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.

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.

The HLA-DRB1 locus as a genetic component in giant cell arteritis. Mapping of a disease-linked sequence motif to the antigen binding site of the HLA-DR molecule.

Giant cell arteritis (GCA) is a granulomatous vasculitis affecting persons over 50 years of age. The inflammatory infiltrate, which is targeted at the aorta and its proximal branches, includes activated CD4+ helper T cells, histiocytes, and giant cells. To investigate whether the genetic polymorphism of the HLA-DRB1 genes contributes to the local accumulation of activated T cells, we have analyzed both HLA-DRB1 alleles in a cohort of 42 patients with biopsy-proven GCA. The majority of patients (60%) expressed the B1*0401 or B1*0404/8 variant of the HLA-DR4 haplotype, both of which also represent the major genetic factors underlying the disease association in RA. GCA patients negative for the disease-linked HLA-DR4 alleles were characterized by a nonrandom distribution of HLA-DRB1 alleles. Sequence comparison among the allelic products identified in the GCA cohort demonstrated heterogeneity for the sequence polymorphism of the third hypervariable region (HVR), but homology for the polymorphic residues within the HVR2 of the HLA-DRB1 gene. The GCA patients shared a sequence motif spanning amino acid positions 28-31 of the HLA-DR beta 1 chain. In the structural model for HLA-DR molecules, this sequence motif can be mapped to the antigen-binding site of the HLA complex, suggesting a crucial role of antigen selection and presentation in GCA. In contrast, the sequence polymorphism linked to RA has been mapped to the HVR3 of the HLA-DRB1 gene and translates into a distinct domain of the HLA-DR molecule, the alpha-helical loop surrounding the antigen-binding groove. A consecutive case series study demonstrated that GCA and RA rarely co-occurred, supporting the interpretation that distinct functional domains of the HLA-DR molecule are implicated in the pathomechanisms of these two autoimmune diseases.

Immune complexes in sera and synovial fluids of patients with rheumatoid arthritis. Radioimmunoassay with monocylonal rheumatoid factor.

Evidence for the presence of immune complexes in blood, synovial fluid, and tisues of patients with rheumatoid arthritis (RA) includes low complement levels in blood and effusions, deposition of immunoreactants in tissues and vessel walls, precipitate formation after addition of monoclonal rheumatoid factor (mRF) to serum or synovial fluid. To quantitate immune complex-like material in RA patients, we developed a radioimmunoassay based on inhibition by test samples of the interaction of (125I)aggregated IgG (agg IgG) and mRF coupled to cellulose. This method could measure immune complexes of human antibody with hemocyanine prepared in vitro. The assay was not influenced by presence of polyclonal RF in test samples, nor by freezing and thawing. Normal levels of immune complex-like material in serum were less than 25 mug agg IgG EQ/ML. 12 of 51 RA sera examined (26%) contained more than 25 mug/ml. The presence of this material in RA sera was found to correlate with severity of disease, as measured by anatomical stage and functional class. There was an inverse correlation of the material with serum C4 level. Rheumatoid synovial fluids generally contained higher levels than serum, and five of 23 contained very much higher levels. The frequency of elevated levels of immune complex-like material in sera of patients with systemic lupus erythematosus (2 of 29) and with miscellaneous vasculitides (2 of 21 was much lower than in RA, suggesting that mRF exhibits a specificity for only certain kinds of immune complexes. The reason for this apparent specificity may explain such distinctive features of RA as the high frequency of polyclonal RF, the lack of immune complex nephritis, and the generally normal levels of serum complement.

Production, degradation, and circulating levels of 1,25-dihydroxyvitamin D in health and in chronic glucocorticoid excess.

The decreased intestinal absorption of calcium and accelerated bone loss associated with chronic glucocorticoid excess may be mediated by changes in vitamin D metabolism, leading to decreased availability of circulating 1,25-dihydroxyvitamin D. This hypothesis was examined in 14 patients with either endogenous or exogenous glucocorticoid excess. Analysis of paired serum samples (mean +/- SE) in 13 patients during euglucocorticoidism and during hyperglucocorticoidism showed that glucocorticoid excess resulted in small decreases of plasma 25-hydroxy-vitamin D concentrations (22 +/- 2- 18 +/- 2 ng/ml; P < 0.05) but no significant changes in plasma 1,25-dihydroxyvitamin D (32 +/- 8- 23 +/- 6 pg/ml) or serum immunoreactive parathyroid hormone (21 +/- 2- 18 +/- 2 muleq/ml). Additionally, we studied plasma kinetics of [3H]1,25-dihydroxyvitamin D3 after intravenous bolus administration in 10 hyperglucocorticoid patients and in 14 normal controls. Assessment with a three-compartment model showed no significant abnormalities in production rates (hyperglucocorticoid patients 1.2 +/- 0.3 micrograms/d, controls 1.5 +/- 0.2 micrograms/d) or metabolic clearance rates (hyperglucocorticoid patients, 18 +/- 2%; controls, 14 +/- 2%) or feces (hyperglucocorticoid patients, 60 +/- 9%, controls, 54 +/- 6%). We conclude that glucocorticoid excess does not effect plasma levels, production, or degradation of 1,25(OH)2D in humans. Thus, other mechanisms must be postulated to explain satisfactorily the abnormalities of bone structure and intestinal calcium absorption that may occur after chronic glucocorticoid therapy.

Recognition of tissue residing antigen by T cells in vasculitic lesions of giant cell arteritis.

The objective of this study was to explore the nature of the antigen-specific T cell response in giant cell arteritis by analyzing clonally expanded T cells in temporal artery specimens. In temporal artery tissue from eight patients, 10% of the T cell receptor beta chain repertoire was systematically screened for clonal T cells by reverse-transcriptase polymerase chain reaction with selected BV, BJ, and BC specific primers and by direct sequencing of the amplified product. In five additional patients tissue-derived T cell clones were characterized. All expanded clonotypes were analyzed for their presence at different sites of the inflamed artery. T cell lines were tested for their proliferation to autologous monocytes pulsed with temporal artery extracts from patients with giant cell arteritis, polymyalgia rheumatica, and unrelated diseases. Clonally expanded T cells were identified in 30% of the BV-J combinations of the sampled repertoire. A subset of these clones were encountered at different sites of the inflammation, but not in the peripheral blood. The T cell receptor beta chain sequences were diverse. The patients had between none and five such clonotypes in the sampled repertoire, suggesting that only few T cell specificities in each patient are involved in antigen recognition. One of these T cell clonotypes was shown to proliferate in response to an antigen selectively expressed in temporal artery specimens from giant cell arteritis and from polymyalgia rheumatica patients. Clonotypes with identical T cell receptor beta chain sequences can be found at distinct sites of the inflammation in giant cell arteritis, suggesting recognition of the same antigen at different locations. At least for some of these T cell clones the antigen is shared between different giant cell arteritis and polymyalgia rheumatica patients but not expressed in temporal arteries of patients with unrelated diseases. While different HLA-DR4+ patients utilize distinct T cell specificities, the actual number of responding T cells in individual patients is small and may be disease limiting.

Corticosteroid requirements in polymyalgia rheumatica.

BACKGROUND: Polymyalgia rheumatica (PMR) is a systemic inflammatory disease of unknown cause that affects older individuals. Clinical symptoms respond promptly to corticosteroids, but treatment is often required for several years, frequently resulting in adverse drug effects. Guidelines for the optimal use of corticosteroids that maximize relief of symptoms but minimize adverse effects of the therapy are needed. OBJECTIVE: To determine whether clinical or laboratory parameters in PMR could be identified that allow for stratifying patients into subsets with differences in corticosteroid requirements. PATIENTS AND METHODS: We studied 27 patients with PMR treated with a standardized schedule of prednisone. Patients were reevaluated at monthly intervals for pain scores and physician and patient assessments. Plasma interleukin 6 level and the erythrocyte sedimentation rate were measured at each visit. The duration of steroid therapy and the cumulative steroid dose were calculated. RESULTS: Based on the initial response to therapy and the duration of disease, the 27 patients could be subdivided into 3 distinct groups. Eight with low erythrocyte sedimentation rates responded rapidly and required corticosteroids for less than 1 year with rare disease flares on tapering of prednisone. Twelve others responded well initially but did not tolerate reduction to lower doses and had remitting disease of more than 1 year. Seven patients had only a partial response to the initial steroid regimen. After 4 weeks of therapy, the erythrocyte sedimentation rates improved, but levels of interleukin 6 remained elevated. Pretreatment pain scores were also higher in these partial responder patients (P = .05). CONCLUSIONS: Polymyalgia rheumatica is a heterogeneous disease with variations in the treatment duration and dose of corticosteroids required for suppression of symptoms. Pretreatment erythrocyte sedimentation rate and nonresponsiveness of interleukin 6 to steroid therapy are helpful in dividing patients into subsets with different treatment requirements.

Jaw claudication in primary systemic amyloidosis.

Amyloid deposits in the temporal artery were observed 40 years ago, but the presence of vascular ischemic symptoms in patients with amyloidosis has been infrequently recognized. We examined 22 patients who had typical jaw claudication with biopsy-proven primary amyloidosis. In none was vasculitis a contributing cause of the claudication. However, two patients were misdiagnosed initially as having temporal arteritis and polymyalgia rheumatica and were treated with corticosteroids, which resulted in significant toxicity. Subsequent temporal artery biopsy revealed extensive amyloid deposits in both patients. Jaw claudication was associated with other ischemic vascular symptoms, such as arm or calf claudication. The median survival for the subset of patients with amyloidosis and jaw claudication was 42 months, and that for the entire group of patients with amyloidosis was 12 months. Appropriate staining of temporal artery biopsy specimens is necessary for the correct diagnosis in such cases.

Takayasu arteritis. A study of 32 North American patients.

Thirty-two patients (26 female, 6 male) with angiographically diagnosed Takayasu arteritis were seen at the Mayo Clinic between 1971 and 1982. Racial composition of this group was 23 North American Caucasians, 4 Mexicans, 3 Orientals, 1 Native American, and 1 patient of Middle Eastern origin. Incidence of the disease in Olmsted County, Minnesota, was 2.6/million/year. Diagnosis was often delayed for long periods of time, with a median delay of 18 months. Patients had both non-vascular symptoms (arthralgias in 56%, fever in 44%, weight loss in 38%) and symptoms of vascular stenosis such as arm claudication (47%) and hypertension due to renal artery stenosis (41%). All patients had either multiple vascular bruits (94%) or absent pulses (50%). Laboratory findings included anemia (44%) and elevations of erythrocyte sedimentation rate (78%). Almost all patients had multiple sites of arterial involvement documented by angiogram with various combinations of stenosis, luminal irregularity and aneurysm formation. Response to corticosteroid treatment was usually very good, with dramatic improvement in non-vascular symptoms and return of pulses in 8 of the 16 patients with absent pulses prior to treatment. Five-year survival rate from time of diagnosis was 94%. Twelve patients underwent surgical procedures involving the carotid arteries (5 cases), subclavian artery (4 cases) and renal arteries (3 cases). Three aneurysms were resected, one had aortic valve replacement for severe aortic regurgitation, and two patients underwent transluminal angioplasty. Pathologic changes were restricted to the media and adventitial layers of the vessel wall and were indistinguishable from those of giant-cell or temporal arteritis. Takayasu arteritis is more common than previously suspected in North America, is not restricted to any one racial group, and is readily treatable with corticosteroids and surgical vascular reconstruction.

A case-control and nerve biopsy study of CREST multiple mononeuropathy.

From 536 patients with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasis), seven were identified as having peripheral neuropathy not attributable to another cause. Peripheral neuropathy developed 0 to 25 years after their first symptoms of scleroderma. Unexplained neuropathy in CREST patients (seven patients) was more frequent than in control subjects (two patients) matched for age, sex, time of evaluation, and geographic referral region. Multiple mononeuropathy occurred significantly more frequently in the CREST group (six patients) than in the control group (0 patients). Four sural nerve biopsy specimens from the CREST patients demonstrated multifocal fiber loss and perivascular inflammation; one was diagnostic for necrotizing vasculitis and two others were highly suggestive for necrotizing vasculitis. The density of myelinated fibers in three nerves from CREST patients was significantly decreased, whereas the index of dispersion (a measure of multifocal fiber loss) was increased, and the frequency of axonal degeneration was significantly increased. Based on these clinical and pathologic findings, we conclude that in the CREST syndrome multiple mononeuropathy, although occurring infrequently, occurs more frequently than by chance and necrotizing vasculitis is the cause of this multiple mononeuropathy.

Neurologic disease in biopsy-proven giant cell (temporal) arteritis.

Neurologic findings were studied in 166 consecutive patients with biopsy-proven giant cell (temporal) arteritis. Neurologic problems occurred in 51 patients (31%): neuropathies (23), TIA/strokes (12), neuro-otologic syndromes (11), tremor (6), neuropsychiatric syndromes (5), tongue numbness (3), and myelopathy (1). Neuro-ophthalmologic problems occurred in 35 patients (21%): amaurosis fugax (AF) (17), permanent vision loss (PVL) (14), scintillating scotoma (8), and diplopia (3). Abnormalities in large arteries in 52 patients (31%) included bruits and diminished pulses. The carotid artery was involved in 31 patients (bilateral in 58%). Overall, 35% of patients with carotid disease had TIA/stroke, AF, or PVL.

Peripheral neuropathy associated with sicca complex.

Peripheral neuropathy occurs in Sjögren's syndrome, a disorder in which systemic immunologic phenomena, including vasculitis, are common. Neuropathy also occurs with isolated sicca complex (keratoconjunctivits sicca and xerostomia); whether this represents a distinct syndrome is unclear. We retrospectively studied 54 patients with sicca complex and peripheral neuropathy to determine mode of presentation, neuropathic patterns, frequency and pattern of serologic abnormalities, and frequency of systemic disease, including necrotizing vasculitis. Peripheral neuropathy was the presenting problem in 87%. Although sicca symptoms occurred in 93%, they were a presenting complaint in only 11% and were usually mild, reported only after specific inquiry. Minor salivary gland biopsy was positive in 73%. Sensory neuropathies strongly predominated; 61% of patients manifested either sensory polyneuropathy or polyganglionopathy. Less common patterns included sensorimotor polyneuropathy (17%) and polyradiculoneuropathy (11%). Vasculitic neuropathy was demonstrated in only two patients, but nonspecific epineurial inflammation was present in 70% of nerve biopsies. Clinical evidence of systemic disease was uncommon, particularly in the sensory polyganglionopathy group, in whom extraglandular features other than weight loss occurred in only 1 of 12 patients. Antibodies to extractable nuclear antigens, the most specific serologic marker of Sjögren's syndrome, were present in 10.4%. We conclude that peripheral neuropathy and isolated sicca complex form a distinctive syndrome in which neuropathy is the presenting feature and sicca is easily overlooked; sensory polyneuropathy and polyganglionopathy predominate; serology is confirmatory but very insensitive; and extraglandular disease, including vasculitis, is uncommon compared with typical Sjögren's syndrome. Tests of ocular or salivary involvement are needed for diagnosis, and demonstration of inflammation in biopsied nerve is supportive. Improved definition of this disorder should permit further studies of natural history and efficacy of immunotherapy.

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.

Peripheral neuropathic syndromes in giant cell (temporal) arteritis.

Of 166 consecutive patients with histologically confirmed giant cell (temporal) arteritis (GCA) seen during a 3-year period, 23 (14%) had clinically diagnosed peripheral neuropathic syndromes temporally coincident with clinically active GCA. Electromyography and nerve conduction studies were performed in 16, confirming abnormalities in all. Of the 23 patients, 11 had a generalized peripheral neuropathy, nine had multiple mononeuropathies, and three had a mononeuropathy. The nerves affected as mononeuropathies were the median, ulnar, peroneal, tibial, and sural nerves, and the C-5 and L-5 nerve roots. Angiography, performed in two patients, demonstrated widespread arteritis involving the lower limbs and, after 3 months of oral corticosteroid treatment in one of these patients, an amputation specimen showed chronic arteritis.

Long-term survival of patients with Wegener's granulomatosis from the American College of Rheumatology Wegener's Granulomatosis Classification Criteria Cohort.

OBJECTIVE: To determine survivorship in Wegener's granulomatosis (WG) in a well-defined multicenter cohort. METHODS: Follow-up was obtained for 77 of the 85 patients enrolled in the 1990 American College of Rheumatology vasculitis classification study. RESULTS: There were 28 deaths (10 females and 18 males) among the 77 patients available for follow-up. Standardized mortality ratios (SMR) were calculated with mortality data from the general population and from this group of patients with WG (an SMR of 1 indicates that expected and observed survival are identical). Overall survivorship among patients with WG was substantially reduced in this cohort (SMR = 4.685 +/- 0.65; for females SMR = 6.814 +/- 1.571; for males SMR = 3.998 +/- 0.69). CONCLUSION: The life expectancy of patients with WG is reduced compared with the general population.

Long-term survival of patients with giant cell arteritis in the American College of Rheumatology giant cell arteritis classification criteria cohort.

OBJECTIVE: To characterize survivorship among patients with giant cell arteritis in a well-defined, multicenter cohort. PATIENTS AND METHODS: Follow-up was obtained for 205 (95.8%) of the 214 patients enrolled in the 1990 American College of Rheumatology vasculitis classification study. Standardized mortality ratios (SMR) were calculated comparing mortality data from this group of patients with giant cell arteritis versus the general population. RESULTS: There were 49 deaths (33 women and 16 men among the 205 patients available for follow-up. Survivorship was virtually identical to that of the general population (SMR = 1.034 +/- 0.121), and was similar for women (SMR = 1.022 +/- 0.149) and men (SMR = 1.078 +/- 0.206) (SMR = 1 indicates that expected and observed survival are identical). CONCLUSION: The life expectancy of patients with giant cell arteritis is the same as that of the general population.

Synovial effusions containing cholesterol crystals report of 12 patients and review.

Cholesterol crystals were identified in 16 synovial fluids from 12 patients who were seen over the 14-year period 1964 through 1977. Ten of the 12 patients had rheumatoid arthritis of a median duration of 12 years. One patient had ankylosing spondylitis and another had iliopectineal bursitis without other joint disease. The fluids were usually turbid, white, or yellow in color and of thick consistency. When the synovial fluid concentration of cholesterol was determined, it was higher than the serum level. The swollen joints and bursae did not respond favorably to simple aspiration or corticosteroid injections but did to surgical synovectomy. No relationship was found between synovial fluid accumulation of cholesterol crystal and previous intra-articular corticosteroid therapy, serum lipoprotein abnormalities, intra-articular hemorrhage, or generalized arteriosclerosis. The results suggest that local factors are most important in the development of synovial fluid cholesterol crystals, but the exact mechanisms are unknown. The presence of cholesterol crystals in synovial fluid should suggest a severe persistent synovitis, knowledge of which may be helpful in diagnosis and planning therapy.

Decreasing prevalence of tophaceous gout.

Retrospective analysis of newly diagnosed gout cases seen at the Mayo Clinic from 1949 through 1972 shows a progressive decline in tophaceous gout, from 14% to 3%. Gout diagnoses remained stable in a range of 1.5 to 2.2/1,000 patients seen.

Joint imaging in polymyalgia rheumatica.

Technetium pertechnetate joint scintigrams were abnormal in 24 of 25 patients with polymyalgia rheumatica, in all 16 with rheumatoid arthritis, in 4 of 13 with nonarticular rheumatism, but in none of 26 control patients. Abnormal uptake in polymyalgia patients was commonest in shoulders and was less likely to be symmetric than in patients with rheumatoid arthritis, in whom distal joint abnormalities predominated. The pattern of abnormal uptake in polymyalgia rheumatica was not different in those with biopsy-proved giant cell arteritis. Correlation between symptoms and abnormal scintigrams was 72%, and abnormal uptake was present in 81% of joints of patients having physical abnormalities. Biopsy showed lymphocytic synovitis in the knee of one patient. After treatment the number of abnormal joints declined. These findings suggest that synovitis is common in polymyalgia rheumatica, and that it may account for some or most of the symptoms in this condition.

Ultrasound evaluation of the popliteal space. Comparison with arthrography and physical examination.

Ultrasound scanning techniques were used to examine the popliteal space in 102 knees. In 30 of 34 knees in which arthrograms were also obtained, the information obtained from both tests was the same. In two instances in which there were different results, the presence of palpable popliteal cysts was confirmed by ultrasound scans but not by arthrography, and in two other cases, small asymptomatic cysts were seen on arthrograms but not on ultrasound scans. In the 68 other knees, ultrasound scans were helpful in the differential diagnosis of popliteal cysts, popliteal artery aneurysms, thrombophlebitis, and a solid poplitieal mass. The results indicate that ultrasound scanning is a valuable, rapid, safe, accurate technique in evaluating patients with symptoms or findings related to the popliteal space.