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Plenty for rheumatologists in NEJM this week: A deadly vasculitis, Phase 2 results for a new psoriatic arthritis drug, and a solution for constipation with opioids.
The latest New England Journal of Medicine is information-rich for rheumatologists, offering :
1. a case study about a deadly vasculitis,
2. interim results for a new biologic for psoriatic arthritis, and
3. a solution for a vexsome side effect of opioid treatment.
Burgin S, Stone JH, Shenoy-Bhangle AS, et al. Case 18-2014 - A 32-Year-Old Man with a Rash, Myalgia, and Weakness. N Engl J Med (2014) 370:2327-2337 doi: 10.1056/NEJMcpc1304161
Fazio S Rash, Myalgia, and Weakness. Now@NEJM, June 13th, 2014
Malignant atrophic papulosis, or Degos’s disease, is a small-vessel vasculopathy that arises in association withsystemic lupus erythematosus, as well as progressive systemic sclerosis, rheumatoid arthritis, discoid lupus, and dermatomyositis. There is a benign, skin-limited form, but most reported cases are systemic. There is no known effective therapy. In this case, a young patient died.
Skin findings usually precede gastrointestinal (GI) and central nervous system involvement by weeks to years. GI symptoms may signal the transition to the systemic form, where GI infarct and bowel perforation are a common cause of death, as in this case.
The 32-year-old man initially presented with dermatomyosis. He was admitted initially for muscle pain, weakness, and respiratory failure, and he had a violaceous rash. Gottron’s papules indicated dermatomyositis.
Despite treatment with prednisone, azathioprine, rituximab, and intravenous immunoglobulin, the weakness (perhaps a response to corticosteroids) progressed until he was unable to lift his arms, legs or head. Worsening respiratory distress mandated intubation. Two bleeding gastric ulcers were cauterized.
Six months later, new erythematous macules and papules appeared on his torso, extremities and face, indicating Degos’s disease, which was confirmed by skin biopsy.
There is some evidence that Degos’s disease involves interferon-Î± and complement C5b-C9 (the membrane attack complex) injuring vascular epithelial cells. In this patient, muscle biopsies showed staining for C5b-C9 in the capillaries. On that basis, the physicians administered eculizumab, a monoclonal antibody directed against C5, with equivocal results.
The patient returned with diffuse abdominal pain. Computed tomography and biopsy indicated bowel wall edema and thickening, with ischemic colitis but without infarction. Upper GI hemorrhage followed quickly, as well as hypertension, shock, and eventual death.
Autopsy revealed the source of hemorrhage in the lower esophagus and widespread obliterative vasculopathy of the GI tract. It also confirmed dermatomyositis.
Mease PJ, Genovese MC, Greenwald MW, et al.Brodalumab, an Anti-IL17RA Monoclonal Antibody, in Psoriatic Arthritis. N Engl J Med (2014) 370:2295-2306. doi: 10.1056/NEJMoa1315231
In a phase 2 randomized trial, brodalumab, a human monoclonal antibody against interleukin-17 (IL-17) receptor A, improved response rates of patients with psoriatic arthritis. Larger, longer studies will be necessary to assess adverse events.
One hundred and sixty-eight patients were randomized to brodalumab 140 mg, brodalumab 280 mg, or placebo, with a primary outcome of 20% improvement in the American College of Rheumatology criteria (ACR20) at 12 weeks. Thirty-seven and 39% of the patients in the 140 mg and 280 mg group, respectively, met the primary outcome, versus 18% in the placebo group.
Fourteen percent of the brodalumab groups met the secondary outcome, ACR50, versus 4% placebo.
An open-label study beginning at week 12 offered the remaining patients the chance to take brodalumab 280 mg for an additional 12 weeks. At week 24, 51% and 64% of the patients originally in the 140 mg and 280 mg group, respectively, met the primary outcome, versus 18% who had originally been in the placebo group. Outcomes were sustained or continued to improve through week 52, although the open-label part of the trial must be interpreted cautiously.
Previous studies of anti-IL-17 treatments have noted neutropenia and leucopenia, but these investigators did not observe them. However, 10 patients, including one in the placebo group, reported serious adverse events.
Genome-wide studies have found susceptibility to psoriatic arthritis associated with genetic loci involving IL-17, and IL-17 receptor A is elevated in synovial fluid and psoriatic plaques of patients with psoriatic arthritis. Many agents are being evaluated targeting IL-17 signaling, but brodalumab targets the IL-17 receptor, and has a broader spectrum of inhibition. Brodalimumab has shown effectiveness against psoriatic arthritis and other spondyloarthritidies, but not against rheumatoid arthritis or Crohn’s, which gives further evidence that those diseases have different causal mechanisms.
Chey WD, Webster L, Sostek M, et al. Naloxegol for Opioid-Induced Constipation in Patients with Noncancer Pain. N Engl J Med (2014) online first. June 4. doi: 10.1056/NEJMoa1310246
In non-cancer patients with constipation from opioid drugs, naloxegol relieved constipation while maintaining opioid analgesia in a study primarily involving patients taking opioids for back pain, arthritis, fibromyalgia, and other musculoskeletal problems.
About 40-50% of the patients on a sufficient dose of naloxegol had an increased number of bowel movements, compared to about 30% in the placebo group, in a phase 3 study. This included patients who already had an inadequate response to laxatives.
Naloxegol is a pegylated derivative of the Î¼-opioid receptor antagonist naloxone. Pegylation limits the ability of naloxegol to cross the blood-brain barrier, and therefore limits its function to the GI tract, preserving centrally mediated analgesia.
Two other peripherally-acting Î¼-opioid receptor antagonists are available, but methylnaltrexone must be administered subcutaneously, and alvimopan is approved only for postoperative ileus.
This report includes two identical phase 3 studies, with a total of 1,352 participants who had been taking an oral opioid at a stable daily dose of 30-1,000 mg morphine or equivalent for 4 weeks or longer. By design, ≥50% had an inadequate response to laxatives. The primary end point was the 12-week response rate of ≥3 spontaneous bowel movements per week and an increase from baseline of ≥1 to ≥3 spontaneous bowel movements.