Stanley R. Pillemer

Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States

OBJECTIVE To provide a single source for the best available estimates of the national prevalence of arthritis in general and of selected musculoskeletal disorders (osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, the spondylarthropathies, systemic lupus erythematosus, scleroderma, polymyalgia rheumatica/giant cell arteritis, gout, fibromyalgia, and low back pain). METHODS The National Arthritis Data Workgroup reviewed data from available surveys, such as the National Health and Nutrition Examination Survey series. For overall national estimates, we used surveys based on representative samples. Because data based on national population samples are unavailable for most specific musculoskeletal conditions, we derived data from various smaller survey samples from defined populations. Prevalence estimates from these surveys were linked to 1990 US Bureau of the Census population data to calculate national estimates. We also estimated the expected frequency of arthritis in the year 2020. RESULTS Current national estimates are provided, with important caveats regarding their interpretation, for self-reported arthritis and selected conditions. An estimated 15% (40 million) of Americans had some form of arthritis in 1995. By the year 2020, an estimated 18.2% (59.4 million) will be affected. CONCLUSION Given the limitations of the data on which they are based, this report provides the best available prevalence estimates for arthritis and other rheumatic conditions overall, and for selected musculoskeletal disorders, in the US population.

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial

BACKGROUND Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. METHODS In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. FINDINGS 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). INTERPRETATION Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. FUNDING MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Minocycline in Rheumatoid Arthritis: A 48-Week, Double-Blind, Placebo-Controlled Trial

Rheumatoid arthritis is a chronic, sometimes incapacitating systemic disease of unknown cause that affects at least two million Americans [1, 2]. Various pharmacologic agents are used to manage rheumatoid arthritis, but none is completely effective. On the basis of the theory that persistent Mycoplasma infection may cause rheumatoid arthritis, some physicians have prescribed and reported benefit from lengthy courses of tetracyclines [3, 4]. A small 1-year clinical trial comparing tetracycline, 250 mg/d, with placebo could not show significant benefit in patients with rheumatoid arthritis [5]. Because of these contradictory outcomes, the treatment of rheumatoid arthritis with antibiotics has remained controversial. Tetracyclines have several nonantibiotic effects that may be beneficial for patients with rheumatoid arthritis. Minocycline, a semi-synthetic tetracycline that is rapidly absorbed and has a prolonged half-life, inhibits collagenase activity of gingival fibroblasts from diabetic rats, even in a germ-free environment [6, 7]. Oral minocycline at a dose of 100 mg twice a day for 10 days reduced collagenase activity in the synovial tissue of patients with rheumatoid arthritis [8]. Moreover, the addition of minocycline to synovial tissue cultures from patients with rheumatoid arthritis also resulted in the inhibition of this enzyme. Other properties of tetracycline analogs include inhibition of protein synthesis by rapidly dividing cells [9], perturbation of leukocyte functions [10, 11], interference with lymphocyte proliferation [12-14], and anti-inflammatory effects [15] that are probably related to its antioxidant activity [16, 17]. Minocycline can also suppress the induction of experimental arthritis in rats [18]. Recently, favorable results from uncontrolled clinical studies of minocycline in rheumatoid arthritis were reported [19, 20]. In addition, Kloppenburg and colleagues [21, 22] observed improvement when minocycline was added to baseline nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs or corticosteroid therapy in a 26-week randomized, placebo-controlled trial. We conducted a 48-week, randomized, double-blind, multicenter trial to determine the efficacy and safety of minocycline in treating rheumatoid arthritis when it is added to background NSAIDs or low-dose prednisone therapy in patients not receiving concomitant disease-modifying antirheumatic drugs. Methods Protocol Development The protocol for the Minocycline in Rheumatoid Arthritis (MIRA) Trial was developed by the investigators from the clinical centers, the coordinating center, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases on the basis of protocols for clinical trials of therapies for rheumatoid arthritis that were previously done by the Cooperative Systematic Studies of Rheumatic Diseases (CSSRD) program [23, 24]. Inclusion criteria for those CSSRD trials were two of the following: nine or more tender joints capable of response, an erythrocyte sedimentation rate of 28 mm/h or greater, and morning stiffness lasting 45 minutes or longer. To simplify recruitment of patients, we modified these criteria to require the presence of nine or more tender joints capable of response with no minimum specified for either the erythrocyte sedimentation rate or for morning stiffness. The study protocol was reviewed and approved by institutional review boards at each participating clinical center. Patients To be eligible for the minocycline trial, patients had to meet the 1987 American Rheumatism Association (now the American College of Rheumatology) classification criteria for rheumatoid arthritis [25]. Patients were required to have active disease, defined as nine or more tender joints and six or more swollen joints capable of assessable improvement. Patients had to be 18 years of age or older and to have experienced onset of rheumatoid arthritis at 16 years of age or older. Patients receiving NSAIDs or low-dose corticosteroids (prednisone equivalent of a daily dose of 10 mg or less) were required to be receiving stable concurrent medication for 4 weeks before entering the study; these medications were to be kept stable throughout the study. One change from equivalent doses of one NSAID to another was permitted during the trial. Phenylbutazone, oxyphenbutazone, or parenteral steroids (including intra-articular corticosteroids) and disease-modifying antirheumatic drugs were not allowed for 4 weeks before the study; the use of these drugs during the trial was a protocol violation. Women were required to be postmenopausal, surgically sterile, or practicing a reliable method of contraception and to have a negative pregnancy test result. Before randomization, eligible patients for the minocycline trial could have received therapeutic trials of hydroxychloroquine and, at most, one other disease-modifying antirheumatic drug (oral or parenteral gold salts, d-penicillamine, azathioprine, methotrexate, or sulfasalazine) unless therapy was discontinued for toxicity. Patients could have tried any number of disease-modifying antirheumatic drugs if discontinued for toxicity, provided that no drug was administered for more than 3 months or, for parenteral gold salts, was not given in a cumulative dose of more than 500 mg. These exclusion criteria were designed to avoid recruiting patients with a history of repeated failures of therapeutic trials of disease-modifying antirheumatic drugs but did allow entry of those who had discontinued therapy with these drugs because of toxicity before prespecified dosages or durations were reached. Patients were not eligible at screening if they had known hypersensitivity to tetracycline; required long-term tetracycline therapy for another disorder; required ongoing therapy with antacids containing aluminum, calcium, or magnesium; or had received anticoagulant therapy. We excluded patients with chronic illnesses that would limit successful participation in the trial and patients classified as American Rheumatism Association-Steinbrocker functional class IV [26]. Three patients who met eligibility criteria at their screening visit were found to have too few affected joints at their baseline (randomization) visit and were inadvertently randomized. We included these patients in the analysis. All three patients were in the placebo group and were not considered responders to treatment. Removing these patients did not change the results of the trial. Study Design The MIRA trial was a six-center, double-blind, randomized, placebo-controlled trial comparing minocycline and placebo in treating rheumatoid arthritis. Patients were randomly assigned within the clinical center (that is, the clinical center was a stratifying factor), and randomization was blocked using randomly chosen block sizes between 4 and 6 to minimize the possibility that staff would guess the next treatment assignment. For 48 weeks, patients received two 50-mg capsules of minocycline hydrochloride or a visually similar placebo taken with water twice daily on an empty stomach. To minimize interference with the absorption of minocycline, patients were instructed not to ingest food or iron within 2 hours of receiving study medication. Investigators were allowed to adjust the dosage (without breaking the treatment code) if patients experienced side effects. Measurements The following measurements were obtained at the baseline and randomization visits and every 12 weeks thereafter. Evaluator Assessments Sixty diarthrodial joints were examined for the presence or absence of tenderness, and 58 were examined for swelling (hips excluded). Joint counts for tenderness and for swelling were the sum of the number of affected joints [27]. These joints were also evaluated for the severity of both tenderness and swelling on a 4-point scale. For tenderness, 0 = none, 1 = mild (positive response on questioning), 2 = moderate (spontaneous response elicited on examination), and 3 = severe (withdrawal by patient on examination); for swelling, 0 = none, 1 = mild (detectable synovial thickening without loss of bony contours), 2 = moderate (loss of distinctness of bony contours), and 3 = severe (bulging synovial proliferation with cystic characteristics). The sum of these determinations for all joints constituted a collective scores for either swelling or tenderness [23]. To foster agreement, evaluators attended a training session at the coordinating center before the trial. During the trial, all joint assessments for each patient were done by the same evaluator if possible. (During the trial, 94% of patients receiving minocycline and 92% of those receiving placebo had their joints evaluated by the same examiner at every visit.) Grip strength was measured bilaterally using a mercury strain sphygmomanometer [28]. An evaluator assessed disease activity on the day of the examination using a scale of 1 to 5: absent, mild, moderate, severe, or very severe activity [29]. For functional class, patients were assessed according to the American Rheumatism Association-Steinbrocker classification [26] (at baseline and 48 weeks only). Patient Assessments Patients were asked about the duration of morning stiffness they experienced on the day before each study visit [23]. Function was assessed on eight activities of daily living with the Modified Health Assessment Questionnaire (MHAQ) [30]. Patients used a scale of 0 to 3: activity without any difficulty, with some difficulty, with much difficulty, and unable to do; thus, the higher the score, the greater the incapacitation. Patients were also asked to give an overall assessment of their disease activity for the preceding day on a scale of 1 to 5: absent, mild, moderate, severe, and very severe [29]. Ancillary Assessments Laboratory determinations included urinalysis, complete blood count with differential, and a chemistry profile at the screening visit and every 4 weeks through week 12 an

Xerostomia and the geriatric patient

Saliva is essential for the preservation of oral‐pharyngeal health, and disorders of salivary physiology are associated with numerous oral and pharyngeal problems, particularly in older people. Although salivary function is remarkably intact in healthy aging, medical problems, medications, and head and neck radiotherapy can cause salivary dysfunction and complaints of xerostomia among older people. Sjögrens syndrome, an autoimmune exocrinopathy, is the most common medical disease associated with salivary dysfunction. Medications with anticholinergic side effects will impair salivary output, and head and neck radiotherapy for cancer will cause permanent destruction of salivary glands. Treatments for salivary problems are based upon establishing a diagnosis, protecting oral and pharyngeal health, stimulating remaining glands, and replacing lost salivary fluids.

Responses of the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis to interleukin‐6: A pilot study in fibromyalgia

OBJECTIVE To determine whether deficient activity of the hypothalamic corticotropin-releasing hormone (CRH) neuron, which stimulates the hypothalamic-pituitary-adrenal (HPA) axis and the central control nuclei of the sympathetic nervous system and inhibits ascending pain pathways, may be pathogenic in patients with fibromyalgia (FM). METHODS We administered interleukin-6 (IL-6; 3 microg/kg of body weight subcutaneously), a cytokine capable of stimulating hypothalamic CRH release, and measured plasma levels of adrenocorticotropic hormone (ACTH), cortisol, and catecholamines and their metabolites and precursors. Thirteen female FM patients and 8 age- and body mass index-matched female controls were studied. The diagnosis of FM was made according to American College of Rheumatology criteria. Tender points were quantitated by pressure algometry. All subjects had HPA axis studies. Seven FM patients and 7 controls also had catecholamine measurements. RESULTS After IL-6 injection, delayed ACTH release was evident in the FM patients, with peak levels at 96.9 +/- 6.0 minutes (mean +/- SEM; control peak 68.6 +/- 10.3 minutes; P = 0.02). Plasma cortisol responses to IL-6 did not differ significantly between patients and controls. Basal norepinephrine (NE) levels were higher in the FM patients than in the controls. While a small, although not significant, rise in NE levels occurred after IL-6 injection in the controls, NE levels dramatically increased over basal levels in the FM patients between 60 and 180 minutes after IL-6 injection. Both peak NE levels (mean +/- SEM 537.6 +/- 82.3 versus 254.3 +/- 41.6 pg/ml; P = 0.0001) and time-integrated NE responses (93.2 +/- 16.6 pg/ml x minutes(-3) versus 52.2 +/- 5.7 pg/ml x minutes(-3); P = 0.038) were greater in FM patients than in controls. Heart rate was increased by IL-6 injection in FM patients and controls, but rose to significantly higher levels in the FM patients from 30 minutes to 180 minutes after IL-6 injection (P < 0.03). CONCLUSION Exaggerated NE responses and heart rate increases, as well as delayed ACTH release, were observed among female FM patients compared with age-matched female controls. Delayed ACTH release after IL-6 administration in FM is consistent with a defect in hypothalamic CRH neuronal function. Exaggerated NE release may reflect abnormal regulation of the sympathetic nervous system, perhaps secondary to chronically deficient hypothalamic CRH. The excessive heart rate response after IL-6 injection in FM patients may be unrelated to the increase in NE, or it may reflect an alteration in the sensitivity of cardiac beta-adrenoceptors to NE. These responses to a physiologic stressor support the notion that FM may represent a primary disorder of the stress system.

Systemic and Local Interleukin-17 and Linked Cytokines Associated with Sjögren's Syndrome Immunopathogenesis

Recently recognized as a distinct CD4(+) T helper (Th) lineage, Th17 cells have been implicated in host responses to infections and in pathogenesis associated with autoimmune diseases. This cytokine is implicated in primary Sjögrens syndrome (pSS) immunopathology because of the increased levels of circulating interleukin (IL)-17 in pSS. Plasma and minor salivary glands (MSGs) from patients with pSS were therefore evaluated for CD4(+) T cells, T regulatory cells, IL-17, and supporting cytokines by immunohistochemistry, RT-PCR, and microbead assays. MSGs from pSS patients contain IL-17-expressing cells as a dominant population within inflammatory lesions. IL-17 protein expression progressively increased with higher biopsy focus scores (P < 0.0001), in parallel with detection by RT-PCR. Transforming growth factor-beta, IL-6 and IL-23, which are requisite promoters of Th17 differentiation, were found in abundance compared with the amounts in control tissues. Although transforming growth factor-beta is also a pivotal differentiation factor for immunosuppressive Foxp3(+) T regulatory cells (Tregs), an increase in Foxp3(+) Tregs was evident in biopsy specimens with mild and moderate inflammation but this increase was disproportionate to escalating pro-inflammatory Th17 populations in advanced disease. Furthermore, the Th17-centric cytokines IL-17, IL-6, IL-23, and IL-12 were significantly elevated in pSS plasma. These data identify a profusion of IL-17-generating cells and supporting cytokines within diseased pSS MSGs without a compensatory increase in immunomodulatory Tregs; this imbalance seems to foster a pathogenic milieu that may be causative and predictive of infiltrative injury and amenable to therapeutic intervention.

Differentiation of human bone marrow-derived cells into buccal epithelial cells in vivo: a molecular analytical study

BACKGROUND Adult bone marrow-derived (BMD) cells could be used to repair damaged organs and tissues, but the intrinsic plasticity of these cells has been questioned by results of in-vitro studies suggesting that such cells might fuse with other cells giving the appearance of differentiation. We aimed to determine whether fusion events are important in vivo. METHODS To test whether BMD cells can colonise an epithelial tissue and differentiate there without fusion, we did in-situ hybridisation with Y and X chromosome probes labelled with 35-sulphur or digoxigenin, or labelled fluorescently. We did immunohistochemistry with anticytokeratin 13 along with fluorescence in-situ hybridisation to identify Y-chromosome positive buccal epithelial cells in cheek scrapings obtained from five females who had received either a bone-marrow transplant or an allogeneic mobilised peripheral-blood progenitor-cell transplant (enriched in CD34+ cells) from male donors. FINDINGS When examined 4-6 years after male-to-female marrow-cell transplantation, all female recipients had Y-chromosome-positive buccal cells (0.8-12.7%). In more than 9700 cells studied, we detected only one XXXY-positive cell (0.01%) and one XXY cell (0.01%), both of which could have arisen when an XY cell fused with an XX cell. INTERPRETATION Male BMD cells migrate into the cheek and differentiate into epithelial cells, an occurrence that does not depend on fusion of BMD cells to recipient cells. This finding might be an example of transdifferentiation of haemopoietic or stromal progenitor cells. Plasticity of BMD cells could be useful in regenerative medicine.

Incidence of Physician-Diagnosed Primary Sjögren Syndrome in Residents of Olmsted County, Minnesota

OBJECTIVES To estimate the incidence of physician-diagnosed primary Sjögren syndrome (SS) among residents of Olmsted County, Minnesota, in the setting of usual medical care and to determine how often objective criteria are available in the medical records of such patients. PATIENTS AND METHODS We reviewed all medical records of residents in Olmsted County with physician-diagnosed SS from 1976 to 1992 to determine whether they had undergone objective tests for keratoconjunctivitis sicca, salivary dysfunction, or serologic abnormality. Confounding illnesses were excluded. To identify misclassified cases, all records from patients with xerostomia or keratoconjunctivitis sicca were also reviewed. The average annual SS incidence rates were calculated by considering the entire population to be at risk. RESULTS Of 75 patients with onset of SS during the study period, 53 had primary SS. All patients were white, 51 (96.2%) were women, and the mean +/- SD age was 59+/-15.8 years. The age- and sex-adjusted annual incidence was 3.9 per 100,000 population (95% confidence interval, 2.8-4.9) for patients with primary SS. Eleven patients (20.8%) with physician-diagnosed SS had no documentation of objective eye, mouth, or laboratory abnormalities. Objective evaluations performed most frequently were laboratory and ocular tests and least often were investigations of xerostomia. CONCLUSIONS The average annual incidence rate for physician-diagnosed primary SS in Olmsted County is about 4 cases per 100,000 population. These data probably underestimate the true incidence because they are based on usual medical care of patients with SS in a community setting, rather than on a case-detection survey. In the future, a true incidence may be possible with a higher index of suspicion, greater attention to objective tests, and increased awareness of new classification criteria for SS. For epidemiological studies based on existing data, application of current criteria may not be feasible, and consensus on criteria for such studies would be useful.

Local adeno-associated virus-mediated interleukin 10 gene transfer has disease-modifying effects in a murine model of Sjögren's syndrome.

Female nonobese diabetic (NOD) mice develop spontaneous autoimmune sialadenitis and loss of salivary flow, and are a widely used model of Sjögrens syndrome. We examined the feasibility of local salivary gland immunomodulatory gene delivery to alter these sequelae in NOD mice. We constructed recombinant adeno-associated virus (rAAV) vectors encoding either human interleukin 10 (rAAVhIL-10) or beta-galactosidase (rAAVLacZ, control vector). Mice received rAAVhIL-10 or rAAVLacZ by retrograde submandibular ductal instillation either at age 8 weeks (early, before onset of sialadenitis), or at 16 weeks (late, after onset of sialadenitis). As a systemic treatment control, separate mice received intramuscular delivery of rAAVhIL-10 at each time point. Both submandibular and intramuscular delivery of vector led to low circulating levels of hIL-10. After submandibular administration of rAAVhIL-10, salivary flow rates at 20 weeks for both the early and late treatment groups were significantly higher than for both rAAVLacZ-administered and untreated mice. Systemic delivery of rAAVhIL-10 led to improved salivary flow in the late treatment group. Inflammatory infiltrates in submandibular glands, however, were significantly reduced only in mice receiving rAAVhIL-10 locally in the salivary gland compared with mice receiving this vector intramuscularly, or rAAVLacZ or no treatment. In addition, after submandibular rAAVhIL-10 delivery, NOD mice exhibited significantly lower blood glucose, and higher serum insulin, levels than all other groups, indicating some systemic benefit of this treatment. These studies show that expression of hIL-10 by rAAV vectors can have disease-modifying effects in the salivary glands of NOD mice, and suggest that local immunomodulatory gene transfer may be useful for managing the salivary gland pathology in Sjögrens syndrome.

Hip osteoarthritis prevalence estimates by three radiographic scoring systems

OBJECTIVE To estimate and compare the age- and sex-specific prevalence of radiographic hip osteoarthritis (RHOA) in a population-based study of the Pima Indians, using 3 atlas-based methods for assessing features of RHOA. METHODS Pelvic radiographs from 755 Pima Indians age > or = 45 years enrolled in a population-based study were read using the Kellgren/Lawrence (K/L) grading scale (grade 0-4) and 2 validated individual-radiographic-features (IRF) scales (grades 0-3 for narrowing and osteophytes). RESULTS The age- and sex-specific prevalence of RHOA among Pima Indians assessed using the K/L scale was < 10% in all age and sex groups. The prevalence of grade > or = 2 osteophytes assessed using the 2 IRF scales were similar to each other in all age and sex groups. However, differences between the 2 IRF scoring systems were found for the prevalence of grade > or = 2 joint space narrowing. CONCLUSION Pima Indians have an age- and sex-specific prevalence of RHOA similar to that found in the US population. Our finding of different joint space narrowing prevalence by the 2 IRF grading scales supports the use of the same atlas-based case definitions for determining disease prevalence for comparative studies.