John M. Esdaile

A Long-Term Study of Hydroxychloroquine Withdrawal on Exacerbations in Systemic Lupus Erythematosus

The ability of antimalarials to moderate severe disease activity in systemic lupus erythematosus (SLE) is plausible but undemonstrated. We evaluated the long-term effectiveness of maintaining treatment with hydroxychloroquine sulphate (HCQ) to prevent major flares in quiescent SLE. Forty-seven patients with quiescent SLE who had been randomized to take HCQ (n = 25) or placebo (n = 22) as part of a 24-week withdrawal trial were evaluated for an additional 3 years. The primary outcome was time to a major flare of SLE which resulted in either the institution of or an increase in the current dosage of prednisone of 10 mg/day or more, or institution of therapy with immunosuppressive agents. Secondary outcomes included the specific subtype of these major flares (glomerulonephritis, vasculitis or other) and hospitalization for an exacerbation of SLE. An intent-to-treat analysis was conducted. Over the 42 months of study, 11 of 22 (50%) patients randomized initially to placebo, and seven of 25 (28%) patients randomized to continue treatment experienced a major flare. The relative risk of major flare for those randomized to continue HCQ compared with controls was 0.43 (95% CI: 0.17, 1.12). The relative risks for subtypes of flares were 0.26 (95% CI: 0.03, 2.54) for nephritis, 0.51 (95% CI: 0.09, 3.08) for vasculitis and 0.65 (95% CI: 0.17, 2.41) for flares characterized by other symptoms. The relative risk of hospitalization for major flare for patients randomized to continue hydroxychloroquine was 0.58 (95% CI: 0.13, 2.60). While the results are not statistically significant, they are compatible with the clinical belief that HCQ has a long-term protective effect against major disease flares in SLE and suggest that on average, HCQ use reduces major flares by 57% (95% CI: 83% reduction to 12% increase).

The Quebec Back Pain Disability Scale: Conceptualization and development

The Quebec Back Pain Disability Scale is a new measure of functional disability for patients with back pain. Functional disability was operationalized in terms of perceived difficulty associated with simple physical activities. The content of the scale was developed in several stages, including a literature review, two studies seeking the opinions of patients and experts, pilot testing, and a large, longitudinal study of back pain patients. Forty-eight disability items were extensively studied using standard methods such as test-retest reliability, item-total correlations, and factor analysis, as well as modern techniques based on item response theory. Items that were highly effective in discriminating between different levels of disability were selected for the final, reduced scale. The scale has 20 items, representing six empirically derived categories of activities affected by back pain. Measurement properties of this instrument have been previously discussed.

Indications for total hip and total knee arthroplasties. Results of orthopaedic surveys.

A lack of consensus regarding the indications for total hip arthroplasty (THA) and total knee arthroplasty (TKA) has been cited as one reason for the variations in the rates of THA and TKA across the United States. The purposes of this study were to survey orthopaedists in a specific geographic area (New York City) regarding the candidacy of patients with osteoarthritis for THA or TKA and to compare indications for THA between orthopaedists at two academic medical centers, The Hospital for Special Surgery in the United States and McGill University in Canada. Orthopaedists were sent mail surveys asking about indications, factors affecting outcomes, and factors that might modify decisions for surgery. Approximately 45% of orthopaedists who performed THA and TKA in New York City in 1992 completed the surveys. Although there were wide variations among surgeons, most surgeons required at least severe pain daily, rest pain several days per week, transfer pain either several days per week (THA) or daily (TKA), and destruction of most of the joint space on radiograph. Younger age, comorbidity, technical difficulties, and lack of motivation modified the decision against surgery, whereas the desire to be independent and return to work swayed the decision for surgery. Most surgeons rated that patients with severe pain, osteoarthritis, or rheumatoid arthritis would have a high likelihood of an excellent outcome, whereas those with comorbidity and certain technical factors would have only a moderate likelihood of an excellent outcome. In the U.S.-Canadian survey of THA, in which more than 90% of surgeons responded, Canadian surgeons tended to require more frequent pain and use of assistive devices for walking. Although there was a majority of opinion for several indications, there was no clear consensus among surgeons regarding the indications for THA and TKA. Possible explanations for this are that isolated indications are not as important as integrating and weighing several indications and that the patients desire to proceed with THA or TKA is an important driving force in the decision to operate.

Time-Dependent Hazard Ratio: Modeling and Hypothesis Testing with Application in Lupus Nephritis

Abstract We investigate the association between duration of untreated disease and survival in lupus nephritis, a rare rheumatologic disease. In this case, as in many other studies of survival, a priori considerations suggest that the effect of the predictor on hazard may change with increasing follow-up time. To accommodate such situations, we use regression splines to model the hazard ratio as a flexible function of time. We propose model-based tests of the hypotheses of hazards proportionality and of no association. We evaluate the accuracy of estimation and inference in simulations and also present analysis of a larger medical data set.

Randomized discontinuation trials: Utility and efficiency

The randomized discontinuation trial (RDT) is a two-phase trial. In phase I all patients are openly treated with the medication being evaluated. In phase II, those who have responded are randomly assigned to continue the same treatment or switch to placebo. Usually, non-compliers and adverse reactors identified in phase I are excluded from phase II. To investigate the value of this design, we reviewed the advantages and limitations of discontinuation studies, and compared the RDT design to the classic randomized clinical trial design in terms of clinical utility and efficiency (sample size). A computer model was used to study the efficiency of the two designs under a broad range of assumptions. The RDT design is particularly useful in studying the effect of long-term, non-curative therapies, especially when the clinically important effect is relatively small, and the use of placebo should be minimized for ethical or feasibility reasons. However, its use is limited if the objective of an investigation is to estimate the magnitude of absolute treatment effects and toxic effects in the source population, or to evaluate a potentially curative treatment. Our results indicate that selecting responders prior to randomization has a very strong effect on the relative efficiency of the trial. Further improvement may be achieved by excluding non-compliers and adverse reactors. Under the assumptions tested in our model, the sample size required in phase II of an RDT was only 20-50% of that in a classic trial.

Cellular immunity to the G1 domain of cartilage proteoglycan aggrecan is enhanced in patients with rheumatoid arthritis but only after removal of keratan sulfate.

OBJECTIVEnTo determine whether patients with rheumatoid arthritis (RA) express cellular immunity to the purified G1 globular domain of cartilage proteoglycan (PG) aggrecan and whether it is influenced by the removal of keratan sulfate (KS) chains from the molecule.nnnMETHODSnThe G1 globular domain of PG was purified from mature bovine articular cartilage, digested with keratanase, and used in proliferation assays with peripheral blood lymphocytes (PBL) isolated from 43 patients with RA, 11 patients with nonarticular rheumatism (NAR), including soft tissue rheumatism and mechanical back pain, and 13 healthy age- and sex-matched control subjects.nnnRESULTSnRemoval of KS chains from the G1 globular domain resulted in significantly increased prevalence and values of cellular immune responses to G1 in RA patients compared with the control and NAR groups. In the majority of RA patients, KS chains on G1 significantly inhibited its immune recognition by PBL. There was no significant effect of KS removal on the immunity to G1 in patients with NAR and in the healthy control group.nnnCONCLUSIONnThese results reveal that immune reactivity to the G1 globular domain of the cartilage PG aggrecan is enhanced in patients with RA but only when KS chains are removed. Thus, KS chains inhibit immune responses to this domain of aggrecan. Since immunity to the G1 globular domain of aggrecan induces an erosive polyarthritis in BALB/c mice after removal of KS chains, immunity to the G1 globular domain, cleaved by proteases to remove KS chains, may play a role in the pathogenesis of RA.

Diagnosis and treatment of ossification of the posterior longitudinal ligament of the spine : report of eight cases and literature review

PURPOSEnOssification of the posterior longitudinal ligament (OPLL) is a common, well-recognized cause of spinal stenosis and myelopathy in Japan. Although also common in whites, especially among the elderly, it has received little scientific attention. We wish to increase awareness of this important cause of myelopathy, and to determine if the clinical characteristics of OPLL are similar in non-Japanese and Japanese patients.nnnPATIENTS AND METHODSnThe clinical and radiologic features of eight cases of OPLL are presented. These cases combined with 73 non-Japanese cases gathered from the English literature are contrasted with 2,125 Japanese cases of OPLL.nnnRESULTSnSimilarities among non-Japanese and Japanese cases included: (1) male predominance; (2) peak age at onset of symptoms in the sixth decade; (3) clinical presentation, which ranged from asymptomatic to quadriplegia, with progressive or acute onset of neurologic deterioration; (4) greater than 95% localization to the cervical spine, spastic quadriparesis being the most common neurologic presentation; (5) an association with several rheumatic conditions including diffuse idiopathic skeletal hyperostosis (DISH), spondylosis, and ankylosing spondylitis; and (6) neurologic improvement with either conservative or surgical treatment in a significant proportion of patients. Differences between the two groups were minimal and included a higher mean age at onset (although onset in both groups occurred within the sixth decade) and a greater proportion of patients with DISH and with the continuous type of OPLL in the non-Japanese group.nnnCONCLUSIONnThe clinical characteristics of OPLL are similar in Japanese and non-Japanese patient populations. Increased awareness of this condition, which has potentially devastating neurologic complications, will favorably influence diagnosis, treatment, and outcome.

A controlled study of the long-term prognosis of adult still's disease

PURPOSEnTo assess the long-term prognosis of patients with adult Stills disease for physical and psychological disability, pain, social functioning, social support, medication use, formal education, occupation, time lost from work, and family income, and to contrast these results with those of same-sex sibling controls.nnnPATIENTS AND METHODSnPatients were recruited from medical center-based cohorts in Pittsburgh and Eastern Canada and from a national survey of rheumatologists. Patients and same-sex sibling controls completed the Health Assessment Questionnaire for physical disability, the psychological and social function domains of the Arthritis Impact Measurement Scales, and the Interpersonal Skills Evaluation List questionnaire for social support, and replied to questions on medication use, formal education, occupation, time lost from work, and family income.nnnRESULTSnOne hundred four of 111 eligible adult Stills patients (94%) provided data. They identified 86 same-sex sibling controls, of whom 60 (70%) participated. The mean duration of adult Stills disease was 10 years. Approximately half of patients continued to require medication even 10 years after diagnosis. Patients had significantly higher levels of pain, physical disability, and psychological disability when compared with the controls. However, the levels of pain and physical disability were low compared to patients with other rheumatic diseases. Educational achievement, occupational prestige, social functioning and support, time lost from work, and family income were similar for both patients and controls.nnnCONCLUSIONSnDespite causing disability, pain, and, in many, the need for long-term medication, patients with adult Stills disease are resilient. The disease did not interfere with educational attainment, occupational prestige, social functioning and support, time lost from work, or family income.

Aberrant Cellular Localization of Rubella Viral Genome in Patients with Adult Still's Disease-A Pilot Study

The rubella virus (RV) genome was detected using polymerase chain amplification techniques in several peripheral blood cell populations in patients with adult Stills disease (ASD) and normal controls (NC), including mononuclear cells (PBMC), B-cells, T-cells, monocyte/macrophages, and polymorphonuclear leukocytes (PMN). Five of 6 ASD patients and 3 of 6 NC subjects had detectable RV genome. Viral genomic load was significantly higher in ASD than in NC subjects (4.4 fold higher, p = 0.03). Interestingly, a differential cellular distribution of viral genome was observed between ASD and NC individuals. RV genome was detected more frequently in the PBMCs of ASD (5 of 6) patients compared to 2 of 6 NC. The viral genome was more localized to the PMN compartment equally in ASD and in NC subjects. On further cellular analysis, RV genome was detected in B-cells and macrophages but not T-cells in one patient. Existence of a differential viral genomic reservoir between ASD and NC suggests that this may play a role in the pathogenesis of disease manifestations and may reflect the inability to clear latent virus.

Prognosis in systemic lupus erythematosus

Knowledge about prognosis assists physicians in informing patients about possible outcomes and in determining treatment. New subsets of patients with distinct prognoses that merit further evaluation or special therapy can be identified. Fortunately, the prognosis for an individual with newly diagnosed systemic lupus erythematosus (SLE) has improved markedly over the past several decades [34, 66, 77]. With the extent that new treatment regimens have been developed or will be developed in the future, the predictive markers of the past may not be the predictive markers of today or tomorrow.ConclusionsIn SLE, morbidity is universal and fatality is significant. One cannot learn too much about the prognostic markers for this disorder. The identification by means of renal biopsy of subclasses of lupus nephritis spurred the development of new treatment regimens that have improved outcomes. While proliferative nephritis remains a marker of serious renal involvement, the newer indices that attempt to quantify the activity and chronicity of the renal lesion, as well as greater awareness of the importance of tubulointerstitial involvement and improvement in the amount of subendothelial electron-dense deposits with therapy, will likely permit further fine-tuning of the treatment of individual patients with lupus nephritis.Neuropsychiatric involvement in SLE is another major determinant of financial costs, morbidity and death. Unfortunately, our knowledge of the prognostic markers for this more heterogeneous group of manifestations is less advanced than for lupus renal involvement. Additional studies are needed urgently to determine the factors that predict the subsequent development of the different forms of neuropsychiatric lupus. The determinants will likely differ among the various forms of neuropsychiatric lupus, thereby permitting different preventative or treatment regimens to be developed.The role of social factors, particularly socioeconomic status, has attracted attention in the United States. The lessons are likely applicable elsewhere. Additional studies to identify social factors that can be modified may bring tangible benefits to SLE patients in this decade.Although not universally accepted, it does appear that as more SLE patients survive the acute disease, there is an inordinately high risk of developing vascular diseases, including coronary artery disease, stroke and peripheral vascular disease. As with neuropsychiatric lupus, the determinants may differ depending on the specific vascular disease. Better knowledge of these determinants will permit a further improvement in the overall prognosis for patients with SLE.