Implant-based Oral Rehabilitation in Systemic Sclerosis Patients: A Systematic Review

Systemic sclerosis (SSc) is a rare multisystem connective tissue disorder characterized by a pathophysiological triad; that is, excessive deposition of collagen and matrix substances leading to widespread fibrosis of the skin and the internal organs, microvascular abnormalities, and immune dysregulation with autoimmunity.^1,2  Systemic sclerosis has a peak of onset during the fifth decade and affects predominantly women.^3,4  It is usually divided into 2 main subsets on the basis of the extent of skin fibrosis that is the hallmark of the disease. In limited cutaneous SSc (lcSSc), skin involvement is restricted to the face and the distal extremities, especially the fingers (sclerodactyly), whereas diffuse cutaneous SSc (dcSSc) is characterized by proximal skin fibrosis up to elbows and knees, including the trunk. In most cases, dcSSc is associated with a more severe clinical course with rapidly progressive skin fibrosis and early development of organ complications (eg, cardiac, renal, pulmonary).^5,6  Besides skin fibrosis, clinical signs include Raynaud phenomenon, which is almost always the inaugural feature and can lead to the development of digital ulcers, digestive manifestations (in particular gastroesophageal reflux), telangiectasia, musculoskeletal problems, interstitial lung disease, calcinosis, pulmonary arterial hypertension, and renal crisis.²  To date, there is still no curative treatment available and given the heterogeneity of the disease, no single therapeutic approach has been shown to be effective.²  Current management frequently relies on immunosuppressants (eg, methotrexate [MTX], mycophenolate mofetil) and complication-specific treatments such as calcium channel blockers for Raynaud phenomenon and proton-pump inhibitors for gastroesophageal reflux.^1,2  Corticosteroids are prescribed for musculoskeletal complications, but should be used with caution at low dose (eg, prednisone < 15 mg per day) considering the risk of renal crisis.⁷  Given the modest benefit of conventional immunosuppressants, several targeted therapies (also named bDMARDs for biological disease-modifying antirheumatic drugs) such as tocilizumab, which blocks interleukin-6 receptor, were recently evaluated.^8,9  However, to date, none has demonstrated significant efficacy and favorable safety profile in SSc.¹⁰  Myeloablation with strong immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation is therefore the only disease-modifying strategy that is currently available. Although it is a high-risk procedure, it allows a subsequent resetting of the immune system, improving long-term survival, and preventing organ complications for refractory dcSSc cases.¹¹ 

Systemic sclerosis has a great impact on the orofacial region that is affected in approximately 80% of the cases with a wide spectrum of manifestations.¹²  It includes microstomia, atrophy and sensitivity of the oral mucosa, xerostomia due to fibrosis of the salivary glands, mandibular osteolysis, temporo-mandibular joint dysfunctions, and increased susceptibility to develop dental plaque bacteria-mediated diseases such as caries and periodontitis.¹²  However, oral manifestations remain frequently underdiagnosed and overshadowed by the systemic involvement. Many factors may contribute to the rapid deterioration of oral health in these patients. At the forefront, maintenance of oral hygiene is challenging in patients with microstomia and impaired manual dexterity due to sclerodactyly and to the presence of digital ulcers. Fibrosis of the buccal mucosa strongly affects the oral functions as it impairs tissue mobility, in particular of the tongue. In addition to a loss of the protective properties of saliva, xerostomia induces a decrease of the mouth pH level, in particular in patients with gastroesophageal reflux.¹²  The subsequent modification of the oral microflora favors the accumulation of dental biofilm and, consequently, the development of caries and periodontal inflammation.^13,14  All these factors contribute to the increased tooth loss.^14–16 

Considering the strong impact of oral health on the quality of life of patients with SSc,¹⁵  it is crucial to restore the oral functions, in particular chewing capacity. Prosthetic rehabilitation is however challenging due to microstomia, and the indication of removable prosthesis is particularly limited. Indeed, the insertion and removal of dentures becomes increasingly difficult to impossible as the disease progression further limits mouth opening and reduces manual dexterity.¹⁷  Wearing removable dentures is frequently painful for the patients due to xerostomia, oral mucosa fragility, and fibrosis/sclerosis. Indeed, pressure and micromovements of the prostheses can cause irritation or even ulcers of the mucosa, and the near absence of saliva impairs their retention.¹⁸  Sclerosis of the mucosa limits prosthesis border extensions, leading to frequent instability.¹⁹  Sectional and collapsible dentures with different attachment systems (ie, midline hinges, stud, or magnetic or swing-lock attachments) have been described, but the protocols are not well standardized.^19–24  Prostheses made of a flexible material (eg, Valplast) to enable optimal insertion and removal may also be proposed but are difficult to adapt with reduced retention and stability.^25,26  In this context, the use of fixed or implant-based rehabilitation should be considered extensively.

Oral rehabilitation with dental implants supporting fixed or removable prostheses is a reliable procedure with very high survival rates.²⁷  In recent years, the spectrum of indications has been expanded and patients with various systemic disorders, as well as concomitant medications, have been selected for dental implantology.²⁸  While some conditions (eg, bleeding disorders, diabetes) have been commonly considered as risk factors for the placement of implants,^29,30  there are only few absolute contraindications, and the benefits of this treatment option frequently outweigh the risks.¹⁸ 

The aim of this systematic review of case reports was to evaluate the feasibility and outcomes related to the use of implants in patients suffering from SSc.

A literature search in the electronic database Medline/PubMed using the following MeSH and search terms combinations: (“dental implants” [MeSH Terms] OR “dental” [All Fields] AND “implants” [All Fields] OR “dental implants” [All Fields]) AND (“scleroderma, systemic” [MeSH Terms] OR “scleroderma” [All Fields] AND “systemic” [All Fields] OR “systemic sclerosis” [All Fields] OR “scleroderma” [All Fields] OR “systemic scleroderma” [All Fields] OR “systemic” [All Fields] AND “sclerosis” [All Fields] OR “scleroderma limited” [MeSH Terms] OR “scleroderma diffuse” [MeSH Terms]) was performed up to July 2020.

English-language case reports and case series were considered eligible if they reported on dental implant-prosthetic treatments in patients suffering from SSc based on the classification criteria from LeRoy et al⁵  and LeRoy and Medsger.⁶  Articles involving patients with SSc with other concurrent systemic and/or syndromic diseases were excluded (except Sjögren syndrome that is frequently associated to SSc).

The following data were collected from the included case reports and case series: time of publication, number of patients, age and gender of the patients, disease form, immunosuppressive treatment at time of implant placement, number and type of inserted implants, preimplant procedures, method of prosthetic rehabilitation, duration of implant follow-up, implant survival rate, and complications.

The performed literature search strategy retrieved a total of 39 articles (Figure). After removal of duplicates, titles and abstracts, 20 records were screened among which 10 were excluded because they were not case reports (reviews, research articles) or because they were not related to implant-based rehabilitation in patients with SSc. Out of the 10 full-text articles that were assessed for eligibility, all of them were included in qualitative synthesis (Figure).^17,31–39 

The first case of implants placed in a patient suffering from SSc was published in 1990,³⁵  and the last one in 2016,¹⁷  with only 4 patients with SSc reported in the last 10 years.^17,32,37,38  The 10 included case-reports described the implant-based rehabilitation of 10 patients with SSc (9 women, 1 man) with a mean age of 55.8 ± 10.4 years. Regarding the disease form, 3 patients had dcSSc,^33,35,39  1 patient had lcSSc,¹⁷  and Sjögren syndrome was associated to SSc in 2 patients.^36,37  Data regarding the use of immunosuppressive treatments were only available for 6 patients^{17,32,33,35,37,38}  with 4 patients treated with immunosuppressants at the time of implant placement,^32,33,35,38  mainly corticosteroids^32,33,38  and MTX.^32,33  Preimplant surgical procedures were reported in 3 cases with bone grafting for 2 of them^17,32  and bilateral sinus lift in 1 of them.³⁷  Among the 71 implants placed in patients with SSc, 38 implants were placed in the maxilla and 33 implants in the mandible. A mean number of 7.1 ± 3.8 implants have been inserted per patient. A sequential placement of the implants has been reported for 4 patients.^17,32,37,39  A fixed prosthetic rehabilitation has been performed in 7 patients with SSc,^{17,31,35–39}  whereas implant-stabilized removable prostheses have been fabricated for 4 of them.^32–34,36  Follow-up data were available for 8 patients^{17,32–36,38,39}  with a mean follow-up of 28.3 ± 18.6 months. The mean implant survival rate was 98.89% ± 3.51%, but implant-related complications have been reported in 3 patients. Indeed, 1 implant had to be removed due to a lack of osseointegration.³⁵  In 2 patients, peri-implant bone loss has been observed. In 1 of them, it was associated with suppuration around 1 implant, but 1 month after nonsurgical treatment (scaling and chlorhexidine irrigation), the inflammation resolved, and the bone level remained stable afterward.¹⁷  Demographic and clinical data are detailed in Table 1.

The literature on oral rehabilitation with dental implants in patients with SSc still remains quite sparse and only few case reports have been published.^17,31–39  In the identified articles, the number of implants placed was quite important with a mean of 7.1 ± 3.8 implants per patient. Survival rates were high (98.99%), but the mean follow-up was only 28.3 months. Implant-related complications have been reported in 3 patients.^17,35,38  Jensen and Sindet-Pedersen³⁵  reported a failure of 1 implant due to a lack of osseointegration. In their case series, Weinlander et al³⁸  observed a higher, although not significant, bone loss (3.1 ± 0.7 mm versus 2.1 ± 0.5 mm) and bleeding index (0.9 ± 0.8 versus 0.5 ± 0.3) in patients with connective tissue diseases (that include SSc) than in patients with rheumatoid arthritis after a 3-year follow-up. However, they did not differentiate patients with Sjögren syndrome from patients with SSc.³⁸  Finally, Baptist¹⁷  reported partial exposition of 3 cover screws during the implants healing phase, peri-implant bone loss, and suppuration around 1 implant, but after treatment, bone levels remained stable after a 2-year follow-up. Although implant survival rates in patients with SSc seem close to those of healthy individuals, the level of evidence remains quite low, and long-term peri-implant survival as well as success-related data are needed.²⁷  Therefore, the establishment of evidence-based clinical guidelines still remains impossible also due to the heterogeneity of SSc disease.

Implant placement in patients with SSc is challenging as several factors may influence treatment feasibility and long-term outcomes. Indeed, several general and oral-related parameters should be considered prior to indicating dental implant placement. We therefore suggest a personalized assessment of the risk-benefit balance in close collaboration with the medical team (Table 2). General parameters are for most of them linked to the severity of SSc (limited/diffuse forms) and to past/current immunomodulatory treatments with potential long-term impact on oral tissues and host response. Oral-related parameters to consider include history of oral diseases, mainly periodontitis, and ability to maintain proper oral hygiene, as dental plaque accumulation is a well-described risk factor for implant complications (eg, peri-implantitis) at long-term.⁴⁰  Nevertheless, technical issues may occur in case of reduced mouth opening and peri-oral tissues fibrosis that will limit the drilling procedures and implant placement. Such parameters should also be modulated depending on the potential treated site, anterior regions being easier to access, and to maintain free of bacterial biofilm.

Different medications from the SSc therapeutic arsenal may have an impact on dental implant osseointegration, in particular proton-pump inhibitors, bisphosphonates (BPs), and immunosuppressants (Table 3).

Proton-pump inhibitors are mainly used for the management of gastroesophageal reflux that affects the majority of patients with SSc.²  They have been associated with an increased risk of vitamin and mineral deficiencies and have an impact on calcium metabolism⁴¹  leading to an higher risk of bone fracture.⁴²  Several recent retrospective studies have suggested that these drugs may negatively affect implants osseointegration with implant failure rates 2 to 4 times higher in patients under proton-pump inhibitors treatment.^28,43–45 

Corticosteroids are used for their anti-inflammatory and immunosuppressant effects, but their long-term administration is associated with several side effects including osteoporosis.⁴⁶  Indeed, corticosteroids have a significant effect on bone metabolism with decreased production of new osteoblast precursors, early apoptosis of mature osteoblasts, and increased survival of osteoclasts.⁴⁶  Although some animal data suggested that glucocorticoid-induced osteoporosis may affect the osseointegration parameters,^47,48  a more recent retrospective study on 31 patients with various systemic diseases showed that the long-term treatment with corticosteroids does neither have a significant impact on the osseointegration of dental implants nor on the 3-year survival.⁴⁹  In these patients, the daily doses of prednisolone ranged between 5 and 60 mg of prednisolone and broad-spectrum antibiotic prophylaxis has been prescribed for 7 days after implant placement. Even high doses were not associated with complications.⁴⁹  In SSc, the risk is even lower as corticosteroids are used at a maximum dose of 15 mg/day given the risk of renal crisis.⁷  Although there are no recommendations to discontinue low-dose corticosteroids treatment before implant placement, it has to be discussed on a case-by-case basis with the medical team.

Conventional immunosuppressants such as mycophenolate mofetil or MTX are used in several patients with SSc as background treatment, in particular those with dcSSc. A recent meta-analysis on implants in immunocompromised patients investigated the influence of autoimmune diseases and treatment modalities (ie, corticosteroids and immunosuppressant drugs). It included 19 studies with a total of 596 implants inserted in 129 patients suffering from autoimmune diseases.⁵⁰  For an average follow-up of 73 months, the mean survival rate of implants was 88.75%, and no direct effect on implant survival of either the immunosuppressive medication or the underlying autoimmune disease was detected.⁵⁰  However, the predominant treatment used in the reported studies was glucocorticoids and in half of the studies, antibiotic prophylaxis was administered for dental implant placement.⁵⁰  Duttenhoefer et al⁵⁰  and others also addressed the impact of long-term pharmacological immunosuppression after solid organ transplantation.^50–54  No restriction for dental implants' placement has been observed in transplanted patients under immunosuppressants, and the implant survival rates were similar irrespective of the type of immunosuppressive drugs that were used.⁵⁰  No significant difference has been measured in the crestal bone level 24 months after implant insertion between healthy individuals and organ transplanted patients under chronic immunosuppressive therapy.⁵⁰ 

Low-dose MTX is often the first-line immunosuppressant for patients with rheumatoid arthritis but is also frequently used in patients with SSc presenting musculoskeletal complications and arthralgia.²  To our knowledge, no data on implant placement in patients treated with low-dose MTX are currently available in the literature. However, it has been shown in vitro that even low-dose MTX can act as a potent inhibitor of osteoblast's proliferation, suggesting a possible negative effect on implants' osseointegration.⁵⁵  The effect of low-dose MTX therapy has also been investigated in vivo in a rabbit and a canine model with a satisfying implant osseointegration, but the latter has been only assessed in the short term, and in the rabbit model, implants were placed in the tibia.^56,57 

To our knowledge, there are no published data on dental implant placement in patients under bDMARDs. Regarding safety of surgeries in general, most of the data come from patients with rheumatoid arthritis in which bDMARDs have been associated with an increased risk of serious infections compared with conventional immunosuppressants.⁵⁸  However, although they may induce a delayed wound healing⁵⁹  and mask the signs of surgical-site infection,⁶⁰  a recent study among patients with rheumatoid arthritis undergoing arthroplasty revealed a similar risk of postoperative prosthetic joint infection across biotherapies that was lower than in patients treated with corticosteroids > 10 mg/day.⁶¹  The British Society for Rheumatology and the French “Rheumatisms and Inflammations Club” made recommendations regarding general surgery timing in patients treated by bDMARDs for inflammatory arthritis.^62,63  For most bDMARDs, surgery should be planned when at least 1 dosing interval has elapsed for that specific drug.⁶²  Regarding tocilizumab treatment, it should be interrupted at least 4 weeks before surgery when it is administered intravenously and 4 to at least 2 weeks before surgery when it is administered subcutaneously (grade 1C).^62,63  The reintroduction of the biotherapy can be considered only after wound healing (typically around 14 days after surgery), sutures removal, and if there is no evidence of infection (grade 1B).⁶²  Dental implant surgery in patients treated with bDMARDs has only been specifically addressed by the French “Rheumatisms and Inflammations Club”. Concerning tocilizumab, there is no definite indication to stop the treatment for dental implant placement, but prophylactic antibiotic administration of at least 1 dose 1 hour before surgery^63,64  as well as a very close follow-up⁶³  are recommended.

Nevertheless, for all patients with SSc under conventional immunosuppressants or bDMARDs, the treatment must be adapted on a case-by-case basis according to the medical context and to the type of surgery that is planned. The risk-benefit balance of immunosuppressive treatment modification/discontinuation must be assessed with the medical team.⁶³  A systematic administration of antibiotic prophylaxis (eg, amoxicillin or clindamycin in case of penicillin allergy) should be considered, and the possibility to suspend the immunosuppressive treatment until complete healing should be discussed and balanced against the risk of a perioperative flare in disease activity. A close monitoring of the healing phase is required to detect any complication including postoperative infections, as the conventional indicators of infection (eg, fever) might not be reliable, in particular in patients under bDMARDs.⁶² 

To prevent glucocorticoid-induced osteoporosis,⁶⁵  few patients with SSc are under BPs to prevent the loss of bone mass through the inhibition of osteoclast-mediated bone resorption and renewal. One of the most serious complications of BP therapy is medication-related osteonecrosis of the jaws (MRONJ), in particular in the mandible.^66,67  It is therefore important to take this additional risk factor into consideration when planning implant-based oral rehabilitation in patients with SSc treated with BPs. To date, although the level of evidence remains low, implant placement in patients under BPs may be associated with a risk of MRONJ and of implant loss or failure, in particular when BPs are administered intravenously or in combination with glucocorticoids.^29,66,68,69  If possible, after discussion with the medical team, oral BP treatment should be interrupted based on the recommendations of the American Association of Oral and Maxillofacial Surgeons.⁶⁶ 

Only 3 papers reported preimplant surgical procedures in patients with SSc.^17,32,37  Zigdon et al³²  performed maxillary teeth extractions in conjunction with bone allograft. Four months later, 6 dental implants have been inserted with no need for further bone augmentation and no evidence of bone loss after a 3-year follow-up.³²  More recently, Baptist¹⁷  performed immediate placement of 5 implants after the extraction of 6 teeth with simultaneous grafting of bone defects with irradiated freeze-dried mineralized ground cortical allograft that has been covered by bovine collagen membranes. Maxillary sinus floor augmentation has been performed in only 1 patient with SSc using the Caldwell-Luc window technique with a composite of autogenous and allogenous graft bone, and simultaneous extraction of 3 teeth.³⁷  This procedure is quite difficult to perform in patients with SSc due to restricted extension of the perioral musculature secondary to fibrosis, and the authors did not provide follow-up data. Due to the very limited amount of data available on preimplant surgery in patients with SSc, less complex treatment options should be favored, and one should avoid as much as possible invasive procedures such as bone graft and maxillary sinus floor augmentation. This should however be modulated according to different parameters (Table 2), in particular disease severity, immunosuppression level, and microstomia.

In patients with SSc with atrophic jaws, the use of short dental implants should be considered. This treatment option has been shown to be a reliable alternative in cases of reduced alveolar bone height. Indeed, short implants achieve similar results as standard length implants placed in combination with sinus floor elevation or in grafted bone.^70,71 

Sequential placement of the dental implants with a 2-stage surgery has been reported for 4 patients.^17,32,37,39  Indeed, considering the very sparse literature on implants' osseointegration in patients with SSc, as well as the micro-vasculopathy and immune dysregulation associated with the disease, it seems crucial to monitor very closely the healing phase after implant insertion in order to allow an early detection of any complication. When it is possible, and even in cases of nonoptimal implant orientation, one should favor screw-retained fixed restorations that are easier to disassemble than cement-retained restorations. Indeed, in particular in patients with severe microstomia, it is mandatory to be able to remove the fixed prostheses to have access to the oral cavity for professional hygiene maintenance and future dental care. A long-term rigorous professional maintenance program should be implemented with close recall intervals and strict oral hygiene to prevent bone loss around the implants and therefore peri-implantitis.⁷²  Among the included articles, the mean follow-up time was only 28.3 months and no specific data on peri-implantitis in patients with SSc were available. Peri-implant bone loss has been reported in 2 patients,^17,38  and it has been shown by several studies that patients with SSc presented a higher prevalence of periodontal diseases.^15,16,73  Periodontitis is a risk factor for peri-implantitis and implant loss.⁷⁴  In addition, chronic fibrosis and microvascular alterations may mask the classical signs of acute inflammation, making the diagnosis of periodontal diseas^16,73  and therefore of peri-implantitis difficult.

The different technical procedures are frequently complicated by the restricted oral access, in particular dental implants' placement and impressions. However, in contrast to removable prostheses that are poorly tolerated by patients with SSc, implant-supported or -fixed rehabilitation enhance the oral health-related quality of life,¹⁸  due to a better stability/retention of the dentures, a minimization of the trauma to the oral mucosa, as well as an improvement of the oral functions, of the comfort and of the facial aesthetic appearance, the latter having a positive psychological impact on self-esteem.^75,76 

The main limitation of this review consisted in the lack of long-term prospective follow-up studies that are mandatory to determine accurately survival and success rates of implants in patients with SSc. In addition, precise periodontal and peri-implant parameters should be collected and analyzed, and a correlation analysis between the medical evolution of the SSc and implants' situation should be performed in future studies.

The data of the case reports included in this systematic review suggest that implant survival rates in patients with SSc may be comparable with those of healthy individuals, but the follow-up period was limited, and complications have been observed in 30% of the cases. Due to the small number of publications, further clinical investigations by comparative studies including control groups with healthy patients and longer follow-up periods are therefore strongly required to establish evidence-based treatment guidelines. Implant-prosthetic treatment guidelines for healthy patients should be meanwhile strictly followed with close recall intervals and rigorous maintenance program, always in close collaboration with the multidisciplinary medical team. In order to help the dentists in the indication of an implant-based rehabilitation in patients with SSc, we suggest several parameters that need to be considered in the individualized risk-benefit balance with an associated risk score.

Abbreviations

bDMARDs:

biological disease-modifying antirheumatic drug (targeted biotherapies)

BP:

bisphosphonate

dcSSc:

diffuse cutaneous SSc

lcSSc:

limited cutaneous SSc

MRONJ:

medication-related osteonecrosis of the jaws

MTX:

methotrexate

SSc:

systemic sclerosis

The authors thank Prof François Clauss for careful proofreading of the manuscript.

The authors declare no conflicts of interest related to this study.