• Psoriatic Arthritis - Basic Science
• Ankylosing Spondylitis - Treatment

Abstract 1637 Osteoclast Precursors are Markedly Increased in the Peripheral Blood of Psoriatic Arthritis Patients. C Ritchlin, SA Hass-Smith, E Schwarz.

Large erosions of bone and osteopenia are characteristic of the joint destruction seen with psoriatic arthritis (PsA). Increased osteoclasts have been demonstrated at the sites of bone resorption in PsA compared with samples of osteoarthritic bone. This study demonstrates an expansion of osteoclast (OC) precursors in the circulation of PsA patients, greater bone resorption in vitro by OC isolated from PsA patients, a possible osteoclastogenic factor in the circulation of PsA patients and a decrease in OC precursors in PsA patients treated with Enbrel.

Peripheral blood mononuclear cells (PBMC) were isolated from 19 PsA patients and 5 healthy controls. OC precursors were identified by >3 nuclei per cell and positive tartrate resistant alkaline phosphatase (TRAP) staining. The geometric mean of OC in PsA patients was 108*/2.7 OC per 106 PBMC compared with 3.1*/4.8 OC per 106 PBMC from controls. PBMC from PsA patients formed deeper resorptive pits on bone wafers compared with PBMC from controls. Supernatants from PsA PBMC when added to PBMC from controls increased the number of OC and their capacity to form resorptive pits on bone wafers. OC decreased in the circulation of 3 PsA patients after treatment with Enbrel.

Editorial comment: This study brings us closer to elucidating the mechanisms of bone erosion and osteopenia seen in PsA patients as well as in other types of inflammatory arthritis such as rheumatoid arthritis. Particularly exciting is the potential for the identification of a circulating factor that stimulates OC production and resorptive activity. If such a factor could be identified, then levels of the factor would provide a quantitative assessment of the degree of ongoing joint damage and an inhibitor of the factor would be a useful therapeutic agents to prevent joint erosions.

Pamidronate
Infliximab
Etanercept

Pamidronate
(reviews by Joan Bathon, M.D. and Andrew Bilderback)
Abstract 642 A 6 Month, Randomized, Controlled, Double-Blinded Dose Response Comparison of Intravenous Pamidronate (60mg vs 10mg) in the Treatment of NSAID-Refractory Ankylosing Spondylitis (AS)
J Colford, H Krug Minneapolis, MN.

Background: Histopathology of sacroiliac joints in ankylosing spondylitis often shows subchondral marrow inflammation. Bisphosponates are commonly used as inhibitors of bone resorption. However, being synthetic analogs of pyrophosphates, bisphosphonates may suppress the generation of proinflammatory cytokines such as IL-1, TNF-a, and macrophages. Bisphosphonates may also suppress the chronic inflammatory response associated with cutaneous granuloma formation.

In this study, 84 ankylosing spondylitis patients (mean age 39.6 years, mean disease duration 14 years) who had had a suboptimal response to NSAID therapy were randomly allocated to receive either a 60mg or a 10mg dose of intravenous pamidronate for 6 months. The study was double-blinded, controlled, and the groups were well matched at baseline. Patients were followed up at -2, 0, 12, and 24 weeks and analysis was by intention-to-treat.

Results: After six months, a >25% reduction in Bath AS Disease Activity Index (BASDAI) scores were observed in a significantly larger proportion of patients in the 60mg group as compared to the 10mg group (63.4% vs 30.2%; p=0.004). A 50% reduction in the BASDAI was observed for 40% of the 60mg group. Larger significant reductions were also observed in the 60mg group as compared to the 10mg group for the Bath Functional AS Index (BFASI), and the Global (BASGI), and Metrology (BASMI) indices. No significant reductions were observed in ESR and CRP measurements.

Conclusion: Pamidronate has a dose-dependent therapeutic effect in AS.

Editorial Comment: There is additional scientific rationale for the exploration of bisphosphonates is AS. These drugs, as sythetic analogs of pyrophosphates, may interfere with the process of calcification of entheses that occurs in AS. This study was too short in duration to measure this effect and a methodology for evaluation such an outcome remains to be discerned. The fact that ESR and CRP levels were not lowered suggests that the primary pathophysiological process in this disease was not altered by pamidronate.

Abstract 643 Lack Of Efficacy Of Pamidronate in Preventing Disease Progression in Murine Progressive Ankylosis
J Colford, H Krug Minneapolis, MN.

Background: Clinically similar to the human spondyloarthropies (SPA), Progressive Ankylosis (MPA) is a mouse analog of the disease characterized by progressive ankylosis of the joints. The genetic basis of MPA is a recessive mutation in the ank gene which encodes for a cell membrane protein that regulates extracellular inorganic pyrophosphate levels, thereby regulating mineralization. Phosphocitrate (PC) is a pyrophosphate analog and is known to delay progression of ankylosis in MPA. Bisphosphonates are also pyrophosphate analogs and can inhibit matrix vesicle induced calcification. This study tested the bisphosphonate pamidronate for efficacy in delaying the progression of ankylosis in MPA.

Overview of Study: Thirty homozygous ank/ank mice were randomly allocated to 1 of 4 treatments; saline, PC (70 mg/kg/day), low dose (0.16 mM/kg/day) pamidronate, or high dose (16 mM/kg/day) pamidronate. Treatment was begun at the time of weaning and was continued for 45 days. Clinical evaluations occurred during the treatment period and radiographic and histological studies were done on completion of the study to evaluate efficacy.

Results: Clinical examinations showed significant delay in the progression of ankylosis in the PC treated animals as compared to those treated with saline. Mice treated with either low dose or high dose pamidronate showed no difference in the progression of ankylosis as compared to saline. Radiography and histology revealed that new bone formation and ankylosis were less severe in the PC treated mice than in the saline controls. Again, there was no difference between the pamidronate groups and the control group.

Conclusion: Phosphocitrate was effective, but pamidronate was not effective in delaying progression of ankylosis in MPA.

Editorial Comments: These studies suggest that phospocitrate, or an analog, could be useful in humans to delay the progression of ankylosis of entheses in ankylosing spondylitis (A.S.). Pamidronate was not efficacious. THis is interesting since studies in humans demonstrated improvement in clinical symptoms of A.S. with pamidronate, although radiographs were not examined. More studies with other bisphosphonates wil be necessary.

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Infliximab
Abstract 223 TNF Blockage with Infliximab in Patients with Active Spondyloarthropathy: Follow-up One Year Maintenance Regimen.
E Kruithof, F Van den Bosch, D Baeten, F De Keyser, H Mielants, EM Veys.

A previous study by the authors (Ann Rheum Dis 2000;59:428-33) demonstrated the effectiveness of infliximab 5 mg/kg infused at weeks 0, 2, 6 in over a 12 week period for active ankylosing spondylitis. In this study 19/21 patients involved in the previous study completed 1 year of infliximab maintenace infusions 5 mg/kg every 14 weeks. All of patients had sustained significant decrease in global, peripheral and axial manifestations. Adverse events included 17 minor events (infusion related, nausea, palpitations), 12 infectious (URI-8, otitis-1, vaginal candiasis -1, pyleo-1, dental abscess-1). ANA were seen in 57%, anti-dsDNA in19%, but no SLE symptoms.

Editorial Comment: These results demonstrate that infliximab therapy is efficacious and well tolerated after one year. The choice of maintenance regimen of infusions every 14 weeks (versus every 8 weeks as FDA approved for RA) is interesting and one wonders if greater efficacy might be seen by shortening the dosing intervals. Nonetheless, these are encouraging results.

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Etanercept
Abstract 224 An Open Label Trial of Etanercept in the Treatment of Ankylosing Spondylitis.
JD Gorman, KE Sack, JC Davis.

Similar to abstract 223, the authors present information on 20 patients who have completed a 6 month open label trial of etanercept. All of the patients completed a previous 3 month blinded study and were refractory to other therapies. Primary outcome measures included noctural spinal pain, global assessment, morning stiffness, Bath Functional Index swollen joints. A composite response score required a 20% improvement in 3 of 5 outcome measures with worsening of none. Of the patients, 95% reached a 20% response in the composite criteria, with 65% of patients reaching a 50% response and 45% of patients reaching a 75% response. Etanercept was well tolerated.

Editorial Comment: Although these trials (abstracts 223, 224) are small, they are making a strong case for the role of TNF inhibitors in the treatment of ankylosing spondylitis. These agents clearly improve symptoms and disability. Whether they are disease modifying remains a yet unanswered question.

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