EMS was called, administered 324mg ASA and was brought to Lebanon. Initial Troponin was 0.05, repeat 0.10. ECG reportedly demonstrated anterior changes concerning for ischemia.
He was transferred to GSRMC for immediate angiography -- Coronary angiogrophy revealed total occlusion of all 3 of his grafts (LIMA to LAD, saphenous venous graft to RCA, and saphenous venous graft to obtuse marginal) and a 75% stenosis of prox LAD.
DES was placed w/in LAD lesion. After PCI he still had CP and SOB. Interoperative notes described pericarditis with extensive adhesions.
-Most common organs affected are skin, nerves, eyes, heart, lungs, brain, GI tract and kidney.
-DMARD prevalence in Tx of RA has caused decrease in incidence in recent years
-
Vasculitis is considered to be secondary when it arises either in the context of a pre-existing connective tissue disease, as a result of direct infection with a limited range of organisms, especially viruses, or when it arises in response to exposure to a number of medications. Rheumatoid vasculitis is probably the most widely recognised form of secondary vasculitis
GPA: Granulomatosis with Polyangiitis (Wegeners)
EPGA: Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss)
The healed scar of past arteritis in a Pt w/ RV. Note loss of elastic lamna and loss of vessel lumen by firbrous scar
-In 1988 MTX received FDA approval for RA Tx
-Late 90’s saw the emergence of biologics -- first Enbrel, then Infliximab and then Humira -- all TNF-Alpha inhibitors
-Felty’s syndrome: Rare condition involving RA, splenomegaly, decreased WBC and repeated infections.
Endothelial cell antibodies — Antibodies directed against the surface of endothelial cells are present in approximately 75 percent of patients with RV compared with 15 to 20 percent of those with rheumatoid arthritis (RA) alone [18,19]. The enhanced presence of these antibodies suggests that antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent complement-mediated cytotoxicity may destroy the vessel wall [18,20]. In theory, this damage may be accelerated by IgG rheumatoid factors, which are ubiquitous in those with RV (see 'Immune complex deposition' below), the level of which correlates with the consumption of complement [21]. Despite some data supporting a role for anti-endothelial antibodies in RV, little progress has been made in defining antigenic targets within the endothelium for such antibodies, and their true importance is unknown.
Immune complex deposition — A relatively nonspecific form of vascular damage can occur with the deposition of circulating immune complexes, which may be detectable in the subendothelium of affected vessels in RV [22]. Circulating IgG immune complexes are a very sensitive marker for RV, being present in virtually all patients. The presence of IgA immune complexes in sera, although slightly less sensitive, may be more specific [23]. Assays for IgA immune complexes are not available routinely for clinical use, however, and their clinical utility would require further investigation.
Immune complex deposition may be found in uninvolved areas of skin in patients with RV [24]. Whether deposited immune complexes cause vessel destruction is, therefore, likely dependent upon additional pathogenic processes. Factors that affect the pathogenicity of immune complexes are likely to include:
-The microscopic shows the leukocytoclastic infiltrate of the vessel and surrounding tissue.
-Thrombosis is a common complication of the vasculitis.
Cell-mediated immunity — A more direct role for activated lymphocytes in vessel wall destruction has been postulated. Circulating T cells with a unique phenotype are present in increased numbers in a large proportion of patients with RV but in a smaller proportion of patients with uncomplicated RA [32]. A large percentage of circulating CD4+ T cells in patients with RV lack expression of the important costimulation molecule, CD28. Such T cells are almost never detectable in normal individuals. These CD4+ CD28-null T cells share several features with cytotoxic lymphocytes (CTLs) and natural killer (NK) cells, releasing large amounts of interferon-gamma. They are also capable of lysing appropriate target cells through the release of cytolytic granules.
Like NK cells, these unusual lymphocytes express killer cell Ig-like receptors (KIR) activated by interaction with distinct class I major histocompatibility complex (MHC) molecules on endothelial and other cells. In particular, virtually all CD4+ CD28-null clones generated from patients with RV express the KIR2DS2 stimulatory receptor, but not the family of related KIR inhibitory receptors [32]. Expression of the KIR2D gene family on chromosome 19q13.4 is highly variable between individuals, but virtually all of 30 patients with RV expressed the KIR2DS2 gene (odds ratio of 7.96 for RV patients versus uncomplicated RA). The odds ratio for a large number of unselected RA patients without RV versus healthy controls was 0.7, suggesting that the KIR2DS2 gene is highly over-represented in RV patients.
The KIR2D receptors are selective for certain alleles at the human leukocyte antigen (HLA)-C locus of the MHC. In particular, HLA-C*03 is overrepresented in RV compared with uncomplicated RA [33]. This association appears not to represent linkage disequilibrium with the DRB1*0401 allele, another established risk factor (see 'Genetic risk factors' below). Thus, the presence of a KIR2D class I-recognizing receptor and its cognate class I MHC allelic ligand represent independent risk factors for development of severe RV, setting the stage for further work to evaluate the specific role of the CD4+ CD28-null lymphocyte in mediating vascular damage [32].
Schematic outline of the effects of costimulatory receptors OX40 and 4-1BB on the functions of CD4+CD28null T cells in acute coronary syndrome (ACS).Classical CD4+CD28+ T cells constitutively express the costimulatory receptor CD28. Activation of CD4+CD28+ T cells induces transient expression of costimulatory (OX40, 4–1BB) and coinhibitory (cytotoxic T lymphocyte associated antigen-4 [CTLA-4], programmed death [PD]-1) receptors. CD4+CD28+ T cells produce moderate levels of inflammatory cytokines (interferon [IFN]-γ, tumor necrosis factor [TNF]-α) when activated and do not express cytotoxic molecules (perforin, granzyme B). CD4+CD28null T cells from ACS patients lack CD28 and upregulate expression of OX40 and 4-1BB. These receptors drive production of high levels of IFN-γ, TNF-α, and perforin. We hypothesize that these mediators could potentially enable CD4+CD28null T cells to trigger plaque rupture via macrophage activation and endothelial and vascular smooth muscle cell lysis. VSMC indicates vascular smooth muscle cell.
Cytokine- and free radical-mediated endothelial injury — Elevated levels of tumor necrosis factor (TNF)-alpha and other cytokines cause endothelial cells to express leukocyte adhesion molecules, resulting in a capacity to bind and activate circulating leukocytes. TNF-alpha itself induces increased vascular permeability, while inducing an activated endothelial cell phenotype that includes triggering of nitric oxide (NO) synthase activity. The NO produced by these TNF-activated endothelial cells further interacts with reactive oxygen species to accelerate endothelial damage [34].
In addition to the counterregulatory role played by TNF receptors (TNF-R1 and -R2), the sympathetic nervous system may play a role in protecting against TNF-mediated vascular injury. The sympathetic nervous system is significantly activated in RA patients and may play a role in maintaining the integrity of the endothelium through production of mediators such as chromogranin A (CgA). One study found higher levels of CgA associated with severe extraarticular manifestations of RA, including RV, and demonstrated an in vitro protective effect of CgA on human microvascular endothelial cells to TNF-alpha [35].
Chromogranin A or parathyroid secretory protein 1 (gene name CHGA) is a member of the granin family of neuroendocrine secretory proteins, i.e., it is located in secretory vesicles of neurons and endocrine cells such as islet beta cell secretory granules in pancreas.
Numerous medications used to treat rheumatoid arthritis (RA) have also been proposed as triggers of RV, partly because of some similarities between drug-induced hypersensitivity vasculitis and RV. In particular, the treatment of RA with glucocorticoids has been implicated in the development of RV. This association is partly circumstantial, because the first cases of RV were appreciated shortly after the discovery of cortisone [49]. In addition, the putative association between glucocorticoid use and the development of RV almost certainly reflects the greater use of glucocorticoids in patients with severe RA, precisely the subset of patients that is predisposed to developing RV. The same considerations apply to the associations reported between the development of RV and treatment with intramuscular gold, oral penicillamine, and azathioprine [50,51].
Constitutional symptoms — Patients who develop RV typically have significant constitutional symptoms. Because RV patients are often significantly debilitated from their previous RA, the onset of constitutional symptoms such as increased fatigue may be insidious. Myalgias may be mistaken for a flare of synovitis, but (as noted), by the time RV develops, patients’ joint disease is usually less active than in the past. Weight loss occurs in a significant percentage of patients, and fevers occur in a smaller subset [2,9,10].
Cutaneous vasculitis — Skin vasculitis, which occurs in as much as 90 percent of patients with RV, is the most common manifestation [2,4,11]. Isolated cutaneous lesions characterized by one or more nailfold lesions, however, are not necessarily associated with necrotizing vasculitis and do not require a modification of therapy if they occur alone (picture 2) [12,13]. Similarly, the appearance of rheumatoid nodules on the finger pads or palmar surfaces of the hands do not mandate intensification of therapy if no manifestations of more severe disease are present [14].
The classic skin lesions of RV are deep cutaneous ulcers on the lower extremities [11]. These lesions, found typically in the area of the medial or lateral malleoli (picture 3), are the result of necrotizing vasculitis of medium-sized arteries (picture 4). Such lesions must be distinguished from pyoderma gangrenosum, much less common in RA. Medium-vessel vasculitis can also lead to digital ischemia, necrosis, and gangrene (picture 5). Clinical manifestations of small-vessel vasculitis (eg, palpable purpura) may also be present in RV, but the clinical picture and most challenging problems are dominated by disease in medium-sized arteries and arterioles. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'Cutaneous findings'.)
The classic cutaneous finding of rheumatoid vasculitis is a medium-vessel inflammatory process associated with ulcerated lesions of the lower extremities.
Neurologic disease — Vasculitic neuropathy, a frequent component of RV, results from infarction of individual peripheral nerves by vasculitis in the vasa nervorum [15,16]. (See "Clinical manifestations of vasculitic neuropathy" and"Neurologic manifestations of rheumatoid arthritis".)
Approximately 40 percent of patients with RA have a sensory neuropathy, and up to 20 percent develop manifestations of a mixed motor or sensory neuropathy [2,15]. Both mononeuritis multiplex and a distal symmetric sensory or sensorimotor neuropathy can occur [15].
Mononeuritis multiplex has three clinical hallmarks: asymmetry, asynchrony, and a predilection for distal nerves. Early in the process, nerve involvement is likely to affect one side (eg, the left peroneal nerve leading to foot drop) more than the other. Within days to weeks, however, the process may develop a more symmetrical appearance, as distal peripheral nerves are affected in an additive fashion. Motor mononeuritis multiplex may cause a devastating loss of function of the hands and feet, requiring assistive devices for feeding and leg braces (ankle-foot orthoses) for ambulation. Recovery from severe vasculitic neuropathy is extremely slow, typically 12 to 18 months. Many patients have permanent sequelae of their nerve infarctions (picture 6).
In contrast to the myriad other causes of peripheral neuropathy, the onset of vasculitic neuropathy in RV is rapid. Patients often experience their first symptoms (numbness, tingling, or other sensory symptoms) after a period of sleep [17]. As a rule, pain is not striking at the onset of vasculitic neuropathy; rather, the predominant symptom is anesthesia. Within days or weeks of the start of sensory symptoms, muscle weakness caused by motor nerve infarction may ensue [15,16]. (See "Neurologic manifestations of rheumatoid arthritis".)
The full development of motor dysfunction within a given nerve may often take place within the day of onset. There is maximal damage at the time the condition is recognized, followed by deficits that persist for weeks or months. Assuming that the inflammatory process is arrested by therapy, most patients then have a slow, gradual return of nerve function, typically to something less than their full neuromuscular function before the nerve injury. Persistent muscle wasting in at least some sites of nerve involvement (eg, the web space between the thumb and first finger secondary to median nerve infarction) is the rule, although many patients make significant recoveries in muscle bulk and strength. During the recuperative period, painful neuropathy from damaged sensory nerves may constitute a major problem.
Ocular disease — The two principal ocular manifestations of RV areepiscleritis/scleritis and peripheral ulcerative keratitis (PUK) [18,19]. Necrotizing scleritis and PUK must be distinguished from the other common but less serious ocular abnormalities that may result in red eyes. In RA, these conditions include keratoconjunctivitis sicca, episcleritis, choroiditis, and other inflammatory conditions of the uveal tract. (See "Ocular manifestations of rheumatoid arthritis".)
Scleritis may occur in either anterior or posterior locations [18,20]. Anterior forms of scleritis are evident not only from the appearance of the eye (picture 7), but also from the substantial pain associated with this condition. One series of nine patients with RA and necrotizing scleritis who underwent scleral biopsies found vasculitis in all [21]. Bilateral scleritis is not unusual.
Anterior scleritis is subdivided further into three clinical variants:
●Diffuse (least severe)
●Nodular (intermediate in severity)
●Necrotizing (most severe)
These three variants are largely non-overlapping; progression from one variant to another is unusual. The necrotizing form of scleritis may lead to scleromalacia perforans.
In contrast to anterior scleritis, which is typically obvious on clinical examination, posterior scleritis must be diagnosed by inference from the patient’s symptoms, primarily a deep-seated pain and ocular tenderness, but also visual blurring as well as thickening of the posterior coat of the eye on B-scan ultrasonography or magnetic resonance imaging [22].
PUK, a process in which inflammatory cells infiltrate the peripheral area of the cornea, often coexists with necrotizing scleritis (picture 8). In PUK, a crescent-shaped ulceration develops near the corneoscleral junction. A major concern in patients with PUK is the complication of the “corneal melt” syndrome, in which corneal keratolysis, perforation of the globe, and visual failure may result in a short timeframe [19]. Following the occurrence of a corneal melt, patients often lose all useful vision in the eye. Both necrotizing scleritis and PUK require urgent therapy with high doses of immunosuppressive medications, generally both high-dose glucocorticoids and cyclophosphamide. (See "Treatment of rheumatoid vasculitis".)
Corneal Melt Syndrome -- This Pt has Sjogrens Syndrome, but the end result would be the same in untreated PUK in RV
PUK -- crescenteric lesions are seen here
Pulmonary disease — Pulmonary disease is a common extraarticular manifestation of RA, but primary vasculitic involvement of the lung is uncommon (see "Interstitial lung disease in rheumatoid arthritis"). Pulmonary vasculitis as a complication of RV must be distinguished from interstitial lung disease that is not vasculitic in nature. Although rheumatoid nodules occur in the lungs and although pathologic evidence of vasculitis is an inherent feature of rheumatoid nodules whenever they are found, most patients with rheumatoid nodules in the lungs do not have evidence of systemic vasculitis
Rheumatoid nodules of the lungs on CXR
The major forms of renal disease in RA patients are acute tubular necrosis related to nonsteroidal antiinflammatory drug (NSAID) use, secondary amyloidosis due to the chronic inflammation, nephrotic syndrome secondary to membranous nephropathy, and, in a small number of cases, true vasculitis, consisting either of necrotizing glomerulonephritis or of destructive inflammation within the walls of renal arteries
Cardiac disease — Much of the early RV literature, drawing on the experience with rheumatic fever, focused on the cardiac valves and vessels [23]. An autopsy series of 72 RA patients described cardiac pathology arteritis within the hearts of 11 patients (15 percent) [24]. The arteritis, which affected small arteries, was often found in subacute and healing forms, typically in different stages, often associated with necrosis. Thrombosis was not observed, and aneurysm formation was not seen. However, all layers of the blood vessel wall, particularly the adventitia, were involved.
Pericarditis is the cardiac manifestation most likely to present early in the setting of RV; its appearance should heighten concern about vasculitis. One series of 50 patients documented cardiac manifestations, including pericarditis, arrhythmia, aortic incompetence, and myocardial infarction, in approximately one-third of patients [2]. Arrhythmias, found in 9 of 44 patients, included atrial fibrillation, ventricular arrhythmias, and complete heart block. The direct attribution of such rhythm disturbances to RV, however, is often problematic given the significant number of comorbidities suffered by many RV patients.
Although cases of coronary vasculitis are well-documented in the medical literature, myocardial infarctions that are the direct result of coronary arteritis in RV are unusual [23-26]. Clinically manifested coronary vasculitis is likely to occur only in RA patients with clear-cut evidence of vasculitis in other organ systems. One case report incorporated detailed autopsy information on a 74-year-old man with RA who developed systemic vasculitis and who died of myocardial infarction. The post-mortem examination revealed granulomatous vasculitis of the left anterior descending and circumflex arteries, with memory T cell and multinucleated giant cell infiltration of the media [27].
Despite the rarity of true coronary vasculitis in RV, one of the most important determinants of the increased mortality in RA patients is an elevated risk of cardiovascular disease. This appears to represent a significant acceleration of common atherosclerosis [28-30]. However, there is no evidence that clinical complications of atherosclerosis are more common in patients with RV than they are in patients with RA who do not have RV. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications".)
Coronary artery disease as a consequence of secondary systemic vasculitis on the ground of autoimmune diseases such as systemic lupus erythematosis, rheumatoid arthritis, primary antiphospholipid syndrome etc is the leading cause of morbidity and mortality in these cases. It may occur in younger age, it is often asymptomatic and it may be clinically silent in early phases. (Caracciolo et al., 2004; Salmon & Roman, 2008; Sitia et al., 2009; Yildiz, 2010; Yiu et al., 2011). Arterial compliance and arterial distensibility may be altered via systemic inflammation and may lead to accelerated atherosclerosis in secondary systemic vasculitis. (Yildiz, 2010). Although coronary angiography remains the cold standard for diagnosing coronary stenosis, non invasive and more reliable methods, such as magnetic resonance imaging and PET scan, have been proposed in order to detect subclinical microcirculation abnormalities. (Pennell, & Keenan, 2011; Sitia et al., 2009)
These findings on coronary angiography are most consistent with severe generalized coronary arteritis. This 25-year-old woman had been given a diagnosis of polyarteritis nodosa 3 years earlier and was receiving prednisolone maintenance therapy when she presented with cardiac arrest. Although severe cardiac involvement in polyarteritis nodosa is unusual, it can result in myocardial infarction and confers a poorer prognosis. Despite treatment, the patient died a few months later
The usual immunofluorescence patterns observed in RA are perinuclear (P-ANCA) and atypical (A-ANCA). Cytoplasmic (C-ANCA) patterns are very rare. In nearly all cases, however, ANCA positivity in RA is caused by one of the “minor” ANCA antigens (eg, lactoferrin, elastase, cathepsin G, or others), not by proteinase-3 or myeloperoxidase, the two antigens strongly associated with systemic vasculitis.
DIAGNOSIS — The diagnosis of rheumatoid vasculitis (RV) should be suspected in any patient with a long history of rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA) who develops new or significantly worse constitutional symptoms. Weight loss, fever, and fatigue may be subtle indicators of the development of RV. Extraarticular manifestations of RA that strongly suggest RV include cutaneous ulcers on the lower extremities, digital infarctions, palpable purpura, new sensory or motor deficits, eye redness (particularly if associated with ocular pain), pericarditis, and the development of an active urine sediment.
Other vasculitides — Other possible causes of biopsy-proven vasculitis in a patient with RA include the following:
●Polyarteritis nodosa – In terms of the size of blood vessels involved and the types of organs affected, polyarteritis nodosa (PAN) and RV overlap nearly completely. The two diseases are histopathologically indistinguishable, with the exception that RV rarely leads to microaneurysm formation (see 'Clinical presentation' above and 'Renal disease' above and 'Gastrointestinal, pancreatic, and hepatic disease'above). The key to distinguishing these two disorders is the clinical setting. Arthritis and other musculoskeletal complaints associated with PAN do not lead to a destructive arthritis. In the patient with a history of many years of seropositive, erosive RA, the correct diagnosis is likely RV.
●ANCA-associated vasculitides – antineutrophil cytoplasmic antibody (ANCA)-associated diseases (granulomatosis with polyangiitis [Wegener’s], the Churg-Strauss syndrome, and microscopic polyangiitis) have several features in common with RA. First, a migratory oligoarthritis is often among the initial disease manifestations of these conditions. Second, a significant proportion of patients with ANCA-associated vasculitides are rheumatoid factor positive. Third, cutaneous nodules known as “Churg-Strauss granulomas,” which tend to occur over extensor surfaces (particularly in the olecranon regions), may mimic rheumatoid nodules. Because of these disease similarities, many patients with ANCA-associated vasculitis are misdiagnosed initially as having RA.
●Hypersensitivity vasculitis – The potential for small-vessel involvement (cutaneous venules) in RV may lead to confusion with other small-vessel vasculitis syndromes such as hypersensitivity vasculitis, usually caused by a reaction to a medication. Antibiotics, for example, are prime offenders (see "Overview of cutaneous small vessel vasculitis"). Although involvement of medium-sized arteries and arterioles is responsible for many RV manifestations, inflammation in cutaneous venules may often be observed.
●Cryoglobulinemic vasculitis – Palpable purpura, cutaneous ulcers, arthralgias (and even frank arthritis), and myalgia typically accompany cryoglobulinemic vasculitis (see "Overview of cryoglobulins and cryoglobulinemia", section on 'Cryoglobulinemia'). In addition, because the IgM component in mixed cryoglobulinemia has rheumatoid factor activity, patients with type II and type III cryoglobulinemia are almost always rheumatoid factor positive. Cryoglobulinemia also shares with RV the tendency to produce hypocomplementemia, although the degree of hypocomplementemia (particularly C4 levels) in cryoglobulinemia is usually more profound in mixed cryoglobulinemia than in RV. Cutaneous features of small-vessel vasculitis (purpura, pustules), nearly universal in cryoglobulinemia, are less common in RV.
●Vasculitis associated with an overlapping connective tissue disease – Arthritis, rheumatoid factor positivity, and joint syndromes such as Jaccoud’s arthropathy frequently occur in connective tissue diseases such as systemic lupus erythematosus, mixed connective tissue disease, and the inflammatory myopathies (polymyositis and dermatomyositis). Cutaneous vasculitis is also a common manifestation of such disorders, potentially leading to confusion with RV (see "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes"). Some connective tissue disorders are also associated with antiphospholipid antibodies, known to cause digital gangrene and cutaneous ulcers.
Ulcerations in Polyarteritis Nodosa -- notice how this distribution is very similar to the classic LE lesions in RV
Skin fragility and ulceration with long term steroid therapy -- just to show what side effects therapy for RV can do
If eschar is present, wet-to-moist saline dressings may be used to debride the ulcer to a base of granulation tissue.
●If the arterial circulation is adequate, compression bandages or stockings may help reduce swelling if there is concomitant venous stasis.
●Occlusive hydrocolloid (or hydrogel) dressings or, for patients with very exudative ulcers, calcium alginate-containing dressings are suggested.
Antibiotic-containing ointments or creams are not recommended. Topical glucocorticoids may be used, but their efficacy for skin ulcers due to RV is uncertain.
Maintenance therapy — Patients who have had remission from RV induced byrituximab should be considered for maintenance therapy with this medication. For patients with severe RV, however, we generally retreat patients at least once following the return of B cells to measurable concentrations, which typically occurs after 6 to 12 months. Alternative approaches include treating patients with rituximab every six months regardless of B cell concentrations or waiting until the return of active disease before reinstituting treatment with rituximab. No consensus has emerged regarding the need for or the timing of retreatment, and these decisions must be determined in practice on a case-by-case basis.
Two large retrospective studies have provided further insight into the prognosis of patients with RV, and explored the question of whether changes in therapy and the availability of biologic agents has impacted the prognosis of those who develop RV:
●In a cohort of 86 patients evaluated between 2000 and 2010, who were treated with various immunosuppressive agents (including glucocorticoids,cyclophosphamide, and traditional and biologic disease-modifying antirheumatic drugs [DMARDs]), complete remission was seen after six months of therapy in 38 percent and partial improvement in 52 percent, while 10 percent showed no clinical improvement [49]. Relapse had occurred in 36 percent by five years, and 26 percent had died.
●Another retrospective study compared 18 patients in the Norfolk Vasculitis Register diagnosed with RV between 2001 and 2010 with 47 patients diagnosed from 1988 to 2000 [50]. Five-year mortality in the more recent cohort was 60 percent, compared with 51 percent in the earlier cohort. The authors concluded that although the incidence of RV may be declining with earlier treatment of RA and the use of biologic therapies, the clinical features remain similar and very high mortality rates persist
