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Vasculitis1
- 1. Carotid system artritis misdiagnosis and best treatment Tarek nasrallah MD rheumatology Ass. Prof. rheumatology department AL AZHAR University
- 3. Vasculitis • Inflammation on blood vessels causing vessel and tissue damage • Classification • Large-vessel vasculitides • Medium-vessel vasculitides • Small-vessel vasculitides (many) • ANCA-associated • Non-ANCA-associated
- 5. VASCULITIS: ACTIVITY VERSUS DAMAGE Disease Activity Disease Damage
- 6. Large Vessel Vasculitides Giant cell arteritis (temporal arteritis) Takayasu’s arteritis Distinguish ed only by age of pt. > or < 50 yo. Both involve the aorta and its primary branches
- 8. What are the characteristic clinical features of GCA? •Common features related to vascular injury (30%-80%) •Headache •Scalp tenderness •Jaw claudication • Less common features related to vascular injury (<20%) • Ocular symptoms, blindness • Painful dysphagia, respiratory symptoms • Limb claudication • Absent or asymmetrical pulses
- 9. Ischemia of the central nervous system Tongue claudication Aortic regurgitation, myocardial infarction Peripheral neuropathy Deafness Tissue gangrene •Infrequent features related to vascular injury (<5%)
- 10. Common features related to systemic inflammation (40%-100%) Intense acute-phase response Anemia (normocytic, normochromic) Polymyalgia rheumatica Wasting syndrome
- 11. What is the role of laboratory testing? Marked elevations in ESR and CRP: common A normal ESR or CRP does not exclude GCA and A biopsy or imaging should be performed when GCA is suspected. Hypochromic or normochromic or normocytic anemia and thrombocytosis: common Liver function test abnormalities: may be found **No autoantibody tests help identify GCA**
- 12. CLINICAL BOTTOM LINE: Diagnosis... Consider GCA in patients older than 50 years with: New onset, localized unilateral headache Ischemic symptoms in cervicocranial and upper extremities Muscle stiffness of the neck, shoulder, pelvic girdle Physical exam: tenderness, swelling, and erythema over temporal artery; flow abnormalities of large vessels Lab: ESR or CRP elevated in most patients Temporal artery biopsy: gold standard for diagnosis
- 13. What is the overall approach to treatment? Don’t delay treating suspected GCA while waiting for a biopsy • High dose oral prednisone • With visual loss: IV pulse corticosteroids Low-dose aspirin may reduce blindness risk Methotrexate, other immunosuppressants for repeated flares during tapering If little improvement within 5 days: revisit diagnosis and consider comorbid conditions causing symptoms
- 14. What is the role of steroids in management? • High dose oral corticosteroids • Prednisone or prednisolone 1 mg/kg, up to 60 mg/d • Treat 2 to 4 weeks, followed by slow taper after symptoms and signs of active disease resolve • High dose IV corticosteroids • Methylprednisolone 1000 mg/d for 3 d • For acute vision loss or critical organ ischemia
- 15. What are the rationale and role of aspirin? Controversial whether patients with GCA have increased risks for cardiovascular disease Studies suggest that low-dose aspirin (≤100 mg/d) diminishes risks of cerebral or ocular and cardiovascular events Prescribe low dose aspirin to patients who have no contraindications to its use
- 16. Immunosuppressant medications? steroid-sparing agents MTX: modest benefit Tocilizumab (humanized monoclonal antibody to IL6 receptor): encouraging results for treating relapsing GCA TNF-a inhibitors: not found to be beneficial for treatment of GCA Relapses increase risk of steroid- related complications
- 17. CLINICAL BOTTOM LINE: TREATMENT... Start corticosteroids when clinical suspicion high enough to warrant a temporal artery biopsy Symptoms and acute phase reactants typically respond promptly, but disease flares common Provide low-dose aspirin to decrease visual and CV ischemic events if no contraindications Follow patients closely for clinical signs of relapse or LV involvement and for corticosteroid-related complications Life-long surveillance advised for large vessel involvement
- 18. Polymyalgia rheumatica •PMR is a common inflammatory rheumatic disease of older individuals •PMR had wide variations of clinical practice •There is no diagnostic laboratory test, inflammatory markers are not specific, and So •clinicians often turn to the corticosteroid response as a “test of treatment” to establish the diagnosis
- 19. Criteria for diagnosis • Age >50 years, bilateral shoulder aching, and abnormal CRP and/or ESR • Morning stiffness duration > 45 minutes (2) • Hip pain or limited range of motion (1) • Absence of RF or ACPA (2) • Absence of other joint involvement (1) • A score of 4 or more is categorized as polymyalgia rheumatica (PMR)
- 20. Diagnostic Criteria for Takayasu’s Arteritis American College of Rheumatology. The patient should fulfil three or more of the criteria listed below: 1. Onset of disease ≤ 40 years 2. Claudication** of an extremity 3. Reduced brachial artery pulsation 4. Difference in systolic blood pressure >10 mmHg between the arms 5. Aortic or subclavian artery bruit 6. Angiographic abnormality
- 21. Takayasu arteritis A rare LVV that mainly affects Young women (9:1 ratio) Typical age of onset between 15 and 25 years Association with TB exposure and HLA-B
- 22. TAKAYASU ARTERITIS • Clinical manifestations: • pre-pulseless: • Night sweats • anorexia • weight loss • fatigue • myalgia • pulseless: • splenomegaly • erythema nodosum, syncope, amaurosis fugax • dilated CM, myocarditis, and pericarditis • (+) vascular bruit. • Labs: ESR>60, microcytic hypochromic anemia • Confirmation of Dx: angiography for occlusive and aneurysmal disease
- 23. Pulseless phase Diminished or absent pulses Vascular bruits Hypertension Mesenteric angina Retinopathy Aortic regurgitation Neurological symptoms (postural dizziness, seizures, amaurosis). Localized aneurysms. Raynaud phenomenon
- 24. Treatment PREDNISOLONE, AN INITIAL DOSE OF 1MG/KG/DAY (TOTAL MAXIMUM DOSE 60MG/DAY), FOR 1-3 MONTHS WITH GRADUAL TAPERING CYTOTOXIC CYCLOPHOSPHAMIDE (1-2 MG/KG/DAY), AZATHIOPRINE (1- 2MG/KG/DAY), METHOTREXATE (0.3 MG/KG/WEEK) EFFECTIVE AT INDUCING REMISSION AND HALTING PROGRESS OF ARTERIAL LESIONS
- 25. Treatment •Mycophenolatemofetil, an inhibitor of guanine nucleotides synthesis • Biological agents • Tumour necrosis factor-𝛼 antagonists •Infliximab and Etanercept • Anti-IL-6 receptor monoclonal antibody tocilizumab
- 27. Doctor, Doctor, I have painful marks on my legs 25 y/o female presents with night sweats, anorexia, weight loss, fatigue, and myalgias of few weeks duration. pt noticed severely painful nodular lesions in the anterior aspects of her legs. Pain is unremitting. Physical exam reveals a thin women in distress secondary pain, (+) carotid bruit on the right, widened and laterally displaced POINT OF MAXIMAL IMPULSE, and Left chest pain relieved with leaning forward. (+) splenomegaly. LL. exam for nodular lesions resembling erythema nodosum and tender to touch. WORKUP?
Editor's Notes
- What is the role of laboratory testing? Marked elevations in ESR and CRP are often found in untreated patients and provide circumstantial evidence for GCA if other reasons for these abnormalities are not identified (e.g., infection, malignancy). In one study (23) that included 177 patients with biopsy-proven GCA, elevated CRP and elevated ESR were 86.9% and 84.1% sensitive, respectively, for a positive temporal artery biopsy. The ESR and/or CRP were elevated in 159 (89.8%) of GCA patients, whereas 10.2% had a normal ESR and CRP at the time of diagnosis. There was good concordance between ESR and CRP, as both were either elevated or normal in 92% of patients; about 8% of patients had discordant result 153 s between CRP and ESR (23). Several studies with smaller sample sizes are more guarded about utility of ESR and CRP. In one study of 25 patients, 24% with biopsy-proven GCA before treatment had a normal ESR (24). Thus, while usually valuable at initial presentation, ESR and CRP are imperfect markers of GCA. A normal ESR or CRP does not exclude GCA and a diagnostic evaluation with biopsy or imaging should be performed when GCA is suspected. Many patients with GCA have a hypochromic or normochromic or normocytic anemia, and thrombocytosis (10). Liver function test abnormalities, particularly an elevated alkaline phosphatase, may also be found. No autoantibody tests help identify GCA.
- Clinical Bottom Line: Diagnosis… The diagnosis of GCA should be considered in patients older than 50 years who present with new onset, localized unilateral headache, ischemic symptoms in the cervico-cranial and upper extremity vascular territories (e.g., jaw claudication, visual aberration or loss), and muscle stiffness of the neck, shoulder, or pelvic girdle. Typical physical examination findings include tenderness, swelling, and erythema over the temporal artery and/or flow abnormalities of large vessels (e.g. bruits, asymmetric pulses or blood pressures). Most patients have markedly elevated ESR or CRP. GCA involvement of large vessels is common and subclinical in most patients. Temporal artery biopsy is considered the gold standard for diagnosis.
- What is the overall approach to treatment of GCA? Treatment of suspected GCA should never be deferred pending biopsy because treatment is rapidly effective and prevents vision loss, and biopsy specimens remain interpretable for at least 2 weeks after treatment initiation (1). In virtually all instances, patients with GCA should receive high dose oral prednisone, or in the case of visual loss, intravenous pulse corticosteroids. The absence of dramatic improvement within 5 days, even in patients with a positive temporal artery biopsy, should raise questions about the accuracy of diagnosis or the presence of comorbid conditions as a cause of the patient’s symptoms. High dose prednisone is generally administered for approximately a month (or until signs and symptoms resolve) with a subsequent gradual taper. Patients should be closely monitored for relapse, which is common, and for steroid-related complications. Co-administration of low-dose aspirin may help reduce the risk of blindness. For patients who repeatedly experience flares during prednisone tapering, immunosuppressive drugs, such as methotrexate (MTX) have been used as corticosteroid-sparing agents, although the evidence of their effectiveness is limited and controversial (discussed below).
- What is the role of steroids in management? Although randomized controlled trials to identify the best use of corticosteroid therapy in GCA do not exist, most patients usually receive oral prednisone [40-60 mg/d (or 1 mg/kg)] immediately after the diagnosis is established or if GCA is strongly suspected (Table 4). Intravenous pulse corticosteroids (typically methylprednisolone, 1000 mg/d for 3 d) has been advocated for patients with transient, partial or complete visual loss, but there have not been any controlled trials comparing this approach to high dose oral prednisone. Partial and rarely complete visual recovery may occur if treatment is initiated within 24 hours of visual loss (38). Patients who receive high dose IV corticosteroids should be hospitalized for close monitoring of visual changes and treatment-related side effects. Oral high dose prednisone should initially be administered for approximately 2-4 weeks. If all symptoms of active disease have resolved and acute phase reactants are normal, subsequent dose reduction should begin at a rate of about 10% every 1-2 weeks. Once a prednisone dose of 10 mg is reached, the dose should be reduced more gradually (i.e., about 1 mg/mo). Attempts to withdraw corticosteroids within 6 months of starting treatment have resulted in relapse rates as high as 90% (39). Slower tapering schedules are less prone to relapses. Treatment often lasts about 24 months; some patients may require years of treatment. The ability to withdraw corticosteroids in asymptomatic patients with normal acute phase reactants does not equate to histologic absence of disease (16). Thus, monitoring for disease progression (i.e., large vessel involvement) remains important in all patients. Table 4: Medical treatment of Giant Cell Arteritis High dose corticosteroids – oral: Prednisone or prednisolone 1mg/kg, up to 60mg/d (2-4 wk, followed by tapering after remission) High dose IV corticosteroids: Methylprednisolone 1000mg/d for 3 days (Consensus endorsement for threatened or actual acute vision loss or critical organ ischemia) Low dose aspirin: dose 81 or 100mg/d (Prevention of ischemic events, especially blindness. Efficacy based on retrospective data.) Methotrexate – oral or subcutaneous injection: dose 15-20mg/week (Uncertain benefit. Controversial. Hazardous in patients with liver disease, renal impairment, blood dyscrasias, or moderate/heavy alcohol use.) Tocilizumab (humanized monoclonal antibody to IL6 receptor): dose 8mg/kg every 4 weeks IV* (Phase 2 RCT** revealed marked efficacy for sustained, corticosteroid-independent remissions. Not yet approved for GCA.) Other monoclonal anti-cytokine antibodies: dose variable (Either of no benefit (anti-TNF) or not yet studied) *Studies are ongoing with self-administered subcutaneous injections. **RCT – randomized controlled trial
- What are the rationale and role of aspirin? Whether patients with GCA have increased risks for cardiovascular disease (CVD) remains controversial (40). In a study involving a U.K. primary care database, outcomes were compared between 3408 patients with incident GCA and 17,027 age- and sex-matched controls without baseline CVD [(myocardial infarction (MI), cerebrovascular accidents (CVA), or peripheral vascular disease (PVD)]. Patients with GCA had an increased hazard (HR) of 1.70 for the combined outcome of MI, CVA and PVD. The risks were highest in the first month after diagnosis (combined outcome HR, 4.92) (41). A population-based study from Canada yielded similar results for MI and CVA (42). It is uncertain if this increased CVD risk is directly related to inflammation or vasculitis, vasculopathy, or factors that promote thrombosis. Regardless, this may help to understand results from studies of low-dose aspirin in GCA. While limited by their retrospective design, these studies suggest that low-dose aspirin (≤100 mg/d) diminished risks of cerebral, ocular, and cardiovascular events in patients with GCA (43, 44). Until more conclusive studies are performed, patients with GCA should receive low dose aspirin, provided they have no contraindications to its use (Table 4).
- When should clinicians consider other immunosuppressant medications? Relapses of GCA are common and require repeated courses of prednisone, placing the patient at increased risk of steroid-related complications. Numerous studies have examined immunosuppressive medications that could be used as disease-modifying or steroid-sparing agents. The French Study Group for Large Vessel Vasculitis (GEFA) investigators (29) endorse the use of MTX in relapsing GCA while recognizing its efficacy in this context may be modest. The 3 studies that informed these recommendations included only 161 patients (39, 45, 46). The studies differed in regard to the doses of MTX employed, steroid-tapering schedules, inclusion of new-onset vs. relapsing GCA and definitions of relapse, making it difficult to directly compare the findings. Two of 3 studies did not demonstrate MTX benefit in reducing relapse rates or cumulative steroid dose. Although no patient developed MTX-induced pneumonitis or pancytopenia, some patients were withdrawn from MTX because of leukopenia, increases in hepatic transaminases and mucositis (46). Furthermore, because GCA affects an elderly population in whom reductions in renal function are common and MTX clearance is dependent on renal excretion, potential life-threatening complications of MTX are a serious concern that must be weighed against questionable or modest benefit. Some studies have examined the use of immunosuppressive agents that block specific components of the immune system involved in the pathogenesis of GCA, such as IL6. Case reports and small observational cohorts of patients with relapsing GCA treated with the humanized monoclonal antibody to the IL6 receptor tocilizumab have been encouraging and have led to several important studies. A recent small phase 2 double-blind randomized controlled trial assigned patients to receive corticosteroids plus either tocilizumab (n=20) or placebo (n=10). Complete remission by week 12 was achieved in 85% of patients given tocilizumab and 40% of those given placebo (Risk Difference 45%, CI 11–79; p=0á0301). By week 52, relapse-free survival was achieved in 85% of patients in the tocilizumab group and 20% in the placebo group (Risk Difference 65%, CI 36–94; p=0á0010). In addition, after 52 weeks patients receiving tocilizumab required 50% less prednisolone (cumulative dose) compared to those receiving placebo (47). Ongoing large double-blind randomized controlled trials are being conducted to determine if these results are reproducible (ClinicalTrials.gov identifiers: NCT01450137, NCT01791153). A trial of Sirukumab, a fully human anti- IL-6 IgG1-kappa with a high affinity and specificity for binding human IL-6 is also underway (ClinicalTrials.gov Identifier: NCT02531633). Because TNF-alpha is present in abundance in temporal artery biopsies, some investigations examined the effect of adding TNF-alpha inhibitors, such as infliximab or adalimumab, to prednisone. These approaches did not increase the number of patients in remission or decrease their corticosteroid requirements (48, 49). Such studies suggest that elevated measures of inflammatory reactants may not equate to having dominant roles in pathogenesis. Furthermore, although some of these treatment strategies may contribute to decreasing disease morbidity, they do not address GCA etiology. Cure is unlikely without eliminating causal agents that may play a role in ongoing disease.
- Clinical Bottom Line: Treatment... Corticosteroid therapy should begin immediately in patients for whom the clinical suspicion of GCA is high enough to warrant a temporal artery biopsy, especially if they have visual symptoms. Patients’ symptoms and acute phase reactants typically respond promptly to effective treatment, but disease flares are common, particularly with tapering of the corticosteroids. Low dose aspirin appears to decrease visual and cardiovascular ischemic events and should be provided to all patients who do not have contraindications. Patients should be followed closely for clinical signs of relapse or large vessel involvement and for development of corticosteroid-related complications. Life-long surveillance for large vessel involvement, especially thoracic aortic aneurysms, is advised.