Bridget Zimmerman

Low dose long-term corticosteroid therapy in rheumatoid arthritis: An analysis of serious adverse events

PURPOSE The purpose of this study was to better define the toxicity of low dose (less than or equal to 15 mg/d prednisone or equivalent) long-term (greater than 1 year) corticosteroids in the treatment of rheumatoid arthritis (RA). PATIENTS AND METHODS We examined an historical cohort of 112 RA patients on low dose (6.1 +/- 3.1 mg/d, mean +/- SD) long-term (6.2 +/- 4.6 years) prednisone (CS) and compared them to 112 matched RA patients not using prednisone (CO). CS were matched one-to-one with CO for sex (75% women), age (+/- 5 yrs), race (98% white), and duration of disease (+/- 5 yrs). Subjects were determined by review of unselected medical records from three distinct rheumatology practice settings. For CS, charts were abstracted from the date of prednisone start for predefined adverse events (AEs). RESULTS Ninety-two (92) AEs were noted in CS versus 31 in CO and included: fracture (CS:21 versus CO:8), serious infections (CS:14 versus CO:4), gastrointestinal (GI) bleed or ulcer (CS:11 versus CO:4), and cataracts (CS:17 versus CO:5). At time of first AE, CS prednisone average dose was 7.0 +/- 2.6 mg with a duration of 4.9 +/- 3.9 years. Stepwise multiple logistic regression analysis was used to create a model which included all clinically relevant variables and all parameters significantly different at the cohort inception. Prednisone average dose of greater than 10 to less than or equal to 15 mg/d correlated most strongly with the development of an AE (Odds Ratio (OR) = 32.3, 95% Confidence Interval (CI) 4.6, 220). Average prednisone 5 to 10 mg (OR = 4.5, 95% CI 2.1, 9.6), RA nodules (OR = 3.9, 95% CI 1.9, 8.0), and bony erosions (OR = 2.4, 95% CI 1.2, 4.7) also entered the final model. Kaplan Meier survival curves for the development of the first AE showed a dose-response relationship between prednisone and AE occurrence, independent of rheumatoid nodules. Subset analyses utilized a nested case control design for the development of three serious AEs: fractures, serious infections, and GI events. These analyses revealed possible relationships between prednisone use and the development of each specific AE (prednisone use OR: fracture 3.9, 95% CI 0.8, 18.1; infection 8.0, 95% CI 1.0, 64.0; and GI event 3.3, 95% CI 0.9, 12.1). CONCLUSIONS Although disease severity is an important confounding factor, low dose long-term prednisone use equal to or greater than 5 mg/d is correlated with the development of specific adverse events in a dose-dependent fashion.

Giant Cell Arteritis: Validity and Reliability of Various Diagnostic Criteria

PURPOSE To ascertain the validity, reliability, sensitivity, and specificity of various signs and symptoms of and diagnostic tests for early diagnosis of giant cell arteritis. METHODS From 1973 to 1994, we studied 363 patients who had temporal artery biopsy for suspected giant cell arteritis. All patients underwent detailed clinical evaluation and had erythrocyte sedimentation rates determined; since 1985, 223 patients had their C-reactive protein values estimated. Erythrocyte sedimentation rate and C-reactive protein levels were also estimated in 749 and 138 control subjects, respectively. Signs and symptoms of giant cell arteritis, erythrocyte sedimentation rate, and C-reactive protein levels among patients with positive and negative biopsies were compared. RESULTS Of the 363 patients, temporal artery biopsy was positive in 106 and negative in 257. The odds of a positive biopsy were 9.0 times greater with jaw claudication (P < .0001), 3.4 times greater with neck pain (P = .0085), 2.0 times greater with an erythrocyte sedimentation rate of 47 to 107 mm/hour (P = .0454), 3.2 times greater with C-reactive protein above 2.45 mg/dl (P = .0208), and 2.0 times greater for age 75 years or more (P = .0105). CONCLUSIONS Clinical criteria most strongly suggestive of giant cell arteritis include jaw claudication, C-reactive protein above 2.45 mg/dl, neck pain, and an erythrocyte sedimentation rate of 47 mm/hour or more, in that order. C-reactive protein was more sensitive (100%) than erythrocyte sedimentation rate (92%) for detection of giant cell arteritis; erythrocyte sedimentation rate combined with C-reactive protein gave the best specificity (97%).

Systemic diseases associated with various types of retinal vein occlusion.

PURPOSE To investigate systemic diseases associated with various types of retinal vein occlusion. METHODS We investigated prospectively in 1090 consecutive patients with retinal vein occlusion, almost all Caucasian (consistent with the racial pattern here), the prevalence of associated systemic disorders before or at the onset of various types of retinal vein occlusion. The patients were categorized into six types of retinal vein occlusion based on defined criteria: nonischemic and ischemic central retinal vein occlusion, nonischemic and ischemic hemi-central retinal vein occlusion, and major and macular branch retinal vein occlusion. The patients had a detailed ophthalmic and systemic evaluation according to our protocol. For data analysis, patients were divided into three age groups: young (younger than 45 years), middle-aged (45 to 64 years), and elderly (65 years or older). The observed prevalence rates of major systemic diseases were compared among central retinal vein occlusion, hemi-central retinal vein occlusion, and branch retinal vein occlusion using a polytomous logistic regression analysis adjusting for gender and age. Logistic regression adjusting for age and gender was also used to compare the observed prevalence of systemic disease between nonischemic and ischemic in central retinal vein occlusion and hemi-central retinal vein occlusion and between major and macular branch retinal vein occlusion. These observed prevalence rates were also compared with those expected in a gender-matched and age-matched control population from estimates from the US National Center for Health Statistics. RESULTS There was a significantly higher prevalence of arterial hypertension in branch retinal vein occlusion compared with central retinal vein occlusion (P < .0001) and hemi-central retinal vein occlusion (P = .028). Branch retinal vein occlusion also had a significantly higher prevalence of peripheral vascular disease (P = .0002), venous disease (P = .011), peptic ulcer (P = .031), and other gastrointestinal disease (P < .0001) compared with central retinal vein occlusion. The proportion of patients with branch retinal vein occlusion with cerebrovascular disease was also significantly (P = .049) greater than that of the combined group of patients with central retinal vein occlusion and patients with hemi-central retinal vein occlusion. There was no significant difference in prevalence of any systemic disease between central retinal vein occlusion and hemi-central retinal vein occlusion. A significantly greater prevalence of arterial hypertension (P = .025) and diabetes mellitus (P = .011) was present in the ischemic central retinal vein occlusion compared with the nonischemic central retinal vein occlusion. Similarly, arterial hypertension (P = .0002) and ischemic heart disease (P = .048) were more prevalent in major branch retinal vein occlusion than in macular branch retinal vein occlusion. Relative to the US white control population, the combined group of patients with central retinal vein occlusion and patients with hemi-central retinal vein occlusion had a higher prevalence of arterial hypertension (P < .0001), peptic ulcer (P < .0001), diabetes mellitus (in ischemic type only, P < .0001), and thyroid disorder (P < .0001). The patients with branch retinal vein occlusion showed a greater prevalence of arterial hypertension (P < or = .005), cerebrovascular disease (P = .007), chronic obstructive pulmonary disease (P = .012), peptic ulcer (P < .0001), diabetes (in young only, P = .0005), and thyroid disorder (P = .003) compared with the US white control population. CONCLUSIONS The findings of our study revealed that a variety of systemic disorders may be present in association with different types of retinal vein occlusion and in different age groups, and that their relative prevalence differs significantly, so that the common practice of generalizing about these disorders for the entire group of patients with retinal vein occlusion can be misleading. The presence of a particular associated systemic disease does not necessarily imply a cause-and-effect relationship with that type of retinal vein occlusion; the particular disease may or may not be one of the risk factors in a multifactorial scenario predisposing an eye to develop a particular type of retinal vein occlusion. Based on our study, we think that apart from a routine medical evaluation, an extensive and expensive workup for systemic diseases is unwarranted in the vast majority of patients with retinal vein occlusion.

Occult giant cell arteritis: ocular manifestations.

PURPOSE To report the incidence, visual symptoms, and ocular signs of occult giant cell arteritis in patients who initially presented with visual symptoms and ocular signs of giant cell arteritis. Occult giant cell arteritis was defined as ocular involvement by giant cell arteritis without any systemic symptoms and signs of giant cell arteritis. METHODS In a prospective study from 1973 to 1995, we investigated 85 patients who had ocular involvement caused by giant cell arteritis and whose diagnosis of giant cell arteritis was confirmed on temporal artery biopsy. At the initial visit, patients were questioned specifically on systemic and ocular symptoms and signs of giant cell arteritis at or before the onset of visual disturbance. Erythrocyte sedimentation rate (Westergren) and C-reactive protein level were evaluated before the start of systemic corticosteroid therapy. RESULTS Eighteen (21.2%) of 85 patients had occult giant cell arteritis. There was no significant difference in age and sex distribution between patients with and without systemic symptoms of giant cell arteritis. Although both groups of patients had abnormal erythrocyte sedimentation rate and C-reactive protein level, there was a significant difference in erythrocyte sedimentation rate (P < .0001) and C-reactive protein level (P=.0133), these being relatively lower in patients with occult giant cell arteritis. The ocular symptoms in the 18 patients with occult giant cell arteritis were visual loss of varying severity in 18 (100%), amaurosis fugax in six (33.3%), diplopia in two (11.1%), and eye pain in one (5.6%). Ocular ischemic lesions consisted of anterior ischemic optic neuropathy in 17 (94.4%), central retinal artery occlusion in two (11.1%), and cilioretinal artery occlusion in two (of 11 patients with satisfactory fluorescein angiography [18.2%]). The ocular symptoms and ischemic lesions were seen in a variety of combinations. CONCLUSIONS Because occult giant cell arteritis is a potential cause of blindness, its early diagnosis is the key to preventing blindness; it is important to recognize that 21.2% of patients with giant cell arteritis and visual loss do not have any systemic symptoms of giant cell arteritis. Thus, in persons older than 55 years, amaurosis fugax or visual loss, development of an acute ocular ischemic lesion (particularly arteritic anterior ischemic optic neuropathy), and abnormal C-reactive protein level, with or without elevated erythrocyte sedimentation rate and systemic symptoms, should raise a high index of suspicion for giant cell arteritis.

Management of Giant Cell Arteritis

Giant cell arteritis (GCA) is the prime medical emergency in ophthalmology because of its dreaded complication of visual loss in one or both eyes, which is preventable if these patients are diagnosed early and treated immediately and aggressively with systemic corticosteroids. However, there is much controversy on diagnostic criteria and various aspects of steroid therapy to prevent visual loss. We discuss in detail the reasons for the controversy, clinical criteria to establish a definite early diagnosis of GCA, and its management. To provide new information on corticosteroid therapy in GCA, we also present our 27-year planned study on steroid therapy in GCA in 145 temporal artery biopsy-confirmed GCA patients (96 with and 49 without visual loss) seen and followed for 6 weeks or more in our clinic. The median follow-up time was 2.43 years, with interquartile range of 1–6 years (range 6 weeks to 20.2 years). Intravenous megadose steroid therapy was initially given to 33% followed by oral steroids, while the rest had only the oral therapy. The median starting oral prednisone dose was 80 mg/day, with 40% on ≧100 mg/day. We found that the most reliable and sensitive parameters to regulate and taper down steroid therapy were the levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and not systemic symptoms. All patients were maintained at the high-dose prednisone till both the ESR and CRP had stabilized at low levels (that usually took 2–3 weeks), after which very gradual tapering of prednisone was started, guided by the ESR and CRP levels only. The median time to reach the lowest maintenance dose of prednisone at which the ESR and CRP stayed low and stable was 48.7 months (95% CI: 34.6, 71.4 months), and the median lowest prednisone dose achieved was 7 mg/day (interquartile range of 1–16 mg/day). A comparison of patients with and without visual loss showed no significant difference in the time to attain the lowest dose (p = 0.359). Our study showed that no generalization is possible for tapering down of prednisone and there is no set formula because of the infinite variation between individuals. Only 10 (7 without visual loss, 3 with visual loss) of 145 patients were able to stop the therapy and maintain stable ESR and CRP levels. We found that only 4% of GCA patients with visual loss showed any visual improvement with high-dose steroid therapy, and 4% developed further visual loss during the first 5 days of high-dose steroid therapy but none after that. Our studies found no evidence that intravenous megadose steroid therapy was more effective than oral therapy in improving vision or preventing visual deterioration due to GCA.

Nonarteritic Anterior Ischemic Optic Neuropathy: Time of Onset of Visual Loss

PURPOSE To study time of day and seasonal variation of onset of visual loss in nonarteritic anterior ischemic optic neuropathy (AION). METHODS From 1975 to 1995, we prospectively investigated the time of discovery of visual loss in 635 patients (871 eyes) with AION--a total of 925 episodes. Data were analyzed for two variables: time of day of discovery of visual loss for 544 episodes and seasonal variation of the onset of AION for 839 episodes. RESULTS Of 544 episodes, time of day for discovery of visual loss was upon awakening from sleep in the morning or a nap in 282 (51.8%), during the first opportunity to use vision critically early in the morning in 117 (21.5%), and later in the day in 145 (26.7%). AION was significantly (P = .0030) more frequent in summer than winter. Estimated monthly onset rates were 82.7 episodes (95% confidence interval [CI], 71.3 to 95.8) in summer, 58.3 (95% CI, 48.9 to 69.6) in winter, 66.0 (95% CI, 55.9 to 77.9) in spring, and 72.7 (95% CI, 62.1 to 85.1) in fall. Onset significantly (P < .0001) occurred more during hot than cold months, with the estimated monthly rate of onset in hot months of 82.2 episodes (95% CI, 73.7 to 91.8) compared with 59.8 (95% CI, 53.3 to 67.1) in cold months. CONCLUSIONS In at least 399 (73.3%) of 544 episodes of AION, patients discovered visual loss upon first awakening or at first opportunity to use vision critically after sleeping, suggesting that nocturnal arterial hypotension may play an important role. Also, AION developed more often in summer than in winter.

Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy

PURPOSE To report the incidence and extent of visual deterioration in patients with giant cell arteritis (GCA) on high doses of systemic corticosteroids during the early stages of treatment; the various factors that may influence the outcome; and whether intravenous megadose corticosteroid therapy is more effective than oral therapy. DESIGN Noncomparative interventional case series. PARTICIPANTS One hundred forty-four patients with GCA (271 eyes) seen initially with visual loss (91 patients) and without visual loss (53 patients). All patients had biopsy-confirmed GCA and were followed while on high doses of systemic corticosteroid therapy for at least 2 weeks. METHODS Every patient at the initial visit had an ophthalmic evaluation, including visual acuity, visual fields, intraocular pressure, slit-lamp and ophthalmoscopic evaluation, erythrocyte sedimentation rate (ESR; Westergren) and C-reactive protein (CRP) estimation, and temporal artery biopsy as soon as possible. If GCA was either strongly suspected or confirmed by biopsy, they were immediately started in our clinic on high doses of oral (80-120 mg) prednisone daily or intravenous megadose systemic corticosteroids (usually 150 mg dexamethasone sodium phosphate every 8 hours for 1-3 days) followed by oral prednisone. At each visit they underwent all the initial ophthalmic evaluations and had an ESR and CRP evaluation done. Tapering of steroid therapy was not started until both ESR and CRP had reached their lowest stable levels. These showed marked interindividual variation and usually took approximately 2 weeks to stabilize. Then the steroid therapy was gradually tapered, guided primarily by the levels of ESR and CRP. No generalization is possible regarding the period required to achieve the maintenance dosage, because this also varied markedly from patient to patient. MAIN OUTCOME MEASURES Visual acuity deterioration. RESULTS While on high doses of steroid therapy during the initial stages of the treatment, only 9 (11 eyes) of the 91 patients seen initially with visual loss developed further visual acuity deterioration in one or both eyes within 5 days after the start of therapy (one of the eyes had normal vision initially), but none of the 53 patients initially seen without visual loss developed any visual deterioration. Six of the 48 patients (13%) who were on intravenous steroid therapy had visual deterioration compared with 3 of 97 patients (3%) who were only on oral steroid therapy (P = 0.060). CONCLUSIONS Our study shows that although a few eyes can develop visual deterioration while on high doses of steroid therapy, early, adequate steroid therapy is effective in preventing further visual loss in most. When further visual deterioration occurred despite high doses of systemic corticosteroids, it almost invariably started within 5 days after the start of the high-dose steroid therapy. There was no evidence that intravenous megadose steroid therapy was more effective than oral therapy in preventing visual deterioration.

Stress and symptoms in patients with interstitial cystitis: a life stress model.

Objectives. Stress-related exacerbation of interstitial cystitis (IC) symptoms has frequently been reported. Previous research has found stress-related IC symptom exacerbation in an experimental model. However, this relationship has not been objectively examined with daily life stressors. We used a prospective daily symptom diary method to investigate the relationships among stress and bladder symptoms in patients with IC and age-matched healthy controls.Methods. Forty-five previously diagnosed female patients with IC completed a bladder symptom and stress diary nightly for 1 month; 31 female age-matched healthy controls completed a similar diary for 7 days. The symptom questions were modified from the Interstitial Cystitis Data Base study.Results. Patients reported greater mean daily stress, bladder pain, urgency, and daytime and nocturnal frequency than controls (all P values less than 0.001). Among all patients, a significant relationship between stress and urgency was observed. In addition, a significant relationship between stress and pain was observed among patients with moderate and severe disease. As the disease severity increased, more pronounced relationships between stress and the symptoms of urgency and pain were evidenced. Greater stress was associated with greater nocturnal frequency among patients with more severe disease. These stress-symptom relationships were not observed among the controls.Conclusions. Higher levels of stress were related to greater pain and urgency in patients with IC but not in the controls. In addition, the relationship of stress and these IC symptoms was stronger among patients with more severe disease. The results indicate that life stress is associated with greater IC symptoms, particularly among patients whose disease is not well controlled.

Long-Term Efficacy of Biofeedback Therapy for Dyssynergic Defecation: Randomized Controlled Trial

OBJECTIVES:Although biofeedback therapy is effective in the short-term management of dyssynergic defecation, its long-term efficacy is unknown. Our aim was to compare the 1-year outcome of biofeedback (manometric-assisted pelvic relaxation and simulated defecation training) with standard therapy (diet, exercise, laxatives) in patients who completed 3 months of either therapy.METHODS:Stool diaries, visual analog scales (VASs), colonic transit, anorectal manometry, and balloon expulsion time were assessed at baseline, and at 1 year after each treatment. All subjects were seen at 3-month intervals and received reinforcement. Primary outcome measure (intention-to-treat analysis) was a change in the number of complete spontaneous bowel movements (CSBMs) per week. Secondary outcome measures included bowel symptoms, changes in dyssynergia, and anorectal function.RESULTS:Of 44 eligible patients with dyssynergic defecation, 26 agreed to participate in the long-term study. All 13 subjects who received biofeedback, and 7 of 13 who received standard therapy, completed 1 year; 6 failed standard therapy. The number of CSBMs per week increased significantly (P<0.001) in the biofeedback group but not in the standard group. Dyssynergia pattern normalized (P<0.001), balloon expulsion time improved (P=0.0009), defecation index increased (P<0.001), and colonic transit time normalized (P=0.01) only in the biofeedback group.CONCLUSIONS:Biofeedback therapy provided sustained improvement of bowel symptoms and anorectal function in constipated subjects with dyssynergic defecation, whereas standard therapy was largely ineffective.

Predictors of weight loss in Parkinson's disease

The objective of this study was to examine the change of body weight (BW) among Parkinsons disease (PD) patients and controls over years and determine the predictors of weight loss among PD patients. Studies on weight loss in PD studies are cross‐sectional, have a short follow‐up, or lack in clinical detail. We examined the percentage of BW change over years among 49 PD patients and 78 controls. The controls were from another study on longitudinal evolution of BW and body composition in the elderly. We determined the BW, Hoehn and Yahr (HY) stage, and dyskinesia status of 49 consecutive nondemented PD patients with symptom duration of 6.1 ± 0.7 years (mean ± SEM) and ascertained their BW at the time of diagnosis and 2.4 ± 0.2 years before the diagnosis from medical records. We collected data again 7.2 ± 0.5 years after the first visit. The PD group lost 7.7% ± 1.5% of BW over the entire symptomatic period (13.1 ± 0.8 years), while the control group lost only 0.2% ± 0.7% of BW over 9.9 ± 0.1 years; weight loss was clinically significant (>5%) in 55.6% of PD patients vs. 20.5% of the controls (both P values < 0.001, adjusted for sex, baseline age, and observation period duration). PD patients lost weight in both the early and advanced phases. While worsening of parkinsonism was the most important factor, age at diagnosis, emergence of visual hallucinations, and possibly dementia were also associated with weight loss. We demonstrated significant weight loss in PD patients compared to controls over approximately 1 decade. Neurodegeneration involving both motor and nonmotor systems may be associated with weight loss in PD.