Bone Disease, Rheumatoid Arthritis Connection Complex

Association may be stronger in some subgroups of postmenopausal rheumatoid arthritis patients

21 june 2009-- In postmenopausal women with rheumatoid arthritis, hip bone mineral density appears to be associated with focal erosions, but the relationship is not significant after controlling for other variables. However, the relationship appears to be stronger in certain subgroups of patients, according to a study published in the June issue of Arthritis & Rheumatism.

Daniel H. Solomon, M.D., of Brigham and Women's Hospital in Boston, and colleagues studied 163 postmenopausal rheumatoid arthritis patients. Nearly all of the patients were treated with a disease-modifying anti-rheumatic drug, but none of them were treated with an osteoporosis drug.

The researchers found that total hip bone mineral density, but not lumbar spine bone mineral density, was associated with erosion scores. After multivariate adjustment, they found that hip bone mineral density was not significantly associated with erosions. However, they observed that the relationship was stronger in women with a younger age, shorter disease duration, higher body mass index, and lower cumulative oral glucocorticoid use.

"Our findings suggest that the relationship between focal erosions and generalized osteoporosis is complicated and modified by many aspects of rheumatoid arthritis and other factors," the authors write. "The fact that the relationship was stronger among patients with a shorter disease duration suggests that, with longer disease duration, other variables dilute the relationship between focal erosions and total hip bone mineral density."

Abstract
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Biologics and Combinations Top Arthritis Recommendations

By Charles Bankhead
ATLANTA, 25 july 2008 -- Early, aggressive treatment of rheumatoid arthritis with biologic agents and potent drug combinations has moved front and center in the newly updated American College of Rheumatology practice guidelines.
Patients with high disease activity and poor-prognosis features warrant consideration for first-line treatment with a biologic response modifier or a combination of nonbiologic disease-modifying antirheumatic drugs (DMARDs), according to the guidelines published in the June 15 issue of Arthritis & Rheumatism.
Even patients with low disease activity at diagnosis might be candidates for biologic DMARDs and combination therapy if they have high-risk or poor-prognosis features.
The guidelines reflect recognition that early aggressive intervention offers patients the best opportunity to minimize or avoid joint damage and disability, Kenneth G. Saag, M.D., of the University of Alabama at Birmingham, who was lead author of the guidelines. However, the guidelines leave ample room for clinical judgment in treating an individual patient.
"The recommendations developed are not intended to be used in a cookbook or prescriptive manner, or to limit a physician's clinical judgment," said Dr. Saag. "They provide guidance based on clinical evidence and expert-panel input."
The update, the first by the ACR since 2002, gave formal recognition and a systematic approach to treatment strategies that have been employed widely for several years: early use of nonbiologic DMARDs and biologic agents.
For example, the panel recommended triple-DMARD therapy "for all patients with poor prognostic features and moderate or high levels of disease activity, regardless of disease duration." The authors noted that the majority of patients with a confirmed diagnosis of rheumatoid arthritis (RA) already are treated with nonbiologic DMARDs or biologics.
The authors addressed only the use of traditional DMARDs and biologics. Steroids, anti-inflammatories, and other therapies used in RA were beyond the scope of the guidelines.
The 2008 guideline also is the first from the ACR to be developed by a formal group process. Prior iterations had evolved primarily from informal consensus, the authors said.
The guidelines panel recommended leflunomide (Arava) or methotrexate monotherapy as initial treatment for virtually all patients, regardless of disease duration, disease activity, or poor-prognosis features. However, clinical flow charts that accompany the recommendations waste little time in arriving at aggressive therapy, particularly in patients with unfavorable clinical characteristics.
Other key recommendations in the guideline include:
Use of tumor necrosis factor inhibitors in patients with new or early RA and severe, worsening symptoms.
Delay the start or resumption of treatment with methotrexate, leflunamide, or a biologic agent in patients who have active bacterial infections, herpes zoster infection, hepatitis B or C, or active or latent or suspected tuberculosis.
Prohibition on anti-TNF agents in patients who have a history of heart failure, lymphoma, or multiple sclerosis.
Dr. Saag and many of the co-authors acknowledged multiple relationships with medical and healthcare industries.
Primary source: Arthritis & RheumatismSource reference:Saag KG, et al "American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis" Arthritis Rheum 2008; 59: 762-784.

Combo Drug Treatment Scores for Early Rheumatoid Arthritis

By Judith Groch
LEEDS, England, 16 july 2008 -- Combining methotrexate and etanercept (Enbrel) for early moderate-to-severe rheumatoid arthritis improved remission and progression rates within a year, a randomized trial found.
At one year those treated with etanercept, an anti-TNF agent, plus methotrexate were 22% more likely to achieve remission as those given methotrexate alone, Paul Emery, M.D., of the University of Leeds, and colleagues reported online in The Lancet.
The industry-funded study included 542 outpatients who were methotrexate-naive and had had early moderate-to-severe RA for three to 24 months. Patients ages 18 or older were enrolled at 70 sites in Europe, Latin America, Asia, and Australia from October 2004 to February 2006.
After randomization masked to both patients and care persons, 268 patients were assigned to methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by the eighth week, and 274 were randomized to combined treatment with methotrexate (same titration) plus etanercept at 50 mg a week.
This study was supported by Wyeth Research, which was responsible for the collection and analysis of data. Wyeth is a marketer of Enbrel.
Altogether, there was severe disease in 487 evaluable patients (DAS 28>5.1).
Coprimary endpoints at 52 weeks were remission measured with the Disease Activity Score in 28 joints (DAS 28) and radiographic non-progression measured by a modified total Sharp score.
Of 265 patients given combined treatments and who were available for assessment, 132 or 50% (95% CI 44% to 56%) achieved clinical remission, while 94% had a good to moderate response.
The 50% response compared with a 28% response among 73 of 263 patients (95% CI 23% to 33%) taking methotrexate alone, making the difference for the effect 22.05% (95% CI 13.96% to 30.15%, P<0.0001).
In the combined treatment group, 80% (196 of 246) showed no radiographic progression of joint damage at 52 weeks compared with 59% of the monotherapy patients. The 21% difference favored combined treatment (95% CI 12.97% to 29.09%, P<0.0001).
Serious adverse events, worsening of rheumatoid arthritis, breast cancer, chest pain, pneumonia, infections, for example, were about 12% in both groups.
The cumulative proportion of patients working full- or part-time at baseline but who stopped working at least once was 9% for those given combined therapy versus 24% for those given monotherapy. Additionally, a lower risk of joint damage might reduce the need for future joint-replacement surgery, the researchers said.
The effect of rheumatoid arthritis is especially significant for women ages 55 to 64, because their rates for stopping work early are high, they added.
Study limitations included the fact that unlike patients treated in the real world, study participants could not decrease the dose of their primary medication other than for adverse events. Thus the combination regimen might have had a similar positive effect with lower methotrexate doses.
Additionally, administration of methotrexate could not be changed from oral to subcutaneous for higher doses, so that results might have differed with a parenteral procedure.
The analyses in this report are of treatment group averages rather than individual patients' responses, including lack of radiographic progression. These results do not indicate that rheumatoid disease was completely eliminated, although more patients continued employment when taking combined treatment versus monotherapy, the researchers said.
Within one year of treatment with methotrexate plus etanercept, both clinical remission and radiographic non-progression were achievable goals in patients with early severe rheumatoid arthritis, Dr. Emery's team said. Results for the combination-therapy group also suggest patients' ability to remain employed.
Furthermore, they added, "these outcomes appear to be achieved without exposing patients to significant additional risk."
In an accompanying commentary, Joel M. Kremer, M.D., of Albany (N.Y.) Medical College, wrote that the study authors acknowledged that the therapeutic value of methotrexate might have been enhanced if methotrexate had been given parenterally rather than orally, because the bioavailability of methotrexate diminishes with oral dosing in the range of the mean doses administered in this study.
Therefore the relevant question is whether the difference between the clinical and radiographic response to methotrexate alone versus combination therapy is worth the additional cost, inconvenience, and potential toxic effects.
Thus the difficulty is to show better outcomes in patients with a lesser disease burden who are given expensive drugs in combination with methotrexate over truly long-term treatment.
The answers, Dr. Kremer wrote, lie with data collection in national registries throughout Europe that use one-payer governmental systems, which can mandate participation. These systems are crucial for buttressing the shorter-term substantial results, such as those reported by Emery and colleagues, with real-world data over much longer treatment periods.
"Experts in health economics can apply rigorous formulae . . . to establish whether the promising data reported in these investigations are sustained, and whether the new biological agents are cost effective," Dr. Kremer said. "The answers are not yet entirely in."
Dr. Emery reported that he has served as a Wyeth consultant and has received Wyeth research grants. Other researchers served as Wyeth consultants or were Wyeth employees at the time of this trial. Dr. Kremer, the comment author, reported no conflicts of interest.
Primary source: The LancetSource reference:Emery P, et al "Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept on active, early, moderate to severe rheumatoid arthritis (COMET): a randomized, double-blind, parallel treatment trial" The Lancet 2008; DOI: 10.1016/S0140-6736(08)61000-4. Additional source: The LancetSource reference: Kremer J "COMET's path, and the new biologicals in rheumatoid arthritis" The Lancet 2008; DOI: 10.1016/S0140-6736(08)61001-6.

Biologic Therapy for Rheumatoid Arthritis Linked to Skin Cancer Risk

August 29, 2007 — Biologic therapy for rheumatoid arthritis (RA) was associated with an increased risk for skin cancer but not for other types of cancers, according to an observational study published in the August 29 Online First issue and in the September print issue of Arthritis & Rheumatism.
"Induction of malignancy is a major concern when rheumatoid arthritis (RA) is treated with biologic therapy," write Frederick Wolfe, MD, and Kaleb Michaud, PhD, from the University of Kansas School of Medicine in Wichita. "A meta-analysis of RA biologic clinical trials found a general increased risk of malignancy, but this risk was not found in a large observational study. We undertook this study to assess the risk of malignancy among biologic-treated patients in a large US observational database."
From 1998 to 2005, the authors studied incident cases of cancer in 13,001 patients who were observed for approximately 49,000 patient-years. Using the US National Cancer Institute Surveillance, Epidemiology, and End-Results (SEER) database, the investigators compared rates of cancer in the observational cohort vs those in the general population.
The risks for biologic therapy were evaluated with conditional logistic regression to calculate odds ratios (ORs) as estimates of the relative risk. Additional adjustments were made for 6 confounders: age, sex, educational level, smoking history, severity of RA, and use of prednisone.
Exposure to biologic therapy occurred in 49% of the study group. Incident cases of cancer included 623 cases of nonmelanotic skin cancer and 537 cases of other cancers.
Compared with the SEER data, the standardized incidence ratios were 1.0 for all cancers (95% confidence interval [CI], 1.0 - 1.1), 0.8 for breast cancer (95% CI, 0.6 - 0.9), 0.5 for colon cancer (95% CI, 0.4 - 0.6), 1.2 for lung cancer (95% CI, 1.0 - 1.4), and 1.7 for lymphoma (95% CI 1.3 - 2.2).
Although biologics were associated with an increased risk for nonmelanotic skin cancer (OR, 1.5; 95% CI, 1.2 - 1.8) and for melanoma (OR, 2.3; 95% CI, 0.9 - 5.4), no other cancer was associated with the use of biologic therapy. The overall risk for any cancer was 1.0 (95% CI, 0.8 - 1.2).
Limitations of the study include limited duration of biologic exposure; observational design; confounding by indication; and use of the National Death Index, which could have introduced possible bias.
"Biologic therapy is associated with increased risk for skin cancers, but not for solid tumors or lymphoproliferative malignancies," the study authors write. "These associations were consistent across different biologic therapies."
Abbott, Amgen, Bristol-Myers Squibb, Centocor, Merck, Pfizer, and Wyeth-Australia supported this study.
Arthr Rheum. Published online August 29, 2007.2007;56:2886-2895.

Hydroxychloroquine for Rheumatoid Arthritis Reduces Risk for Diabetes

July 10, 2007 — Hydroxychloroquine reduces the risk of developing diabetes mellitus, according to a prospective, multicenter observational study involving 4905 patients who were enrolled to collect data about the course of rheumatoid arthritis. This analysis, reported in the July 11 issue of the Journal of the American Medical Association, also found that the longer the patients took hydroxychloroquine, the lower their risk of diabetes.
The study began in 1976, when researchers enrolled patients diagnosed with rheumatoid arthritis who were aged 16 years or older into a longitudinal, observational study involving 7 outpatient rheumatology practices in North America. Follow-up continued at 6-month intervals into 2006 (for 21.5 years).
Of the 4905 patients included in this analysis, 1808 (37%) reported hydroxychloroquine use at some time during the observation period. Also during this time, researchers recorded incident diabetes in 54 patients who had taken hydroxychloroquine at some point vs 171 patients who had never taken the drug. This is an incidence rate of 5.2 per 1000 patient-years vs 8.9 per 1000 patient-years of observation, respectively (P < .001).
Overall, the hazard ratio for incident diabetes among patients who had taken hydroxychloroquine was 0.62% compared with those who had never taken it (95% confidence interval, 0.42 – 0.92). Poisson regression analysis revealed that the risk of incident diabetes was significantly reduced when the duration of hydroxychloroquine use was increased (P < .001). Among the 384 patients who took hydroxychloroquine for more than 4 years, the adjusted, relative risk of developing diabetes was 0.23 (95% confidence interval, 0.11 – 0.50; P < .001) compared with patients who had never taken the drug.
Although hydroxychloroquine is often used to treat malaria, it is also a "long-standing safe and inexpensive treatment for autoimmune diseases such as rheumatoid arthritis and system lupus erythematosus," write Mary Chester M. Wasko, MD, MSc, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pennsylvania, and colleagues. They note that in vitro and animal studies suggest that antimalarials improve insulin secretion and peripheral insulin sensitivity, and that in humans, hypoglycemia is a rare but known adverse effect of treatment.
The authors also write that their findings may occur in patients without rheumatoid arthritis because the beneficial changes in glucose metabolism and insulin sensitivity appear independent of a diagnosis of rheumatoid arthritis.
The authors conclude: "Further prospective studies are needed to determine whether this treatment option should be considered a standard component of rheumatoid arthritis combination therapy in the future, and to evaluate the potential role of hydroxychloroquine as a preventative agent for diabetes among high-risk individuals in the general population."
This study was funded by the Arthritis Foundation of Western Pennsylvania, the National Arthritis Foundation, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and an Intramural Research Program of the National Institutes of Health. Dr. Wasko has been a consultant to Centocor and has served as a coinvestigator for Merck. She has also received reimbursement as an investigator for Centocor, Aventis (ending in 2002), Roche, Human Genome Sciences, and Novartis. No other authors reported any relevant financial relationships.
JAMA. 2007;298(2):187–193.

Treatment of Rheumatoid Arthritis with Corticosteroids Linked to Lower Lymphoma Rates

June 15, 2007 (Barcelona) — Patients with rheumatoid arthritis (RA) who are treated on a long-term basis with corticosteroids are less likely to develop lymphoma, according to a team of Swedish investigators who presented their findings here at the annual European Congress of Rheumatology (EULAR).
"There are many patients who hesitate to use steroids because of their known side effects," said principal investigator Eva Baecklund, MD, from the department of rheumatology, Uppsala University Hospital, in Sweden, in her presentation. "This study adds a new, positive aspect to steroid treatment in RA." Dr. Baecklund noted that this finding is important because the incidence of lymphoma is increasing among patients with RA.
She and her coinvestigators wanted to know more about this beneficial link because their previous research had shown that treatment with corticosteroids was associated with a reduced risk for lymphoma. Therefore, in a case-control study nested within the Swedish Hospital Inpatient Register, they identified 424 cases of lymphoma among 74,651 RA patients, and 424 individually matched RA controls. The investigators identified the cases in the Swedish Cancer Register between 1965 and 1996. Dr. Baecklund and her team also collected clinical data, including inflammatory load and steroid treatment from the medical records of cases and controls, from which they identified all lymphomas. The final analysis consisted of 378 cases and 378 controls.
Among the patients, 183 cases (48%) and 217 controls (57%) received at least 4 weeks of treatment with oral corticosteroids for RA; 168 cases (44%) and 240 controls (63%) received intra-articular steroids at flares.
The investigators found that oral steroid treatment that lasted less than 2 years was not associated with an increase or decrease in the risk for lymphoma, with a relative risk (RR) of 0.9. However, among patients whose total treatment with corticosteroids lasted longer than 2 years, the RR was 0.4, a marked reduction.
Interestingly, the duration of RA at the time that oral steroid treatment first began did not change the protective effect of steroids on lymphoma risk. Among those who had had RA for less than 5 years at the time steroid treatment was begun, the RR was 0.6. For those who had lived with RA for at least 5 years, the RR was unchanged. The investigators found that the protective effect of steroids was more pronounced for diffuse large B-cell lymphomas, with an odds ratio (OR) of 0.7, compared with all other subtypes. The investigators found no association between steroid treatment and the presence of Epstein-Barr virus in the lymphomas. Therefore, concerns about the risk for lymphoma should not limit long-term treatment of RA patients with oral steroids, the investigators concluded.
This presentation spoke to the fact that there are many patients who do not tolerate disease-modifying anti-rheumatoid drugs and biological agents," said Tore Kvien, MD, president of EULAR and a professor of rheumatology at Diakonhjammet Hospital, in Oslo, Norway, in an interview with Medscape. "It's important to remember that corticosteroids have a beneficial effect." Dr. Kvien was not involved in the study.
"Lymphoma is not a common complication of RA but it is a known compilation," he said. "Knowing that steroids can reduce the risk is important. Reducing the inflammatory activity, a property of corticosteroid treatment, may have wide-ranging implications in the management of RA," he said.
EULAR 2007: Abstract OP0047. Presented June 14, 2007.

New Drugs Cool Rheumatoid Arthritis Flames

VIENNA, June 13 -- Three drugs, two approved and one in the pipeline, are improving care for patients with severe rheumatoid arthritis (RA) according to clinicians here.
The three agents -- rituximab (Rituxan), abatacept (Orencia), and toclizumab (Acterma) -- all reduce signs and symptoms of RA, improve physical function and health status, and slow joint damage progression, said Josef S. Smolen, M.D., of the Medical University of Vienna, and colleagues.
The heterogeneity of the disease is one of the reasons why no single therapy is effective for all patients or for one patient at all times, the authors wrote in a review article published in the online edition of The Lancet.
Disease-modifying anti-rheumatic drugs such as the anti-tumor necrosis factor (TNF) agents etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira), in combination with methotrexate, have significant anti-inflammatory and joint-protecting activity, they noted.
Yet, they noted, the combination of a TNF antagonist and methotrexate is better at protecting against radiographically confirmed progression of joint damage in patients with low disease activity than in patients with highly active disease.
To see if there might be relief for those patients, the investigators reviewed the action, efficacy, and safety of the three newer agents, each of which has a mechanism of action different from that of established anti-arthritis agents.
Rituximab, an anti-CD20 antibody with proven efficacy in the treatment of both rheumatoid arthritis and B-cell non-Hodgkin's lymphoma, is approved in the U.S. and Europe for treatment of rheumatoid arthritis in patients who have failed TNF-inhibitor therapy.
"The rationale for use of rituximab in treatment of this disease comes from the fact that B cells have several functions in disease pathogenesis, including antigen presentation and (auto)antibody and cytokine production," the investigators wrote. "Although rituximab leads to considerable reduction of concentrations of rheumatoid factor, the mechanism of action in rheumatoid arthritis is not clear."
In clinical trials, rituximab was associated with reduction in rheumatoid arthritis symptoms by more than 50% for more than a third of patients. Although the drug rapidly depleted B cells in all clinical trials, with an effect lasting for more than six months in most cases, the disease flares up again as B cells repopulate, and retreatment is necessary to maintain efficacy, the authors noted.
Abatacept is approved in the U.S. for treatment of rheumatoid arthritis patients who have failed all other types of disease-modifying drugs, and in Europe for patients who have failed other disease-modifying drugs, including the TNF inhibitors.
It is a recombinant fusion protein that interferes with T-cell activation by binding to CD28 and competing with this receptor for CD80 and CD86.
In a phase III trial of abatacept 10 mg/kg IV in patients on methotrexate, 68% of 433 patients had a 20% improvement from baseline at six months in American College of Rheumatology criteria (ACR20), 40% had ACR50, and 20% had ACR70 responses, all of which were significantly higher than the responses among the 219 patients who received placebo (P<0.001).
In a second phase III trial, 393 patients with active rheumatoid arthritis and an inadequate response to TNF inhibitors received abatacept (10 mg/kg) or placebo until day 141.
The patients had stopped taking etanercept at least 28 days before, or infliximab at least 60 days before enrollment and had to be stable on disease-modifying antirheumatic drugs, with 75% to 82% continuing methotrexate treatment (about 15 mg a week). These patients also had significantly higher ACR20, 50, and 70 response rates (P<0.001) starting at the second treatment week.
Toclizumab is a humanized anti-interleukin 6 receptor agent that blocks the action of the inflammatory cytokine. The drug is in phase III trials worldwide, and is licensed in Japan as an orphan drug for treatment of Castleman's disease.
In a phase II European trial of toclizumab, 61% of patients had an ACR20 response, 43% had an ACR50 response, and 16% had an ACR70 response at a dose of 8 mg/kg.
"Abatacept, rituximab, and tocilizumab all achieved better clinical results in combination with methotrexate than when used as monotherapy," the authors wrote.
"These findings are in line with similar observations for TNF blockers, which indicated that methotrexate monotherapy has similar clinical effectiveness to monotherapy with TNF inhibitors," they said, "lending support to the pivotal role of methotrexate in general and in combination with biological agents in particular."
The investigators recommended aiming for remission in patients with rheumatoid arthritis, starting with a traditional disease-modifying antirheumatic drug, usually methotrexate.
"At the present time, in patients who continue to show high or moderate disease activity, adding or switching disease-modifying therapy- including addition of a TNF blocker-is typically considered," the authors wrote.
"If active disease prevails despite anti-TNF treatment," they said, "rituximab or abatacept constitute novel alternatives, although abatacept could be administered before use of a TNF inhibitor (such practice is not currently licensed in Europe). The minimum therapeutic aim is low disease activity, but remission should constitute the ultimate goal."
Dr. Smolen has consulted with or conducted clinical trials for Abbott, Amgen/Wyeth, Bristol-Myers Squibb, Centocor/Schering Plough, Human Genome Sciences, Roche, Sanofi-Aventis, and UCB, and receives research funding from Bristol-Myers Squibb, Centocor, and Roche. His co-authors have also provided consulting services and/or conducted research for TAP Pharmaceutical Products, Rigel, Vertex Pharmaceuticals, Bio-Rad Laboratories, and Pfizer. Primary source: The Lancet OnlineSource reference: Smolen JS et al. "New therapies for treatment of rheumatoid arthritis." DOI:10.1016/S0140-6736(07)60784-3

Dose Escalation of Infliximab Is Helpful in Active Rheumatoid Arthritis

In patients with active rheumatoid arthritis (RA), dose escalation of infliximab is associated with more than 20% improvement in tender and swollen joint count, according to the results of a study published in the June 1 Online First issue of the Annals of the Rheumatic Diseases.
"The recommended dosage of infliximab for RA is an induction regimen of 3 mg/kg followed by maintenance dosing every 8 weeks," write Mahboob U. Rahman, and colleagues. "For patients with an incomplete response to 3 mg/kg infliximab, the product labelling for the United States allows for increasing the dose up to 10 mg/kg or reducing the interval between infusions to 4 weeks. Recent retrospective studies of governmental and private medical insurance databases, registries and medical records indicate that dose escalation of infliximab in patients with an inadequate response is not uncommon in actual clinical practice."
In 1 of the 3 groups of the Safety Trial for Rheumatoid Arthritis with Remicade Therapy (START), patients with RA that was still active after treatment with methotrexate received 3 mg/kg of infliximab at weeks 0, 2, 6, and 14. Beginning at week 22, the infliximab dose was increased in a double-blind fashion in increments of 1.5 mg/kg if the total tender and swollen joint count did not improve by at least 20% from baseline (criterion for lack of response) or if the improvement at week 22 or later worsened by 50% or more (criterion for flare).
Of the 329 patients eligible for dose escalation, 100 (30.4%) required dose escalation at or after week 22 because of flare or lack of response. After their last dose escalation, most patients (80%) who received up to 3 dose escalations had more than 20% improvement in the total tender and swollen joint count. Compared with patients who did not require dose escalations, those who did generally had lower preinfusion serum infliximab concentrations. Rates of adverse events and serious adverse events were similar for the patients who received dose escalation(s) compared with those who did not receive dose escalation.
Study limitations include lack of data on Clinical Disease Activity Index scores and 1-year study duration.
"Fewer than one-third of patients required a dose escalation," the authors write. "The majority of patients showed improvement after receiving increased doses of infliximab, without an increased risk of adverse events."
Centocor Research and Development Inc funded this study and employs 4 of its authors. Some other authors have disclosed various financial relationships with Johnson and Johnson, Inc, Schering-Plough Belgium, Bristol-Myers Squibb, Abbott, Centocor, and/or Genentech.
Ann Rheum Dis. Published online June 1, 2007.

Researchers Detect Variations in DNA That Underlie Seven Common Diseases

Applying a new genomic technique to a large group of patients, researchers in Britain have detected DNA variations that underlie seven common diseases, discovering unexpected links between them.
The variations pinpoint biological pathways underlying each of the diseases, and researchers hope that as the pathways are analyzed, new drugs and treatments will emerge.
The seven common diseases are bipolar disorder, coronary artery disease, Crohn’s disease, hypertension, rheumatoid arthritis, and Type 1 and Type 2 diabetes.
Unveiling the complex genetics of common diseases was the promised payoff of the $3 billion human genome project, completed in 2003, but progress was slow until the recent development of devices that in a single operation can read the DNA sequence at up to 500,000 points across an individual’s genome. With the devices, called chips, researchers can compare large numbers of patients with healthy individuals, looking for points of differences in their genomes that may be associated with disease.
The approach is known as whole genome association, and studies on Type 2 diabetes, heart disease and breast cancer have been reported within the last few weeks. Those and the new study, which was financed by the Wellcome Trust of London, demonstrate the power and reliability of the whole genome association method, which stands in contrast to the many uncorroborated claims of disease genes made previously.
“It’s now absolutely clear that this is a new dawn in the genetics of common human diseases,” said Peter Donnelly, a statistical geneticist at Oxford University who was chairman of the consortium of 50 institutions involved in the Wellcome Trust study.
The consortium compared 2,000 patients with each disease from across Britain with 3,000 healthy individuals as controls, half of whom were born in a single week in 1958. The consortium’s findings are published in today’s Nature, along with reports from two groups that largely confirm the consortium’s genomic hits in independent patient groups suffering from Crohn’s disease and Type 1 diabetes.
The consortium discovered some 24 variants strongly linked to disease, about half of which have been found already by other groups and half of which are new.
Among its most interesting findings is that genetic variants close to a gene known as PTPN2 are associated with both Crohn’s disease and Type 1 diabetes. The link may be that both are autoimmune diseases and that the gene helps regulate the immune system. Researchers hope that analysis of the gene’s operations may produce a treatment for the two diseases.
The consortium also found a genetic variant on chromosome 7 that carries a high risk of rheumatoid arthritis for women, but none for men. Very few such variants are known in diseases common to both sexes, Dr. Donnelly said.
Anne Bowcock, a geneticist at the Washington University School of Medicine in St. Louis, said the Wellcome Trust study was a “tour de force” that established how large-scale studies should be conducted.
Marie Nierras, an official of the Juvenile Diabetes Research Foundation, which supported the companion study of Type 1 diabetes, said the research was “a significant advance that identifies additional pathways that need to be looked at.”
Dr. Kari Stefansson, chief executive of DeCode Genetics, an Icelandic company that has dominated the search for common disease genes until the arrival of the whole genome association method, said the Wellcome Trust study was “a large body of work, done by very good people” but that it “hadn’t come up with any big discovery.”
Dr. Stefansson said the study had been delayed because of problems with the Affymetrix chip it used, and would have had greater impact in the fast-moving field if it had appeared several months earlier.
In the course of screening for any geographically related genetic bias, the Wellcome Trust researchers discovered a southeast-to-northwest gradient across Britain composed of 13 genes. The genes were probably under natural selection in the people who became the island’s first inhabitants.
One of the genes, which arose among Europe’s first cattle herders 5,000 years ago, enables people to drink milk in adulthood, an ability known as lactose tolerance. The other genes, the researchers speculate, may confer resistance to former scourges like pellagra, tuberculosis and leprosy.
Another possible source of statistical bias relates to race. The Wellcome Trust consortium asked their 17,000 subjects to identify their race, then genetically tested them and excluded 153 people who had non-European ancestry. The procedure is necessary because whole genome association studies look for small differences between patients and controls, which can be confounded by the genetic differences between races.
The Wellcome Trust’s findings apply to populations of European descent and need to be verified in other races. Geneticists do not yet know what proportion of the genetic variants associated with common disease will be found in all races, but hope the overall biology will be much the same.
“The genetics gives us a whole new foothold into the biology of disease,” Dr. Donnelly said. “If you find a variant in one population you might learn a lot about that disease which is relevant to the disease in other populations.”
Because whole genome association studies work only in people of a single race, researchers are concerned that follow-up studies should then be done in other races. “I think everyone is committed to make sure that is the case,” said Mark Daly, a geneticist at Massachusetts General Hospital.