Primary central nervous system vasculitis: comparison of patients with and without cerebral amyloid angiopathy.

OBJECTIVES: To describe the clinical features and outcomes of patients with primary central nervous system vasculitis (PCNSV) and cerebral amyloid angiopathy (CAA) from a large cohort of consecutive patients with PCNSV treated at a single institution. METHODS: We identified 101 consecutive patients with PCNSV admitted between January 1983 and December 2003. PCNSV diagnoses were based on findings from a central nervous system (CNS) biopsy (n = 31) and conventional angiography (n = 70). CNS tissue specimens from 49 cases were examined histologically, and 49 were stained for amyloid deposits. Those with vascular amyloid deposits (CAA) were compared with those without histological evidence of amyloid deposition. RESULTS: Eight cases (26%) with CNS biopsy specimens positive for PCNSV also showed findings of CAA. Compared with patients with PCNSV only, these patients were older at diagnosis, predominantly male, had a more acute onset, a higher frequency of cognitive dysfunction and showed prominent gadolinium-enhanced leptomeningeal lesions with MRI. Histologically, all had a granulomatous vascular inflammatory pattern. Six patients responded promptly to therapy. Outcomes at last follow-up were similar in the two groups. CONCLUSIONS: PCNSV with CAA appears to form a clinical subset of PCNSV. The vasculitis influences the clinical findings to a greater degree than the presence of amyloid deposits in the vessels.

Primary CNS vasculitis with spinal cord involvement.

BACKGROUND: Primary CNS vasculitis (PCNSV) is an uncommon disease in which lesions are limited to the brain and spinal cord. Our objective was to evaluate the frequency, clinical features, and outcome of spinal cord involvement in PCNSV. METHODS: We retrospectively identified 101 consecutive patients with PCNSV. Spinal cord involvement was documented for five. Clinical findings, laboratory studies, and outcomes of patients with spinal cord involvement were assessed and compared with those without spinal cord manifestations. RESULTS: Spinal cord symptoms developed before cerebral symptoms in one patient, concurrently in two, and after cerebral symptoms in two. CNS biopsy specimens showed necrotizing vasculitis in three patients and granulomatous vasculitis in two. MRI of the spinal cord showed enhanced thoracic lesions in all five. Cerebral angiograms from four patients had normal findings. One patient had a fatal clinical course. The other four had relapses during follow-up but responded well to therapy and had favorable overall outcomes. At the last follow-up (median, 19 months after diagnosis), the four patients had recovered with slight or moderate residual disability. No significant differences in clinical and laboratory features were observed when comparing patients with or without spinal cord involvement. Cerebral angiograms with evidence of vasculitis were significantly more frequent for patients without spinal cord involvement (p = 0.002). CONCLUSION: Spinal cord involvement was documented in 5% of patients with primary CNS vasculitis. The thoracic cord was the predominantly affected site. Other than myelopathy, clinical characteristics were similar to those of the patients without spinal cord involvement.

Cervical interspinous bursitis in active polymyalgia rheumatica.

OBJECTIVE: To evaluate the inflammatory involvement of cervical interspinous bursae in patients with polymyalgia rheumatica (PMR) using MRI. METHODS: In all, 12 consecutive, untreated new patients with PMR were investigated. Five patients with fibromyalgia, two patients with cervical osteoarthritis and six patients with spondyloarthritis with neck pain served as controls. MRI of the cervical spine was performed in all 12 PMR case patients and in 13 control patients. Two of the four patients with PMR with pelvic girdle pain also had MRI of the lumbar spine. RESULTS: MRI evidence of interspinous cervical bursitis was found in all patients with PMR, and in three patients with fibromyalgia, in two with psoriatic spondylitis and one with cervical osteoarthritis. A moderate to marked (grade >or=2 on a semiquantitative 0-3 scale) cervical bursitis occurred significantly more frequently in patients with PMR than in control patients (83.3% compared with 30.7%, p = 0.015). In all patients and controls with cervical bursitis the involvement was found at the C5-C7 cervical interspaces. MRI of the lumbar spine showed lumbar interspinous bursitis at the L3-L5 lumbar interspaces in the two patients with PMR and pelvic girdle pain examined. CONCLUSIONS: Cervical interspinous bursitis is a likely basis for discomfort in the neck of patients with PMR. The prominent inflammatory involvement of cervical bursae supports the hypothesis that PMR is a disorder of prominent involvement of extra-articular synovial structures.

Laboratory investigations useful in giant cell arteritis and Takayasu's arteritis.

A raised erythrocyte sedimentation rate (ESR) is considered a hallmark for the diagnosis of giant cell arteritis (GCA). The American College of Rheumatology 1990 criteria for GCA include ESR greater than or equal to 50 mm/h as one of the five criteria. Although the presence of a normal ESR made GCA less likely, the results of a population-based study showed that the occurrence of a low/normal value in GCA at diagnosis is not rare. Pre-treatment ESR may be a prognostic indicator for duration of treatment. C-reactive protein (CRP) and interleukin-6 (IL-6) may be more sensitive indicators of disease activity than ESR in GCA patients. However, it is unclear whether the use in clinical practice of CRP and IL-6 has some apparent advantage over ESR. ESR is the most often used tool to assess disease activity in Takayasu's arteritis (TA). However, some studies have found that ESR and CRP are not able to differentiate patients with clinically active and inactive TA. Furthermore, histopathological studies have shown that over 40% of patients thought to be in clinical remission with normal acute phase reactants have active arteritis. IL-6 could be a promising marker of disease activity in TA; however, further studies are required to confirm its usefulness in clinical practice. Other laboratory investigations could be useful in the diagnosis or follow-up of GCA and TA, but more studies are required.

Vasculitis. A collection of pearls and myths.

Important strides have been made in unraveling the pathophysiologic characteristics of some individual forms of vasculitis, but vasculitides continue to pose enormous challenges for clinicians. Over time, numerous myths and an occasional pearl have arisen from the care of patients with these disorders. In this collection of pearls and myths, we have attempted to pool our knowledge about the clinical care of vasculitis patients.

Giant cell arteritis with low erythrocyte sedimentation rate: frequency of occurence in a population-based study.

OBJECTIVE: To determine the frequency of a low erythrocyte sedimentation rate (ESR) in patients with giant cell arteritis (GCA) and evaluate their clinical features in a defined population. METHODS: A total of 167 patients with GCA were identified in the population of Olmsted County, Minnesota, between the years 1950 and 1998 using methods described in previous studies. All fulfilled American College of Rheumatology criteria for GCA. RESULTS: In 9 of the 167 patients the ESR was less than 40 mm/hour (Westergren method) at diagnosis. These patients had less frequent systemic symptoms and visual symptoms than the others. No patient with low ESR developed blindness. Other manifestations were similar in those with low and those with high ESR. The response of symptoms to prednisone treatment was within 1 week, and after a median of 25 days of therapy the median ESR dropped from 19 mm/hour to 3 mm/hour. The median duration of glucocorticoid therapy in the 9 patients was 21.5 months and median followup after diagnosis was 12.5 years. Over a long period of observation (median 44 years) in the 9 patients with low ESR, 9 inflammatory events other than GCA were observed in 7 patients. The ESR was normal in 7 of these 9 other events. CONCLUSION: A low ESR in active GCA is not a rare occurrence. Causes may include localized arteritis in some patients and an inability to mount an acute phase serologic response in others.

Polymyalgia rheumatica and giant cell arteritis.

PMR and GCA are related conditions that seem to represent a continuum of disease. These conditions are relatively common and seem to be mediated by a cellular inflammatory response. Increasing evidence suggests an infectious cause (or causes) precipitating this immune response in genetically susceptible individuals. Whereas previously thought to affect primarily branch vessels of the aortic arch, GCA is now thought of as a disease in which proximal aortic involvement is frequent. Despite the potential for serious, even fatal complications, overall prognosis for patients with GCA or PMR is excellent. Corticosteroids remain the standard treatment, although not curative. Whereas the ESR is a useful indicator of disease activity, other markers which may be more precise such as creative protein and Il-6 seem to offer added information about disease activity.

The spectrum of conditions mimicking polymyalgia rheumatica in Northwestern Spain.

OBJECTIVE: To examine the spectrum and the main clinical data of patients presenting with polymyalgia symptoms who have conditions other than polymyalgia rheumatica (PMR) or PMR associated with giant cell arteritis (GCA) during a 10 year period in Northwestern Spain. METHODS: Clinical records of patients presenting with polymyalgia symptoms diagnosed at the Hospital Xeral-Calde Lugo from 1987 to 1996 were reviewed by rheumatology staff members. Patients were considered as having a condition suggestive of PMR if they met the following criteria: (1) Age > or =50 years at the onset of symptoms; (2) severe bilateral pain associated with morning stiffness for > 1 mo in at least 2 of 3 areas: neck, shoulder, and/or pelvic girdle; (3) erythrocyte sedimentation rate at the time of diagnosis > or =40 mm/h. Patients with pure PMR or with PMR associated with GCA were excluded from study. RESULTS: Twenty-three of the 208 patients (age 67.8 +/- 9.0 yrs) presenting with PMR symptoms were finally diagnosed as having conditions different from PMR and GCA. Men outnumbered women (61%). Malignancies and rheumatic diseases, especially seronegative symmetrical polyarthritis (SSP), were the most common entities. Elderly patients with solid malignancies had a poor response to low doses of prednisone. In patients with hematologic malignancies atypical symptoms of PMR such as lack of accentuation of symptoms with movement and a more diffuse continuous aching were observed. During followup 5 patients developed episodes of SSP (median duration 13 months, range 5 to 24), particularly in both hands, satisfying the American College of Rheumatology 1987 criteria for rheumatoid arthritis. However, arthritis responded promptly to corticosteroids with no disease progression. No cortical erosions or new episodes of PMR were seen in these patients after a followup of 6.8 +/- 2.6 years. With the exception of these 5 patients, duration of polymyalgia symptoms was not longer than 3 months from the onset of polymyalgia symptoms until a specific diagnosis was made. CONCLUSION: Polymyalgia symptoms are not uncommon as presenting manifestations of a wide spectrum of conditions. Special concern about the presence of diseases different from PMR or GCA must be considered in patients presenting with atypical symptoms of PMR. Also, the possibility of developing a SSP has to be considered during the followup of these patients.

Clinical features of GCA/PMR.

Giant cell arteritis (GCA) is a common vasculitis of unknown cause that affects persons in middle age and older. Its incidence rises with increasing age. The inflammatory lesions involve larger arteries that contain an abundance of elastic tissue. Although cranial symptoms such as headache, tender scalp, jaw claudication and visual symptoms are common, the disease presents in many different fashions, often with symptoms not directly related to the arteries. These latter presentations include fever, severe malaise, polymyalgia rheumatica, high erythrocyte sedimentation rate and anemia, thrombocytosis, sore throat, and hepatic dysfunction. GCA appears to have a self-limited course, but is also characterized by relapses and recurrences. Visual loss due to occlusion of the optic arteries is the most important early manifestation and aortic aneurysm is the most important late complication. Patients respond promptly to varying doses of glucocorticoids but drug side effects are common.

Classification/diagnostic criteria for GCA/PMR.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are two common rheumatic diseases occurring in middle-aged and older persons. Their cause is unknown and in neither is there a single specific diagnostic test. As a result a combination of findings is needed for their diagnosis. The American College of Rheumatology has established criteria for the classification of GCA using two methods. These criteria are best used in research studies involving patients with a diagnosis of vasculitis. One method is based on the so-called traditional format. In this method the patient with vasculitis is classified as GCA if he/she manifests any 3 among the list of 5 criteria selected. The second method, the tree format or recursive partitioning method, starts with the clinical finding that best separates patients with GCA from others with vasculitis and then uses other criteria successively to point to a final decision regarding the presence or absence of GCA. Diagnostic criteria for GCA have not been formulated. Diagnostic criteria have been established for PMR by analysis of a series of patients, but in practice most rheumatologists use criteria established informally by consensus.

Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity.

OBJECTIVE: To determine the value of the erythrocyte sedimentation rate (ESR) and plasma interleukin-6 (IL-6) as biologic markers for monitoring disease activity in giant cell arteritis (GCA). METHODS: Twenty-five patients with biopsy-proven GCA were enrolled into a prospective treatment study. Therapy was initiated with prednisone, 60 mg/day, followed by a predetermined tapering schedule. Patients were monitored monthly for clinical signs of active vasculitis and laboratory parameters indicative of inflammation, including elevated ESR (>30 mm/hour) and elevated plasma IL-6 concentrations (>6.1 pg/ml). RESULTS: Upon initiation of corticosteroid treatment, clinical signs of GCA disappeared in all patients; however, 60% of the patients developed symptoms of recurrent disease, on 1 or more occasions, while the prednisone dosage was being reduced. These 31 disease flares diagnosed over 550 days were associated with symptoms of systemic inflammation but did not result in vascular complications. The ESR was elevated in 76% of the patients prior to initiation of treatment (median 65 mm/hour) and normalized by day 28 of therapy (median 6 mm/hour). The median ESR remained in the normal range during the followup period. Plasma IL-6 levels, which were abnormal in 92% of untreated patients (median 16 pg/ml), were partially responsive to the initial high doses of corticosteroids by day 28 (median 6 pg/ml), but levels did not completely normalize with continued therapy. Elevation of the ESR was seen during only 58% of all disease flares, but 89% of disease recurrences were associated with increased plasma IL-6 levels (P = 0.03). CONCLUSION: Plasma IL-6 is more sensitive than ESR for indicating disease activity in untreated and treated GCA patients. Standard corticosteroid regimens only partially suppress vascular inflammation. Smoldering disease activity may expose GCA patients to the risk of progressive vascular disease (e.g., formation of aortic aneurysms) and chronic systemic complications such as IL-6-mediated osteopenia.

Polymyalgia manifestations in different conditions mimicking polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a generally benign syndrome involving the neck, shoulder, and hip girdles in the elderly. However, none of the clinical and laboratory findings are specific for this syndrome. Different diseases may present with features suggesting PMR. The consideration of other conditions which in some cases resemble PMR is very important, as their therapy and prognosis differ completely from that of PMR. Four patients presenting with typical PMR manifestations, who were finally diagnosed as having conditions very different from PMR, are described. The importance of the differential diagnosis in patients presenting with polymyalgia symptoms is underlined.

Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM): a reversible form of encephalopathy.

Five patients, age 54 to 80 years, presented between 3 weeks and 18 months after symptomatic onset of progressive cognitive decline, psychosis, and unsteady gait that proved to be due to a steroid-responsive nonvasculitic autoimmune inflammatory meningoencephalitic syndrome. CSF examination showed elevated immunoglobulin (Ig)G index and IgG synthesis rate in all three patients in whom it was checked, and brain biopsy revealed perivascular lymphocytic infiltrates without vessel wall invasion.

Polymyalgia rheumatica with low erythrocyte sedimentation rate at diagnosis.

OBJECTIVE: To determine the frequency and clinical characteristics of polymyalgia rheumatica (PMR) with low erythrocyte sedimentation rate (ESR) at diagnosis in a community based cohort of 232 patients. METHODS: A retrospective review of medical records of all the patients with a diagnosis of PMR in Olmsted County, Minnesota, seen and followed over a 22 year period, from 1970 through 1991. RESULTS: Seventeen (7.3%) patients had ESR < 40 mm/h at diagnosis. The findings and outcome in these patients were compared with the others in the group. There was no difference in sex or age between the 2 groups. Both groups had the same delay to diagnosis, typical gradual onset of the disease, the same frequency of both proximal and distal stiffness/pain, and the same frequency of synovitis. Systemic features were less frequent in the low ESR group than in the high ESR group (59 vs 81%, p = 0.05). Mean ESR in the low ESR group was 26+/-9 mm/h versus 74+/-24 mm/h in the high ESR group. The mean hemoglobin concentration was significantly lower (p = 0.0015) in the high compared to the low ESR group (12.2+/-1.4 g/dl versus 13.3+/-1.3 g/dl). The frequency of positive temporal artery biopsy and of diagnosed giant cell arteritis was the same in the 2 groups. Initial response to therapy, frequency of relapses, number of patients going into remission, time to remission, and daily dose of steroids were the same in both groups. CONCLUSION: Other than more frequent systemic symptoms, our population of patients with PMR and low ESR at diagnosis had similar clinical characteristics and course of disease as patients with high ESR at diagnosis.

The role of parvovirus B19 in the pathogenesis of giant cell arteritis: a preliminary evaluation.

OBJECTIVE: To determine whether parvovirus B19 DNA is more likely to be present in the temporal arteries of patients with giant cell arteritis (GCA) than in the temporal arteries of control subjects. METHODS: We prospectively examined temporal artery biopsy (TAB) tissue from 50 consecutive patients presenting for TAB for the presence of B19 DNA using the polymerase chain reaction (PCR). Clinical and demographic information was obtained from the patients' medical records. A separate PCR analysis of 30 original tissue specimens was conducted at the Centers for Disease Control and Prevention (CDC) using primers directed toward another target sequence in the nonstructural coding area of B19. RESULTS: The 50 patients had an average age of 70.8 years; 27 (54%) were female. Amplicons for human beta-globulin, but not for cytomegalovirus, were produced for all tissue samples. The PCR results for B19 agreed in 29 of 30 samples tested by our institution and by the CDC (97% agreement; kappa = 0.9). A comparison of the B19 DNA analysis and the results of TAB indicated a statistically significant association between histologic evidence of GCA and the presence of B19 DNA in TAB tissue (chi2 = 10.38, P = 0.0013). CONCLUSION: These findings suggest that B19 may play a role in the pathogenesis of GCA.

Musculoskeletal manifestations in a population-based cohort of patients with giant cell arteritis.

OBJECTIVE: To define musculoskeletal manifestations occurring in a population-based cohort of patients with giant cell (temporal) arteritis (GCA). METHODS: The records of 128 patients with GCA diagnosed over a 42-year-period (1950-1991) in Olmsted County, MN, were reviewed for the presence and type of musculoskeletal manifestations, their relationship to the onset and course of GCA, and their response to treatment. RESULTS: Fifty-three patients (41%) developed polymyalgia rheumatica: 23 before, 17 concurrently with, and 13 after the diagnosis of GCA. Thirty patients (23%) developed 1 or more peripheral musculoskeletal manifestations. These included peripheral synovitis in 23 patients (6 of whom fulfilled criteria for rheumatoid arthritis), distal extremity swelling with pitting edema in 13, distal swelling without pitting in 5, tenosynovitis in 6, and carpal tunnel syndrome in 2. Fifty-seven episodes of peripheral manifestations occurred in the 30 patients at different times during the course of GCA. In most, the onset of PMR and peripheral manifestations was within 2 years of the diagnosis of GCA. CONCLUSION: Musculoskeletal symptoms in GCA are common and varied. Most appear linked temporally to the underlying GCA, indicating that the nature of this illness and its clinical expression are broader than often considered.