Surfactant treatment for osteoarthritis

P. Vecchio1, R. Thomas2 and B. A. Hills2,3

1 Rheumatology Department, Princess Alexandra Hospital,
2 Department of Medicine, University of Queensland, and
3 Paediatric Respiratory Research Centre, Mater Children's Hospital, Brisbane, Australia

Correspondence to: B. A. Hills, Paediatric Respiratory Research Centre, Mater Children's Hospital, South Brisbane, Queensland 4101, Australia.

SIR, Much scientific and clinical data have been collected [1, 2] to support the theory [3, 4] that the vital load-bearing boundary lubricant in the joint is surface-active phospholipid (SAPL). Oligolamellar layers of SAPL adsorbed to the articular surface have been observed by electron microscopy [4] to be the outermost hydrophobic layer which imparts superb lubrication, reducing wear and lowering friction to physiological levels that are extremely low by engineering criteria. SAPL is also an effective release agent capable of inhibiting articular gelling/fusion implicated in stiffness [5].

Articular surfaces from hips and knees removed at joint replacement surgery in patients with osteoarthritis (OA) were found to be appreciably deficient in SAPL [6], raising the possibility that the introduction of exogenous SAPL to osteoarthritic joints might arrest or even reverse joint degeneration. Administration of exogenous SAPL to the lungs (`surfactant rescue') of neonates with the respiratory distress syndrome (RDS) is now a well-established clinical modality [7].

Preliminary studies in vitro clearly demonstrated that oligolamellar layers of SAPL, very similar to those found on sliding surfaces in vivo [3, 4], could be formed on the surface of agar gel by administration of SAPL as a solution in propylene glycol (PG). PG is approved by the Food and Drug Administration (FDA) as a lipid vehicle for i.m. and i.v. injectates, and is miscible in all proportions with dipalmitoyl phosphatidylcholine (DPPC), which is the surface-active component of lung surfactant [7]. To investigate the possibility of an inflammatory reaction in vivo, various DPPC solutions in PG were injected intra-articularly (i.a.) and found to produce no overt symptoms in ovine or equine joints. Moreover, synovial fluid (SF) markers of inflammation, including alkaline phosphatase (ALP), neutrophil count, density and protein, changed less after DPPC than after prilocaine administration in five horses.

In this study, we report the effects of a single injection of SAPL into one knee of 10 patients (six male, four female) with bilateral moderate–severe OA. With permission from the ethics committee of the Princess Alexandra Hospital, Brisbane, each test joint was injected i.a. with an autoclaved solution of 400 mg of L-{alpha}-DPPC (Sigma, St Louis, MO, USA) dissolved in 2 ml of PG (clinical grade) via a sterile medial approach after aspiration of the joint to dryness. All patients underwent a clinical assessment pre-treatment and 1, 2, 4, 6, 10 and 14 weeks post-injection, in which the Lequesne index [8] and WOMAC scores for pain, stiffness and disability [9] were recorded.

Five patients experienced discomfort or transient pain upon injection, while one developed an effusion which resolved upon aspiration with no re-accumulation over 2 months, nor deterioration in clinical state. Synovial fluid analysis revealed an inflammatory cell count and non-wax, non-pyrophosphate crystalline debris. He was not assessed further. In each of the remaining nine patients, all four scores decreased within 2–4 weeks of treatment, lasting several weeks in all but one (#8 in Fig. 1Go). Mean values for all nine patients are plotted in Fig. 2Go for pain, disability and stiffness. Using each patient as his/her own control, statistical analysis using the paired t-test shows significant improvement in all four scores for at least one assessment time. The reduction in pain was highly significant (P<0.0086) for the whole period of monitoring post-injection.



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FIG. 1.  The average improvement for each of nine individuals relative to baseline for all four scores: Lequesne and WOMAC for stiffness, pain and disability. Note that only one patient (#8) did not maintain her initial improvement, while at least five patients displayed 60% improvement lasting several weeks.

 


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FIG. 2.  Values recorded pre-treatment and post-treatment for the Lequesne index [8] and WOMAC scores for stiffness, pain and disability [9] shown as the mean for nine patients administered a single injection of SAPL. Note how each mean reaches a peak improvement from 2 to 6 weeks and then recedes, but has not returned to baseline by 14 weeks.

 
When averaging the percentage changes in all four scores, five patients displayed 60% improvement sustained for between 1 and 10 weeks (Fig. 1Go). After 14 weeks, the overall improvement averaged 29%. At the conclusion of the trial, each patient was asked whether they would like to receive another injection of the medication if it were offered to them, and all responded positively except patient #8.

Although this was an open study, the improvement, particularly in pain, indicates that a placebo-controlled evaluation of DPPC/PG injections is warranted. In addition, the dose response and the effect of multiple doses require study. In ongoing equine clinical trials, repeat doses at 2 monthly intervals are proving expedient and radiological evidence indicates improvement in the articular topography.

The scores and time course for improvement displayed in this study are comparable to those following i.a. injection of corticosteroids [10]. This is in keeping with the 3-fold elevation of synovial SAPL recorded in equine synovial fluid following an i.a. injection of corticosteroid commonly administered to degenerating joints [10].

Although administered ostensibly as a lubricant, SAPL could have other physiological benefits, including putative roles in the control of cartilage hydration [1] and scavenging of oxygen free radicals implicated in chondrocyte destruction [6]. Hence, exogenous SAPL may act as a `disease-modifying' drug in degenerative joint disease that offers potential clinical benefits.

References

  1.  Hills BA. Synovial surfactant and the hydrophobic articular surface. J Rheumatol 1996;23:1323–5.[ISI][Medline]
  2.  Hills BA, Monds MK. Enzymatic identification of the load-bearing boundary lubricant in the joint. Br J Rheumatol 1998;37:137–42.[ISI][Medline]
  3.  Hills BA. Oligolamellar lubrication of joints by surface active phospholipid. J Rheumatol 1989;16:82–91.[ISI][Medline]
  4.  Hills BA. Oligolamellar nature of the articular surface. J Rheumatol 1990;17:349–53.[ISI][Medline]
  5.  Hills BA, Thomas K. Joint stiffness and `articular gelling': Inhibition of the fusion of articular surfaces by surfactant. Br J Rheumatol 1998;37:532–8.[ISI][Medline]
  6.  Hills BA, Monds MK. Deficiency of lubricating surfactant lining the articular surfaces of replaced hips and knees. Br J Rheumatol 1998;37:143–7.[ISI][Medline]
  7.  Robertson B. The European Multicentre trial of surfactant replacement in neonatal respiratory distress syndrome. In: Lachmann B, ed. Surfactant replacement therapy in neonatal and adult respiratory distress syndrome. Berlin: Springer-Verlag, 1988.
  8.  Lequesne MG, Mery C, Samson M, Gerard P. Indexes of severity for osteoarthritis of the hip and knee: Validation-value in comparison with other assessment tests. Scand J Rheumatol 1987;suppl. 65:85–9.
  9.  Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: A health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833–40.[ISI][Medline]
  10.  Hills BA, Ethell MT, Hodgson DR. Release of lubricating synovial surfactant by intra-articular steroid. Br J Rheumatol 1998; 37:649–52.[ISI][Medline]
Accepted 19 April 1999





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