NEWS & VIEWS meaningful laboratory abnormalities were also infrequent, self-limited, and compar able between the apremilast treatment and placebo groups. Whilst not yet published in full, the PALACE 2 and 3 studies have been pre‑ sented in abstract form.6,7 Both were similar in design to PALACE 1, with patients in PALACE 2 allowed to continue DMARDs at stable doses. In PALACE 3, patients were required to have at least one psoriatic lesion ≥2 cm in diameter at baseline. In both studies, the ACR20 primary outcome measure was achieved at week 16 and maintained over 52 weeks’ follow-up. Secondary outcome measures, such as PASI scores, also improved and adverse events were similar to those reported for PALACE 1. The FDA approval notes that weight loss occurred in a small number of patients in the PALACE studies and recommends that patients should have their weight monitored regularly;8 they also noted that apremilast treatment was associ‑ ated with an increase in reports of depression compared with placebo. The FDA approval of apremilast in PsA is to be welcomed for a number of reasons. Firstly, therapeutic options for PsA are limited with no synthetic DMARD approved for use and only anti-TNF therapies and uste kinumab approved biologic drugs. Approxi mately 70% of anti-TNF-treated patients achieve an ACR20 response,9 which means that ~30% do not, and for many the treat‑ ment responses are not adequate enough for the patient to be considered as in a minimal disease activity state. Additional options are, therefore, required. Secondly, the PALACE studies suggest that disease features such as enthesitis might also respond to apremilast. With little or no data on response of enthesi‑ tis to DMARDs such as methotrexate, this possible benefit of apremilast is potentially of importance when selecting appropri‑ ate therapy. Thirdly, the sustained response associated with a low frequency of serious adverse events is important when compared to a drug like methotrexate, which can be difficult to persuade patients to take because of concerns, perhaps exaggerated, regarding adverse effects and its listing as a ‘cancer drug’. Many questions remain that will require furt her study. These questions include whether apremilast can or should be used in combination with other synthetic or bio logic DMARDs. Further analysis of the PALACE studies might shed some light on this matter, but a specific study of apremilast versus a competitor versus a combination of the two may well be required. The question 386 | JULY 2014 | VOLUME 10
of a specific comparison with methotrexate is going to be of especial interest, for might it not only assist in answering once and for all whether or not methotrexate is effective, but also it will position apremilast along the treatment pathway and perhaps indicate that, in certain patients, a combination of apremi‑ last with methotrexate could be considered. Whilst welcoming the arrival of apremi‑ last, the rheumatology community eagerly awaits the answers to these questions.
4.
5.
6.
Rheumatology Group, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. [email protected] Competing interests The author has received speaker’s honoraria from Celgene. 1.
2.
3.
US Food and Drug Administration. FDA news release: FDA approves Otezla to treat psoriatic arthritis. US Department of Health and Human Services [online], http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ ucm390091.htm. Pages, L. Gavalda, A. & Lehner, M. D. PDE4 inhibitors: a review of current developments (2005–2009). Expert Opin. Ther. Pat. 19, 1501–1519 (2009). Schafer, P. H. et al. Apremilast, a cAMP phosphodiesterase‑4 inhibitor, demonstrates
7.
8. 9.
anti-inflammatory activity in vitro and in a model of psoriasis. Br. J. Pharmacol. 159, 842–855 (2010). Schett, G. et al. Oral apremilast in the treatment of active psoriatic arthritis. Results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 64, 3156–3167 (2012). Kavanaugh, A. et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebocontrolled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis‑2013‑205056. Cutolo, M. et al. Long-term (52-week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis (PALACE 2) [abstract #815]. Arthritis Rheum. 65 (Suppl. 10), S346 (2013). Edwards, C. J. et al. Long-term (52-week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement (PALACE 3) [abstract #311]. Arthritis Rheum. 65 (Suppl. 10), S132 (2013). Otezla®(apremilast) full prescribing information (Celgene, 2014). Atteno, M. et al. Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drugs. Clin. Rheumatol. 29, 399–403 (2010).
BONE
Silk, metal and bone: why take implants out? Per Aspenberg
Degradable screws and plates for bone surgery have been produced from silk protein. The idea is to eliminate the need to take the implant out when the bone has healed. Will they provide sufficient strength, and will they degrade without causing inflammation? And why take implants out in the first place? Aspenberg, P. Nat. Rev. Rheumatol. 10, 386–387 (2014); published online 8 April 2014; doi:10.1038/nrrheum.2014.57
Fractured bones normally heal spontaneously but, to ensure that they heal in a correct posi‑ tion, they are often fixed with metal nails, screws or plates. These implants are often removed by a new operation when the fracture is healed. In an article published in Nature Communications, Perrone et al.1 pre‑ sented for the first time a solid, machinable material made of silk protein. They manu factured self-tapping screws that could be inserted in bone and that degrade slowly over time; the ability to degrade would eliminate the need for surgical removal of the implant. The material seemed to soften and swell with
hydration, which is an obvious problem. The study authors implanted silk screws in intact rat femora, and measured the force needed to pull them out after 4 and 8 weeks. This force reflects the strength of the new bone that has formed within the screw threads. For the silk screws, it amounted to less than one-third of that reported for similar-sized metal screws in rat tibiae,2 but this finding might be explained by differences in study design. Histological analysis of the implant site showed degrada‑ tion of the implant surface and giant cells, possibly indicating a foreign body reaction, together with bone formation. Obviously, www.nature.com/nrrheum
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
Image developed with P. Aspenberg.
more work is needed before it can be con‑ cluded for what purpose this material might become useful in bone surgery. Removal of fracture fixation implants after healing is a surgical operation not without risk. Avoiding such surgery has been a main rationale for the development of degradable implants. Degradable implants made of dif‑ ferent polylactic-glycolic acids have been available for decades, but gained limited popularity. The main improvement with the new silk material would be that it can be machined to form more precisely shaped devices, and sterilized by autoclaving. Furthermore, the degradation of polylacticglycolic acid implants is associated with local inflammation and sometimes sinus forma‑ tion in the bone that can be detrimental.3,4 Perrone et al.1 hope that this issue will be less of a problem with silk. Removal of internal fracture fixation dev ices can be commonplace, but it is unclear how often it is necessary. Any surgery should have a clear motivation, but for implant removal the underlying reasoning behind the procedure is often simply that the implant is in there and so must be taken out. If implant retainment is not associated with any risk or discomfort, this reason for removal is irra‑ tional. Such irrationality is not uncommon: benign cavities in bone are often treated with unnecessary void fillers, as a result of some kind of orthopaedic ‘horror vacui’.5 Similarly, there might be an orthopaedic ‘xenophobia’ behind unnecessary removal of foreign materials. Interestingly, implant retainment is not regarded as a problem in the context of total joint replacements (and who would like to have a degradable hip replacement?). Perrone et al.1 argue that metal implants need removal because of stress shielding, which relates to loss of mechanical loading of the bone adjacent to the implant as a result of its placement, and subsequent bone resorption in that area due to lack of mechan‑ ical stimulation. Stress shielding under metal plates has previously been thought to neces‑ sitate early removal of the plate or the use of less stiff materials. However, the bone changes observed under metal plates seem
to be caused by surgical devascularization during the implantation procedure.6 With less-traumatic surgery and plates designed to cause less disturbance of the vascular supply to the bone, the problems ascribed to stress shielding have largely disappeared.6 Regardless of the design of fracture fixa‑ tion devices, the bone normally seems to be sufficiently loaded to maintain itself.7 When implants really need to be removed, it is almost exclusively because they protrude out of the bone and cause discomfort, for example at the tibial tuberosity when kneel‑ ing. Plates can also interfere with tendons gliding over them, causing local inflam‑ mation, and such complications might necessitate implant removal. Howe ver, if these implants were instead deg radable, the inflammation associated with degrada tion might even cause worse local prob‑ lems. For instance, the new silk material is degraded enzymatically, and histological analysis demonstrated formation of frag‑ ments and particles at the screw surface.1 Phagoc ytosable particles tend to cause inflammation, even if the material is bio compatible in bulk form. This process can reduce formation and increase resorption of bone, which might explain the low pull-out force of the silk screws. As metal implants cause minor issues, it is imperative that a solution to those issues does not itself cause further problems. Implant removal is surprisingly common. In Sweden, 37,000 adult patients received metal fracture fixation implants in 2011, and 13,000 underwent implant removal. The number of adults undergoing fracture surgery in Sweden increased from 2005 to 2011 by 20%, but removals increased by 35%.8 The highest rate of removal (70%) was reported for ankle and foot implants. Ligamentous healing and adaptation after an ankle fracture can take years, and symp‑ toms can be erroneously ascribed to remain‑ ing, palpable implants. Removal rates might also be influenced by economic incitements. Still, in many cases, the reason can just be tradition. In children, metal implants are routinely removed, although it can often be unnecessary.9,10 In many cases, a retained implant would be hidden inside the larger bone eventually formed by growth. An argument put forward for implant remo val in children is that an implant left behind from young age might interfere with fracture surgery later in life. Children are exposed to surgery just to reduce possible technical problems in the unlikely event that the same bone needs surgery in adulthood!
NATURE REVIEWS | RHEUMATOLOGY
Implants for fracture fixation some times do need to be removed, and a perfect implant therefore would maintain strength until the fracture is healed, and then dis‑ appear quickly without substantial local inflammation. Unfortunately, an implant that is required to remain intact for months would probably take years to disappear. Situations do, however, exist (for example, in the treatment of ankle fractures) in which screws are expected to hold only for the short time needed for soft tissue healing and then loosen their grip to enable small motions. Silk screws might become a prac‑ tical possibility in this scenario. Crucially, this new material1 might enable applica‑ tions we have not yet thought of and future experimentation is warranted. Howe ver, degradation of implants might sometimes cause problems related to inflammation, metal implants work well, and unnecessary removal of metal implants might be a greater issue than implant retainment. Department of Orthopaedics, Linköping University, Linköping, SE 581 85, Sweden. [email protected] Competing interests The author owns stock in and acts as a consultant for AddBIO AB. 1.
Perrone, G. S. et al. The use of silk-based devices for fracture fixation. Nat. Commun. 5, 3385 (2014). 2. Wermelin, K., Tengvall, P. & Aspenberg, P. Surface-bound bisphosphonates enhance screw fixation in rats—increasing effect up to 8 weeks after insertion. Acta Orthop. 78, 385–392 (2007). 3. Ambrose, C. G. & Clanton, T. O. Bioabsorbable implants: review of clinical experience in orthopedic surgery. Ann. Biomed. Eng. 32, 171–177 (2004). 4. Bostman, O. M. & Pihlajamaki, H. K. Adverse tissue reactions to bioabsorbable fixation devices. Clin. Orthop. Relat. Res. 371, 216–227 (2000). 5. Aspenberg, P. Black holes in bone—irresistible attractors of foreign materials? Acta Orthop. 80, 2–3 (2009). 6. Perren, S. M. Evolution of the internal fixation of long bone fractures. J. Bone Joint Surg. Br. 84, 1093–1110 (2002). 7. Cordey, J., Perren, S. M. & Steinemann, S. G. Stress protection due to plates: myth or reality? A parametric analysis made using the composite beam theory. Injury 31 (Suppl. 3), C1–C13 (2000). 8. Statistikdatabasen. Socialstyrelsen [online], http://www.socialstyrelsen.se/statistik/ statistikdatabas (2014). 9. Vopat, B., Kane, P., Fitzgibbons, P., Got, C. & Katarincic, J. Complications associated with retained implants after plate fixation of the pediatric forearm. J. Orthop. Trauma http:// dx.doi.org/10.1097/01.bot.0000435630. 63770.3d. 10. May, C. et al. Complications of plate fixation of femoral shaft fractures in children and adolescents. J. Child. Orthop. 7, 235–243 (2013).
VOLUME 10 | JULY 2014 | 387 © 2014 Macmillan Publishers Limited. All rights reserved
of a specific comparison with methotrexate is going to be of especial interest, for might it not only assist in answering once and for all whether or not methotrexate is effective, but also it will position apremilast along the treatment pathway and perhaps indicate that, in certain patients, a combination of apremi‑ last with methotrexate could be considered. Whilst welcoming the arrival of apremi‑ last, the rheumatology community eagerly awaits the answers to these questions.
4.
5.
6.
Rheumatology Group, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. [email protected] Competing interests The author has received speaker’s honoraria from Celgene. 1.
2.
3.
US Food and Drug Administration. FDA news release: FDA approves Otezla to treat psoriatic arthritis. US Department of Health and Human Services [online], http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ ucm390091.htm. Pages, L. Gavalda, A. & Lehner, M. D. PDE4 inhibitors: a review of current developments (2005–2009). Expert Opin. Ther. Pat. 19, 1501–1519 (2009). Schafer, P. H. et al. Apremilast, a cAMP phosphodiesterase‑4 inhibitor, demonstrates
7.
8. 9.
anti-inflammatory activity in vitro and in a model of psoriasis. Br. J. Pharmacol. 159, 842–855 (2010). Schett, G. et al. Oral apremilast in the treatment of active psoriatic arthritis. Results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 64, 3156–3167 (2012). Kavanaugh, A. et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebocontrolled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis‑2013‑205056. Cutolo, M. et al. Long-term (52-week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis (PALACE 2) [abstract #815]. Arthritis Rheum. 65 (Suppl. 10), S346 (2013). Edwards, C. J. et al. Long-term (52-week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement (PALACE 3) [abstract #311]. Arthritis Rheum. 65 (Suppl. 10), S132 (2013). Otezla®(apremilast) full prescribing information (Celgene, 2014). Atteno, M. et al. Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drugs. Clin. Rheumatol. 29, 399–403 (2010).
BONE
Silk, metal and bone: why take implants out? Per Aspenberg
Degradable screws and plates for bone surgery have been produced from silk protein. The idea is to eliminate the need to take the implant out when the bone has healed. Will they provide sufficient strength, and will they degrade without causing inflammation? And why take implants out in the first place? Aspenberg, P. Nat. Rev. Rheumatol. 10, 386–387 (2014); published online 8 April 2014; doi:10.1038/nrrheum.2014.57
Fractured bones normally heal spontaneously but, to ensure that they heal in a correct posi‑ tion, they are often fixed with metal nails, screws or plates. These implants are often removed by a new operation when the fracture is healed. In an article published in Nature Communications, Perrone et al.1 pre‑ sented for the first time a solid, machinable material made of silk protein. They manu factured self-tapping screws that could be inserted in bone and that degrade slowly over time; the ability to degrade would eliminate the need for surgical removal of the implant. The material seemed to soften and swell with
hydration, which is an obvious problem. The study authors implanted silk screws in intact rat femora, and measured the force needed to pull them out after 4 and 8 weeks. This force reflects the strength of the new bone that has formed within the screw threads. For the silk screws, it amounted to less than one-third of that reported for similar-sized metal screws in rat tibiae,2 but this finding might be explained by differences in study design. Histological analysis of the implant site showed degrada‑ tion of the implant surface and giant cells, possibly indicating a foreign body reaction, together with bone formation. Obviously, www.nature.com/nrrheum
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
Image developed with P. Aspenberg.
more work is needed before it can be con‑ cluded for what purpose this material might become useful in bone surgery. Removal of fracture fixation implants after healing is a surgical operation not without risk. Avoiding such surgery has been a main rationale for the development of degradable implants. Degradable implants made of dif‑ ferent polylactic-glycolic acids have been available for decades, but gained limited popularity. The main improvement with the new silk material would be that it can be machined to form more precisely shaped devices, and sterilized by autoclaving. Furthermore, the degradation of polylacticglycolic acid implants is associated with local inflammation and sometimes sinus forma‑ tion in the bone that can be detrimental.3,4 Perrone et al.1 hope that this issue will be less of a problem with silk. Removal of internal fracture fixation dev ices can be commonplace, but it is unclear how often it is necessary. Any surgery should have a clear motivation, but for implant removal the underlying reasoning behind the procedure is often simply that the implant is in there and so must be taken out. If implant retainment is not associated with any risk or discomfort, this reason for removal is irra‑ tional. Such irrationality is not uncommon: benign cavities in bone are often treated with unnecessary void fillers, as a result of some kind of orthopaedic ‘horror vacui’.5 Similarly, there might be an orthopaedic ‘xenophobia’ behind unnecessary removal of foreign materials. Interestingly, implant retainment is not regarded as a problem in the context of total joint replacements (and who would like to have a degradable hip replacement?). Perrone et al.1 argue that metal implants need removal because of stress shielding, which relates to loss of mechanical loading of the bone adjacent to the implant as a result of its placement, and subsequent bone resorption in that area due to lack of mechan‑ ical stimulation. Stress shielding under metal plates has previously been thought to neces‑ sitate early removal of the plate or the use of less stiff materials. However, the bone changes observed under metal plates seem
to be caused by surgical devascularization during the implantation procedure.6 With less-traumatic surgery and plates designed to cause less disturbance of the vascular supply to the bone, the problems ascribed to stress shielding have largely disappeared.6 Regardless of the design of fracture fixa‑ tion devices, the bone normally seems to be sufficiently loaded to maintain itself.7 When implants really need to be removed, it is almost exclusively because they protrude out of the bone and cause discomfort, for example at the tibial tuberosity when kneel‑ ing. Plates can also interfere with tendons gliding over them, causing local inflam‑ mation, and such complications might necessitate implant removal. Howe ver, if these implants were instead deg radable, the inflammation associated with degrada tion might even cause worse local prob‑ lems. For instance, the new silk material is degraded enzymatically, and histological analysis demonstrated formation of frag‑ ments and particles at the screw surface.1 Phagoc ytosable particles tend to cause inflammation, even if the material is bio compatible in bulk form. This process can reduce formation and increase resorption of bone, which might explain the low pull-out force of the silk screws. As metal implants cause minor issues, it is imperative that a solution to those issues does not itself cause further problems. Implant removal is surprisingly common. In Sweden, 37,000 adult patients received metal fracture fixation implants in 2011, and 13,000 underwent implant removal. The number of adults undergoing fracture surgery in Sweden increased from 2005 to 2011 by 20%, but removals increased by 35%.8 The highest rate of removal (70%) was reported for ankle and foot implants. Ligamentous healing and adaptation after an ankle fracture can take years, and symp‑ toms can be erroneously ascribed to remain‑ ing, palpable implants. Removal rates might also be influenced by economic incitements. Still, in many cases, the reason can just be tradition. In children, metal implants are routinely removed, although it can often be unnecessary.9,10 In many cases, a retained implant would be hidden inside the larger bone eventually formed by growth. An argument put forward for implant remo val in children is that an implant left behind from young age might interfere with fracture surgery later in life. Children are exposed to surgery just to reduce possible technical problems in the unlikely event that the same bone needs surgery in adulthood!
NATURE REVIEWS | RHEUMATOLOGY
Implants for fracture fixation some times do need to be removed, and a perfect implant therefore would maintain strength until the fracture is healed, and then dis‑ appear quickly without substantial local inflammation. Unfortunately, an implant that is required to remain intact for months would probably take years to disappear. Situations do, however, exist (for example, in the treatment of ankle fractures) in which screws are expected to hold only for the short time needed for soft tissue healing and then loosen their grip to enable small motions. Silk screws might become a prac‑ tical possibility in this scenario. Crucially, this new material1 might enable applica‑ tions we have not yet thought of and future experimentation is warranted. Howe ver, degradation of implants might sometimes cause problems related to inflammation, metal implants work well, and unnecessary removal of metal implants might be a greater issue than implant retainment. Department of Orthopaedics, Linköping University, Linköping, SE 581 85, Sweden. [email protected] Competing interests The author owns stock in and acts as a consultant for AddBIO AB. 1.
Perrone, G. S. et al. The use of silk-based devices for fracture fixation. Nat. Commun. 5, 3385 (2014). 2. Wermelin, K., Tengvall, P. & Aspenberg, P. Surface-bound bisphosphonates enhance screw fixation in rats—increasing effect up to 8 weeks after insertion. Acta Orthop. 78, 385–392 (2007). 3. Ambrose, C. G. & Clanton, T. O. Bioabsorbable implants: review of clinical experience in orthopedic surgery. Ann. Biomed. Eng. 32, 171–177 (2004). 4. Bostman, O. M. & Pihlajamaki, H. K. Adverse tissue reactions to bioabsorbable fixation devices. Clin. Orthop. Relat. Res. 371, 216–227 (2000). 5. Aspenberg, P. Black holes in bone—irresistible attractors of foreign materials? Acta Orthop. 80, 2–3 (2009). 6. Perren, S. M. Evolution of the internal fixation of long bone fractures. J. Bone Joint Surg. Br. 84, 1093–1110 (2002). 7. Cordey, J., Perren, S. M. & Steinemann, S. G. Stress protection due to plates: myth or reality? A parametric analysis made using the composite beam theory. Injury 31 (Suppl. 3), C1–C13 (2000). 8. Statistikdatabasen. Socialstyrelsen [online], http://www.socialstyrelsen.se/statistik/ statistikdatabas (2014). 9. Vopat, B., Kane, P., Fitzgibbons, P., Got, C. & Katarincic, J. Complications associated with retained implants after plate fixation of the pediatric forearm. J. Orthop. Trauma http:// dx.doi.org/10.1097/01.bot.0000435630. 63770.3d. 10. May, C. et al. Complications of plate fixation of femoral shaft fractures in children and adolescents. J. Child. Orthop. 7, 235–243 (2013).
VOLUME 10 | JULY 2014 | 387 © 2014 Macmillan Publishers Limited. All rights reserved
