Thomas R. Cupps

Glucocorticoids have profound and complex effects on the human immune response. However, the precise mechanisms of the corticosteroid-induced immunoregulation in man have not been precisely defined. Intracytoplasmic corticosteroid-specific receptors appear to be an important common pathway for steroid-induced changes, but variations of receptor parameters do not account for the multifaceted effects on the immune system. Human circulating mononuclear cells redistribute out of the intravascular compartment following treatment with corticosteroids. Although certain components at this redistribution phenomenon have been well-characterized, the importance of this compartmental cellular shift with respect to the mechanisms of corticosteroid-induced immunoregulation are less well-defined. Recent observations that activated lymphocytes may be sensitive to the lytic effects of glucocorticoids suggest that under certain situations the elimination of selected subsets of cells may be a relevant mechanism of corticosteroid-mediated immunoregulation in man. Corticosteroid-mediated effects on monocyte function may be an important mechanism of drug-induced immunoregulation in monocyte-dependent responses. In some experimental conditions, corticosteroids inhibit Interleukin 1 production by monocytes. The immunoregulatory effects of corticosteroids on lymphocyte immune responses are complex. In vitro corticosteroids appear to selectively affect early immunoregulatory events as opposed to altering an established response. Multiple sites of steroid-induced modulations of human B cell responses have been defined.

OBJECTIVE: To review the occurrence of neurologic events suggestive of demyelination during anti-tumor necrosis factor alpha (anti-TNFalpha) therapy for inflammatory arthritides. METHODS: The Adverse Events Reporting System of the Food and Drug Administration (FDA) was queried following a report of a patient with refractory rheumatoid arthritis who developed confusion and difficulty with walking after receiving etanercept for 4 months. RESULTS: Nineteen patients with similar neurologic events were identified from the FDA database, 17 following etanercept administration and 2 following infliximab administration for inflammatory arthritis. All neurologic events were temporally related to anti-TNFalpha therapy, with partial or complete resolution on discontinuation. One patient exhibited a positive rechallenge phenomenon. CONCLUSION: Further surveillance and studies are required to better define risk factors for and frequency of adverse events and their relationship to anti-TNFalpha therapies. Until more long-term safety data are available, consideration should be given to avoiding anti-TNFalpha therapy in patients with preexisting multiple sclerosis and to discontinuing anti-TNFalpha therapy immediately when new neurologic signs and symptoms occur, pending an appropriate evaluation.

OBJECTIVE: Although the American College of Rheumatology (ACR) criteria for fibromyalgia are used to identify individuals with both widespread pain and tenderness, individuals who meet these criteria are not a homogeneous group. Patients differ in their accompanying clinical symptoms, as well as in the relative contributions of biologic, psychological, and cognitive factors to their symptom expression. Therefore, it seems useful to identify subsets of fibromyalgia patients on the basis of which of these factors are present. Previous attempts at identifying subsets have been based solely on psychological and cognitive features. In this study, we attempt to identify patient subsets by incorporating these features as well as the degree of hyperalgesia/tenderness, which is a key neurobiologic feature of this illness. METHODS: Ninety-seven individuals meeting the ACR criteria for fibromyalgia finished the same battery of self-report and evoked-pain testing. Analyzed variables were obtained from several domains, consisting of 1) mood (evaluated by the Center for Epidemiologic Studies Depression Scale [for depression] and the State-Trait Personality Inventory [for symptoms of trait-related anxiety]), 2) cognition (by the catastrophizing and control of pain subscales of the Coping Strategies Questionnaire), and 3) hyperalgesia/tenderness (by dolorimetry and random pressure-pain applied at suprathreshold values). Cluster analytic procedures were used to distinguish subgroups of fibromyalgia patients based on these domains. RESULTS: Three clusters best fit the data. Multivariate analysis of variance (ANOVA) confirmed that each variable was differentiated by the cluster solution (Wilks' lambda [degrees of freedom 6,89] = 0.123, P < 0.0001), with univariate ANOVAs also indicating significant differences (all P < 0.05). One subgroup of patients (n = 50) was characterized by moderate mood ratings, moderate levels of catastrophizing and perceived control over pain, and low levels of tenderness. A second subgroup (n = 31) displayed significantly elevated values on the mood assessments, the highest values on the catastrophizing subscale, the lowest values for perceived control over pain, and high levels of tenderness. The third group (n = 16) had normal mood ratings, very low levels of catastrophizing, and the highest level of perceived control over pain, but these subjects showed extreme tenderness on evoked-pain testing. CONCLUSION: These data help support the clinical impression that there are distinct subgroups of patients with fibromyalgia. There appears to be a group of fibromyalgia patients who exhibit extreme tenderness but lack any associated psychological/cognitive factors, an intermediate group who display moderate tenderness and have normal mood, and a group in whom mood and cognitive factors may be significantly influencing the symptom report.

OBJECTIVE: F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in a prospective cohort of patients with large vessel vasculitis (LVV) and comparator subjects. METHODS: Patients with Takayasu arteritis and giant cell arteritis were studied, along with a comparator group consisting of patients with hyperlipidemia, patients with diseases that mimic LVV, and healthy controls. Participants underwent clinical evaluation and FDG-PET imaging, and patients with LVV underwent serial imaging at 6-month intervals. We calculated sensitivity and specificity of FDG-PET interpretation for distinguishing patients with clinically active LVV from comparator subjects and from patients with disease in clinical remission. A qualitative summary score based on global arterial FDG uptake, the PET Vascular Activity Score (PETVAS), was used to study associations between activity on PET scan and clinical characteristics and to predict relapse. RESULTS: A total of 170 FDG-PET scans were performed in 115 participants (56 patients with LVV and 59 comparator subjects). FDG-PET distinguished patients with clinically active LVV from comparator subjects with a sensitivity of 85% (95% confidence interval [95% CI] 69, 94) and a specificity of 83% (95% CI 71, 91). FDG-PET scans were interpreted as active vasculitis in most patients with LVV in clinical remission (41 of 71 [58%]). Clinical disease activity status, disease duration, body mass index, and glucocorticoid use were independently associated with activity on PET scan. Among patients who underwent PET during clinical remission, future clinical relapse was more common in patients with a high PETVAS than in those with a low PETVAS (55% versus 11%; P = 0.03) over a median follow-up period of 15 months. CONCLUSION: FDG-PET provides information about vascular inflammation that is complementary to, and distinct from, clinical assessment in LVV. FDG-PET scan activity during clinical remission was associated with future clinical relapse.

The vasculitides are a group of disorders that include the polyarteritis nodosa group of systemic necrotizing vasculitides, hypersensitivity vasculitis, Wegener's granulomatosis, lymphomatoid granulomatosis, giant cell arteritis, Behçet's disease, and isolated angiitis of the central nervous system. Classification is based on clinical, angiographic, and histological features. The frequency and distribution of neurological involvement vary with the underlying disorder and may provide the initial symptoms. Polyarteritis nodosa and Wegener's granulomatosis may affect both the central and peripheral nervous systems, whereas isolated angiitis of the central nervous system and Behçet's disease affect the central nervous system alone. Neurological dysfunction occurs in 80% of patients with polyarteritis nodosa and fewer than 10% of patients with hypersensitivity vasculitis. The mechanism of neurological dysfunction in the vasculitides is tissue ischemia. The clinical effects of ischemia vary, and symptoms may be transient or prolonged. Mononeuritis multiplex, polyneuropathy, and stroke are frequent complications, but encephalopathies, cranial neuropathies, and brachial plexopathies are seen as well. The occurrence of symptoms late in the course of a disease suggests ischemia resulting from healed, scarred vessels as well as from those that are acutely inflamed; this is the case in Takayasu's arteritis and possibly also in polyarteritis nodosa. Treatment is based on identifying and removing the sensitizing agent when possible. Wegener's granulomatosis requires therapy with cyclophosphamide; temporal arteritis, with corticosteroids. In other vasculitides a balance must be reached between the progression of the disease and the side effects of immunosuppression.