VBCR - December 2012, Volume 1, No 6 - Rheumatology Update

By Wayne Kuznar

Washington, DC—Over the past year, several publications in the peer-reviewed literature were worthy of influencing clinical practice. At the 2012 meeting of the American College of Rheumatology (ACR), David A. Isenberg, MD, FRCP, FAMS, Arthritis Research Campaign’s Diamond Jubilee Professor of Rheumatology, University College London, discussed a handful of articles with the most impact from each of 5 clinical areas: trials, observations, treatment studies (not clinical trials), translational medicine, and quirky reports. This article includes the first 3 categories; a separate article will cover translational medicine and quirky reports.

Clinical Trials
Tofacitinib (Xeljanz) 5 mg and 10 mg twice daily and adalimumab (Humira) 4 mg every 2 weeks were significantly better than placebo on the primary end point of an ACR 20% improvement criteria (ACR20) response at 6 months in a randomized study of 717 patients with rheumatoid arthritis (RA) on stable doses of methotrexate (Rheumatrex; van Vollenhoven RF, et al. N Engl J Med. 2012;367:508-519). Six-month ACR20 responses occurred in 51.5% (5 mg) and 52.6% (10 mg) of the tofacitinib groups, 47.2% of the adalimumab group, and 28.3% of the placebo group. There also were improvements in the Health Assessment Questionnaire (HAQ) at 3 months and the 28-joint Disease Activity Score (DAS28) at 6 months in the treatment groups versus placebo. Tofacitinib had a tendency to increase levels of both low-density lipoprotein cholesterol and high-density lipoprotein cholesterol.

In a 6-month, double-blind, randomized controlled trial comparing methotrexate 15 mg weekly and placebo in patients with active psoriatic arthritis (PsA; Kingsley GH, et al. Rheumatology. 2012;51:1368-1377), there was no evidence that methotrexate improved synovitis clinically or serologically. Methotrexate did improve assessors’ and patients’ global assessment scores and had a positive effect on psoriasis skin scores. The findings “challenge us to ask the very important question: Should methotrexate continue to be used as an effective control of synovitis in patients with PsA?” Dr Isenberg said.

In patients with moderate-to-severe RA who had an inadequate response to disease-modifying antirheumatic drugs, tocilizumab (Actemra) 8 mg/kg every 4 weeks produced an ACR 50% improvement criteria response of 30.1% and an ACR20 response of 44% at 24 weeks, which were both significantly superior to placebo (Yazici Y, et al. Ann Rheum Dis. 2012;71:198-205). The rates of serious infection were 7.87 per 100 patient-years in the tocilizumab group versus 1.2 per 100 patient-years in the placebo group.

A 2-year follow-up study comparing 2 dosages of rituximab (Rituxan; either 500 mg intravenously × 2 plus methotrexate or 1 g × 2 plus methotrexate) versus placebo plus methotrexate in 755 patients found no radiologic progression of disease in 57% of the high-dose rituximab group versus 37% of the placebo group (Tak PP, et al. Ann Rheum Dis. 2012;71:351-357). The results with the lower rituximab dosage were less clear-cut.

A pooled univariate and multivariate analysis showed superior systemic lupus erythematosus Responder Index rates at week 52 with belimumab (Benlysta; 1 mg/kg and 10 mg/kg) versus placebo in patients with low-complement, anti–double-stranded DNA positivity (van Vollenhoven RF, et al. Ann Rheum Dis. 2012;71:1343-1349). Belimumab was also beneficial in this group in regard to secondary end points (eg, severe flares, steroid use). “It seems like if we select appropriate patients, we will get much better responses with belimu­mab,” Dr Isenberg said.

Clinical Observations
In 2 North American cohorts of patients with Takayasu’s arteritis (TAK) or giant-cell arteritis (GCA), patients with TAK had more left carotid and mesenteric artery diseases, whereas those with GCA had more left and right auxiliary artery diseases (Grayson PC, et al. Ann Rheum Dis. 2012;71:1329-1334). Of the total patients, 56% were classified in a subgroup with little difference, which suggests that TAK and GCA may exist on a spectrum within the same disease.

Of 813 patients with RA who were followed for a mean of 9.6 years, venous thromboembolic events were more than twice as common in patients with RA versus controls, whereas there were no significant increases in the rates of cerebrovascular and peripheral arterial events in patients with RA (Bacani AK, et al. Arthritis Rheum. 2012;64:53-61).

Schreiber and colleagues assessed 386 patients with systemic sclerosis, comparing an easily applied formula to determine pulmonary function against data from right heart catheterization (Schreiber BE, et al. Arthritis Rheum. 2011;63:3531-3539). The formula, which incorporates mean pulmonary artery pressure, oxygen saturation, and diffusing capacity for carbon monoxide, can identify subgroups with low, average, or high prevalence of pulmonary hypertension, and thus should improve the selection of patients for right heart catheterization.

In comparing 611 patients with PsA and 449 patients with psoriasis, the rates of hypertension, obesity, hyperlipidemia, type 2 diabetes, and admission to an intensive care unit were all significantly higher in the patients with inflammatory joint disease (Husted JA, et al. Arthritis Care Res [Hoboken]. 2011;63:1729-1735).

A comprehensive review of several databases found no overall increase in the risk of malignancy with long­er exposure to tumor necrosis factor (TNF)-alpha blockers, with the sole exception of a small increase in skin cancer (Mariette X, et al. Ann Rheum Dis. 2011;70:1895-1904).

Treatment Studies
(Not Clinical Trials)
Emery and colleagues studied 493 patients with an inadequate response to methotrexate and randomized them to 1 of 2 treatment strategies: a treat-to-target strategy in which assessments were made 24 weeks after each course of rituximab, with retreatment if the patient was not in remission; or retreatment at the physician’s discretion at least 24 weeks after the first course and 16 weeks after later courses (Emery P, et al. Rheumatology [Oxford]. 2011;50:2223-2232). The treat-to-target strategy was associated with significant improvement in the DAS28 and with lower HAQ Disability Index scores. It also resulted in significantly more patients achieving a major clinical response and in a reduction in the incidence of RA flares.

In a prospective study of 1991 pa­tients receiving total knee replacement, the strongest determinants of achieving a favorable 6-month postoperative Oxford Knee Score were preoperative pain or function, the diagnosis of RA rather than osteoarthritis, deprivation (those in poorer areas did worse), and anxiety or depression (Judge A, et al. Rheumatology [Oxford]. 2012;51:1804-1813). Body mass index was not an important predictor.

A retrospective case-control study of 54 cases of allopurinol (Zyloprim) hypersensitivity syndrome and 157 controls (ie, patients with gout and allopurinol hypersensitivity syndrome) found an increased risk of allopurinol hypersensitivity syndrome as the starting dosage of allopurinol increased (Stamp LK, et al. Arthritis Rheum. 2012;64:2529-2536). “The key point is that you need to start allopurinol rather cautiously if you want to avoid this syndrome,” Dr Isenberg said. “With normal kidney function, it is okay to start at 100 to 150 mg per day; with moderate chronic kidney disease, start with 50 mg per day; and for severe kidney disease, start with 50 mg per day on alternative days.”

In a population-based study looking at risk factors for progressive multifocal leukoencephalopathy (PML) among >2 million patients with rheumatic diseases, 53 patients with PML were identified (Bharat A, et al. Arthritis Care Res [Hoboken]. 2012;64:612-615). Most of the patients with PML were positive for HIV and/or cancer; 9 had received biologic drugs before a hospitalization for PML. The incidence of PML was very low (0.2 cases per 100,000 patients) among patients with rheumatic diseases in the absence of HIV and/or cancer.

Soliman and colleagues looked at the British Society for Rheumatology’s biologic resister of 18,194 patients with RA in whom a first TNF-alpha blocking drug had failed (Soliman MM, et al. Arthritis Care Res [Hoboken]. 2012;64:1108-1115). Of these, 5338 patients switched from their first TNF-alpha blocker; 4158 of whom switched to a second TNF-alpha blocker and 1180 of whom switched to rituximab. Both the European League Against Rheumatism response and clinically important improvement in HAQ scores were superior in those patients who switched to rituximab rather than another TNF-alpha blocker.

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