User login
Folliculitis decalvans (FD) is classified as a rare primary neutrophilic cicatricial alopecia occurring predominantly in middle-aged adults. Although the true etiology is still unknown, the pathogenesis behind the inflammatory follicular lesions stems from possible Staphylococcus aureus infection and an impaired host immune system in response to released superantigens. 1 The clinical severity of this inflammatory scalp disorder can range from mild to severe and debilitating. Multiple treatment regimens have been developed with the goal of maintaining full remission. We provide a summary of tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies being utilized for patients with therapy-recalcitrant FD.
Methods
We conducted a PubMed, Medline, and Google Scholar search for the terms refractory FD, recalcitrant FD, or therapy-resistant FD to identify articles published in English from 1998 to 2022. Articles that reported recalcitrant cases and subsequent therapy with TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies were included. Articles were excluded if recalcitrant cases were not clearly defined. Remission was defined as no recurrence in lesions or pustules or as a reduction in the inflammatory process with stabilization upon continuation or discontinuation of the therapy regimen. Two reviewers (T.F. and K.U.) independently searched for and screened each report.
Results
Treatment of recalcitrant FD with biologics or small molecule inhibitors was discussed in 9 studies with a combined total of 35 patients.2-10 The treatment regimens included TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies (Table).
The TNF inhibitors were utilized in 6 reports with a combined total of 29 patients. Treatments included adalimumab or biosimilar adalimumab (27/29 patients), infliximab (1/29 patients), and certolizumab pegol (1/29 patients). Remission was reported in 26 of 29 cases. There were 2 nonresponders to adalimumab and marked improvement with certolizumab pegol without complete resolution. The use of the JAK inhibitor baricitinib in 4 patients resulted in remission. In all 4 patients, baricitinib was used with concurrent treatments, and remission was achieved in an average of 2.25 months. The use of a PDE4 inhibitor, apremilast, was reported in 1 case; remission was achieved in 3 weeks. Secukinumab, a monoclonal antibody that targets IL-17, was utilized in 1 patient. Marked improvement was seen after 2 months, with complete remission in 7 months.
Comment
Traditional treatment regimens for FD most often include a combination of topical and oral antibiotics; isotretinoin; and oral, topical, or intralesional corticosteroids. In the past, interventions typically were suppressive as opposed to curative; however, recent treatment advancements have shown promise in achieving lasting remission.
Most reports targeting treatment-resistant FD involved the use of TNF inhibitors, including adalimumab, biosimilar adalimumab, infliximab, and certolizumab pegol. Adalimumab was the most frequently used TNF inhibitor, with 24 of 26 treated patients achieving remission. Adalimumab may have been used the most in the treatment of FD because TNF is pronounced in other neutrophilic dermatoses that have been successfully treated with TNF inhibitors. It has been reported that adalimumab needs to be continued, as stoppage or interruption led to relapse.3
Although there are few reports of the use of JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies for FD, these treatment modalities show promise, as their use led to marked improvement or lasting remission with ongoing treatment. The use of the PDE4 inhibitor apremilast displayed the most rapid improvement of any of the reviewed treatments, with remission achieved in just 3 weeks.9 The rapid success of apremilast may be attributed to the inhibitory effect on neutrophils.
Miguel-Gómez et al11 provided a therapeutic protocol for FD based on the severity of disease (N=60). The protocol included rifampicin plus clindamycin for the treatment of severe disease, as 90.5% (19/21) of resistant cases showed clinical response, with remission of 5 months’ duration. Although this may be acceptable for some patients, others may require an alternative approach. Tietze et al12 showed that rifampicin and clindamycin had the lowest success rate for long-term remission, with 8 of 10 patients relapsing within 2 to 4 months. In addition, the emergence of antimicrobial resistance remains a major concern in the treatment of FD. Upon the review of the most recent reports of successful treatment of therapy-resistant FD, biologics and small molecule inhibitors have shown remission extending through a 12-month follow-up period. We suggest considering the addition of biologics and small molecule inhibitors to the treatment protocol for severe or resistant disease.
Limitations—In the articles reviewed, the definition of remission was inconsistent among authors—some characterized it as no recurrence in lesions or pustules and some as a reduction in the inflammatory process. True duration of remission was difficult to assess from case reports, as follow-up periods varied prior to publication. The studies included in this review consisted mainly of small sample sizes owing to the rarity of FD, and consequently, strength of evidence is lacking. Inherent to the nature of systematic reviews, publication bias may have occurred. Lastly, several studies were impacted by difficulty in obtaining optimal treatment due to financial hardship, and regimens were adjusted accordingly.
Conclusion
The relapsing nature of FD leads to frustration and poor quality of life for patients. There is a paucity of data to guide treatment when FD remains recalcitrant to traditional therapy. Therapies such as TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies have shown success in the treatment of this often difficult-to-treat disease. Small sample sizes in reports discussing treatment for resistant cases as well as conflicting results make it challenging to draw conclusions about treatment efficacy. Larger studies are needed to understand the long-term outcomes of treatment options. Regardless, disease severity, patient history, patient preferences, and treatment goals can guide the selection of therapeutic options.
- Otberg N, Kang H, Alzolibani AA, et al. Folliculitis decalvans. Dermatol Ther. 2008;21:238-244. doi:10.1111/j.1529-8019.2008.00204.x
- Shireen F, Sudhakar A. A case of isotretinoin therapy-refractory folliculitis decalvans treated successfully with biosimilar adalimumab (Exemptia). Int J Trichology. 2018;10:240-241.
- Iorizzo M, Starace M, Vano-Galvan S, et al. Refractory folliculitis decalvans treated with adalimumab: a case series of 23 patients. J Am Acad Dermatol. 2022;87:666-669. doi:10.1016/j.jaad.2022.02.044
- Kreutzer K, Effendy I. Therapy-resistant folliculitis decalvans and lichen planopilaris successfully treated with adalimumab. J Dtsch Dermatol Ges. 2014;12:74-76. doi:10.1111/ddg.12224
- Alhameedy MM, Alsantali AM. Therapy-recalcitrant folliculitis decalvans controlled successfully with adalimumab. Int J Trichology. 2019;11:241-243. doi:10.4103/ijt.ijt_92_19
- Mihaljevic´ N, von den Driesch P. Successful use of infliximab in a patient with recalcitrant folliculitis decalvans. J Dtsch Dermatol Ges. 2012;10:589-590. doi:10.1111/j.1610-0387.2012.07972.x
- Hoy M, Böhm M. Therapy-refractory folliculitis decalvans treated with certolizumab pegol. Int J Dermatol. 2022;61:e26-e28. doi:10.1111/ijd.15914
- Moussa A, Asfour L, Eisman S, et al. Successful treatment of folliculitis decalvans with baricitinib: a case series. Australas J Dermatol. 2022;63:279-281. doi:10.1111/ajd.13786
- Fässler M, Radonjic-Hoesli S, Feldmeyer L, et al. Successful treatment of refractory folliculitis decalvans with apremilast. JAAD Case Rep. 2020;6:1079-1081. doi:10.1016/j.jdcr.2020.08.019
- Ismail FF, Sinclair R. Successful treatment of refractory folliculitis decalvans with secukinumab. Australas J Dermatol. 2020;61:165-166. doi:10.1111/ajd.13190
- Miguel-Gómez L, Rodrigues-Barata AR, Molina-Ruiz A, et al. Folliculitis decalvans: effectiveness of therapies and prognostic factors in a multicenter series of 60 patients with long-term follow-up. J Am Acad Dermatol. 2018;79:878-883. doi:10.1016/j.jaad.2018.05.1240
- Tietze JK, Heppt MV, von Preußen A, et al. Oral isotretinoin as the most effective treatment in folliculitis decalvans: a retrospective comparison of different treatment regimens in 28 patients. J Eur Acad Dermatol Venereol. 2015;29:1816-1821. doi:10.1111/jdv.13052
Folliculitis decalvans (FD) is classified as a rare primary neutrophilic cicatricial alopecia occurring predominantly in middle-aged adults. Although the true etiology is still unknown, the pathogenesis behind the inflammatory follicular lesions stems from possible Staphylococcus aureus infection and an impaired host immune system in response to released superantigens. 1 The clinical severity of this inflammatory scalp disorder can range from mild to severe and debilitating. Multiple treatment regimens have been developed with the goal of maintaining full remission. We provide a summary of tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies being utilized for patients with therapy-recalcitrant FD.
Methods
We conducted a PubMed, Medline, and Google Scholar search for the terms refractory FD, recalcitrant FD, or therapy-resistant FD to identify articles published in English from 1998 to 2022. Articles that reported recalcitrant cases and subsequent therapy with TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies were included. Articles were excluded if recalcitrant cases were not clearly defined. Remission was defined as no recurrence in lesions or pustules or as a reduction in the inflammatory process with stabilization upon continuation or discontinuation of the therapy regimen. Two reviewers (T.F. and K.U.) independently searched for and screened each report.
Results
Treatment of recalcitrant FD with biologics or small molecule inhibitors was discussed in 9 studies with a combined total of 35 patients.2-10 The treatment regimens included TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies (Table).
The TNF inhibitors were utilized in 6 reports with a combined total of 29 patients. Treatments included adalimumab or biosimilar adalimumab (27/29 patients), infliximab (1/29 patients), and certolizumab pegol (1/29 patients). Remission was reported in 26 of 29 cases. There were 2 nonresponders to adalimumab and marked improvement with certolizumab pegol without complete resolution. The use of the JAK inhibitor baricitinib in 4 patients resulted in remission. In all 4 patients, baricitinib was used with concurrent treatments, and remission was achieved in an average of 2.25 months. The use of a PDE4 inhibitor, apremilast, was reported in 1 case; remission was achieved in 3 weeks. Secukinumab, a monoclonal antibody that targets IL-17, was utilized in 1 patient. Marked improvement was seen after 2 months, with complete remission in 7 months.
Comment
Traditional treatment regimens for FD most often include a combination of topical and oral antibiotics; isotretinoin; and oral, topical, or intralesional corticosteroids. In the past, interventions typically were suppressive as opposed to curative; however, recent treatment advancements have shown promise in achieving lasting remission.
Most reports targeting treatment-resistant FD involved the use of TNF inhibitors, including adalimumab, biosimilar adalimumab, infliximab, and certolizumab pegol. Adalimumab was the most frequently used TNF inhibitor, with 24 of 26 treated patients achieving remission. Adalimumab may have been used the most in the treatment of FD because TNF is pronounced in other neutrophilic dermatoses that have been successfully treated with TNF inhibitors. It has been reported that adalimumab needs to be continued, as stoppage or interruption led to relapse.3
Although there are few reports of the use of JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies for FD, these treatment modalities show promise, as their use led to marked improvement or lasting remission with ongoing treatment. The use of the PDE4 inhibitor apremilast displayed the most rapid improvement of any of the reviewed treatments, with remission achieved in just 3 weeks.9 The rapid success of apremilast may be attributed to the inhibitory effect on neutrophils.
Miguel-Gómez et al11 provided a therapeutic protocol for FD based on the severity of disease (N=60). The protocol included rifampicin plus clindamycin for the treatment of severe disease, as 90.5% (19/21) of resistant cases showed clinical response, with remission of 5 months’ duration. Although this may be acceptable for some patients, others may require an alternative approach. Tietze et al12 showed that rifampicin and clindamycin had the lowest success rate for long-term remission, with 8 of 10 patients relapsing within 2 to 4 months. In addition, the emergence of antimicrobial resistance remains a major concern in the treatment of FD. Upon the review of the most recent reports of successful treatment of therapy-resistant FD, biologics and small molecule inhibitors have shown remission extending through a 12-month follow-up period. We suggest considering the addition of biologics and small molecule inhibitors to the treatment protocol for severe or resistant disease.
Limitations—In the articles reviewed, the definition of remission was inconsistent among authors—some characterized it as no recurrence in lesions or pustules and some as a reduction in the inflammatory process. True duration of remission was difficult to assess from case reports, as follow-up periods varied prior to publication. The studies included in this review consisted mainly of small sample sizes owing to the rarity of FD, and consequently, strength of evidence is lacking. Inherent to the nature of systematic reviews, publication bias may have occurred. Lastly, several studies were impacted by difficulty in obtaining optimal treatment due to financial hardship, and regimens were adjusted accordingly.
Conclusion
The relapsing nature of FD leads to frustration and poor quality of life for patients. There is a paucity of data to guide treatment when FD remains recalcitrant to traditional therapy. Therapies such as TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies have shown success in the treatment of this often difficult-to-treat disease. Small sample sizes in reports discussing treatment for resistant cases as well as conflicting results make it challenging to draw conclusions about treatment efficacy. Larger studies are needed to understand the long-term outcomes of treatment options. Regardless, disease severity, patient history, patient preferences, and treatment goals can guide the selection of therapeutic options.
Folliculitis decalvans (FD) is classified as a rare primary neutrophilic cicatricial alopecia occurring predominantly in middle-aged adults. Although the true etiology is still unknown, the pathogenesis behind the inflammatory follicular lesions stems from possible Staphylococcus aureus infection and an impaired host immune system in response to released superantigens. 1 The clinical severity of this inflammatory scalp disorder can range from mild to severe and debilitating. Multiple treatment regimens have been developed with the goal of maintaining full remission. We provide a summary of tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies being utilized for patients with therapy-recalcitrant FD.
Methods
We conducted a PubMed, Medline, and Google Scholar search for the terms refractory FD, recalcitrant FD, or therapy-resistant FD to identify articles published in English from 1998 to 2022. Articles that reported recalcitrant cases and subsequent therapy with TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies were included. Articles were excluded if recalcitrant cases were not clearly defined. Remission was defined as no recurrence in lesions or pustules or as a reduction in the inflammatory process with stabilization upon continuation or discontinuation of the therapy regimen. Two reviewers (T.F. and K.U.) independently searched for and screened each report.
Results
Treatment of recalcitrant FD with biologics or small molecule inhibitors was discussed in 9 studies with a combined total of 35 patients.2-10 The treatment regimens included TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies (Table).
The TNF inhibitors were utilized in 6 reports with a combined total of 29 patients. Treatments included adalimumab or biosimilar adalimumab (27/29 patients), infliximab (1/29 patients), and certolizumab pegol (1/29 patients). Remission was reported in 26 of 29 cases. There were 2 nonresponders to adalimumab and marked improvement with certolizumab pegol without complete resolution. The use of the JAK inhibitor baricitinib in 4 patients resulted in remission. In all 4 patients, baricitinib was used with concurrent treatments, and remission was achieved in an average of 2.25 months. The use of a PDE4 inhibitor, apremilast, was reported in 1 case; remission was achieved in 3 weeks. Secukinumab, a monoclonal antibody that targets IL-17, was utilized in 1 patient. Marked improvement was seen after 2 months, with complete remission in 7 months.
Comment
Traditional treatment regimens for FD most often include a combination of topical and oral antibiotics; isotretinoin; and oral, topical, or intralesional corticosteroids. In the past, interventions typically were suppressive as opposed to curative; however, recent treatment advancements have shown promise in achieving lasting remission.
Most reports targeting treatment-resistant FD involved the use of TNF inhibitors, including adalimumab, biosimilar adalimumab, infliximab, and certolizumab pegol. Adalimumab was the most frequently used TNF inhibitor, with 24 of 26 treated patients achieving remission. Adalimumab may have been used the most in the treatment of FD because TNF is pronounced in other neutrophilic dermatoses that have been successfully treated with TNF inhibitors. It has been reported that adalimumab needs to be continued, as stoppage or interruption led to relapse.3
Although there are few reports of the use of JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies for FD, these treatment modalities show promise, as their use led to marked improvement or lasting remission with ongoing treatment. The use of the PDE4 inhibitor apremilast displayed the most rapid improvement of any of the reviewed treatments, with remission achieved in just 3 weeks.9 The rapid success of apremilast may be attributed to the inhibitory effect on neutrophils.
Miguel-Gómez et al11 provided a therapeutic protocol for FD based on the severity of disease (N=60). The protocol included rifampicin plus clindamycin for the treatment of severe disease, as 90.5% (19/21) of resistant cases showed clinical response, with remission of 5 months’ duration. Although this may be acceptable for some patients, others may require an alternative approach. Tietze et al12 showed that rifampicin and clindamycin had the lowest success rate for long-term remission, with 8 of 10 patients relapsing within 2 to 4 months. In addition, the emergence of antimicrobial resistance remains a major concern in the treatment of FD. Upon the review of the most recent reports of successful treatment of therapy-resistant FD, biologics and small molecule inhibitors have shown remission extending through a 12-month follow-up period. We suggest considering the addition of biologics and small molecule inhibitors to the treatment protocol for severe or resistant disease.
Limitations—In the articles reviewed, the definition of remission was inconsistent among authors—some characterized it as no recurrence in lesions or pustules and some as a reduction in the inflammatory process. True duration of remission was difficult to assess from case reports, as follow-up periods varied prior to publication. The studies included in this review consisted mainly of small sample sizes owing to the rarity of FD, and consequently, strength of evidence is lacking. Inherent to the nature of systematic reviews, publication bias may have occurred. Lastly, several studies were impacted by difficulty in obtaining optimal treatment due to financial hardship, and regimens were adjusted accordingly.
Conclusion
The relapsing nature of FD leads to frustration and poor quality of life for patients. There is a paucity of data to guide treatment when FD remains recalcitrant to traditional therapy. Therapies such as TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies have shown success in the treatment of this often difficult-to-treat disease. Small sample sizes in reports discussing treatment for resistant cases as well as conflicting results make it challenging to draw conclusions about treatment efficacy. Larger studies are needed to understand the long-term outcomes of treatment options. Regardless, disease severity, patient history, patient preferences, and treatment goals can guide the selection of therapeutic options.
- Otberg N, Kang H, Alzolibani AA, et al. Folliculitis decalvans. Dermatol Ther. 2008;21:238-244. doi:10.1111/j.1529-8019.2008.00204.x
- Shireen F, Sudhakar A. A case of isotretinoin therapy-refractory folliculitis decalvans treated successfully with biosimilar adalimumab (Exemptia). Int J Trichology. 2018;10:240-241.
- Iorizzo M, Starace M, Vano-Galvan S, et al. Refractory folliculitis decalvans treated with adalimumab: a case series of 23 patients. J Am Acad Dermatol. 2022;87:666-669. doi:10.1016/j.jaad.2022.02.044
- Kreutzer K, Effendy I. Therapy-resistant folliculitis decalvans and lichen planopilaris successfully treated with adalimumab. J Dtsch Dermatol Ges. 2014;12:74-76. doi:10.1111/ddg.12224
- Alhameedy MM, Alsantali AM. Therapy-recalcitrant folliculitis decalvans controlled successfully with adalimumab. Int J Trichology. 2019;11:241-243. doi:10.4103/ijt.ijt_92_19
- Mihaljevic´ N, von den Driesch P. Successful use of infliximab in a patient with recalcitrant folliculitis decalvans. J Dtsch Dermatol Ges. 2012;10:589-590. doi:10.1111/j.1610-0387.2012.07972.x
- Hoy M, Böhm M. Therapy-refractory folliculitis decalvans treated with certolizumab pegol. Int J Dermatol. 2022;61:e26-e28. doi:10.1111/ijd.15914
- Moussa A, Asfour L, Eisman S, et al. Successful treatment of folliculitis decalvans with baricitinib: a case series. Australas J Dermatol. 2022;63:279-281. doi:10.1111/ajd.13786
- Fässler M, Radonjic-Hoesli S, Feldmeyer L, et al. Successful treatment of refractory folliculitis decalvans with apremilast. JAAD Case Rep. 2020;6:1079-1081. doi:10.1016/j.jdcr.2020.08.019
- Ismail FF, Sinclair R. Successful treatment of refractory folliculitis decalvans with secukinumab. Australas J Dermatol. 2020;61:165-166. doi:10.1111/ajd.13190
- Miguel-Gómez L, Rodrigues-Barata AR, Molina-Ruiz A, et al. Folliculitis decalvans: effectiveness of therapies and prognostic factors in a multicenter series of 60 patients with long-term follow-up. J Am Acad Dermatol. 2018;79:878-883. doi:10.1016/j.jaad.2018.05.1240
- Tietze JK, Heppt MV, von Preußen A, et al. Oral isotretinoin as the most effective treatment in folliculitis decalvans: a retrospective comparison of different treatment regimens in 28 patients. J Eur Acad Dermatol Venereol. 2015;29:1816-1821. doi:10.1111/jdv.13052
- Otberg N, Kang H, Alzolibani AA, et al. Folliculitis decalvans. Dermatol Ther. 2008;21:238-244. doi:10.1111/j.1529-8019.2008.00204.x
- Shireen F, Sudhakar A. A case of isotretinoin therapy-refractory folliculitis decalvans treated successfully with biosimilar adalimumab (Exemptia). Int J Trichology. 2018;10:240-241.
- Iorizzo M, Starace M, Vano-Galvan S, et al. Refractory folliculitis decalvans treated with adalimumab: a case series of 23 patients. J Am Acad Dermatol. 2022;87:666-669. doi:10.1016/j.jaad.2022.02.044
- Kreutzer K, Effendy I. Therapy-resistant folliculitis decalvans and lichen planopilaris successfully treated with adalimumab. J Dtsch Dermatol Ges. 2014;12:74-76. doi:10.1111/ddg.12224
- Alhameedy MM, Alsantali AM. Therapy-recalcitrant folliculitis decalvans controlled successfully with adalimumab. Int J Trichology. 2019;11:241-243. doi:10.4103/ijt.ijt_92_19
- Mihaljevic´ N, von den Driesch P. Successful use of infliximab in a patient with recalcitrant folliculitis decalvans. J Dtsch Dermatol Ges. 2012;10:589-590. doi:10.1111/j.1610-0387.2012.07972.x
- Hoy M, Böhm M. Therapy-refractory folliculitis decalvans treated with certolizumab pegol. Int J Dermatol. 2022;61:e26-e28. doi:10.1111/ijd.15914
- Moussa A, Asfour L, Eisman S, et al. Successful treatment of folliculitis decalvans with baricitinib: a case series. Australas J Dermatol. 2022;63:279-281. doi:10.1111/ajd.13786
- Fässler M, Radonjic-Hoesli S, Feldmeyer L, et al. Successful treatment of refractory folliculitis decalvans with apremilast. JAAD Case Rep. 2020;6:1079-1081. doi:10.1016/j.jdcr.2020.08.019
- Ismail FF, Sinclair R. Successful treatment of refractory folliculitis decalvans with secukinumab. Australas J Dermatol. 2020;61:165-166. doi:10.1111/ajd.13190
- Miguel-Gómez L, Rodrigues-Barata AR, Molina-Ruiz A, et al. Folliculitis decalvans: effectiveness of therapies and prognostic factors in a multicenter series of 60 patients with long-term follow-up. J Am Acad Dermatol. 2018;79:878-883. doi:10.1016/j.jaad.2018.05.1240
- Tietze JK, Heppt MV, von Preußen A, et al. Oral isotretinoin as the most effective treatment in folliculitis decalvans: a retrospective comparison of different treatment regimens in 28 patients. J Eur Acad Dermatol Venereol. 2015;29:1816-1821. doi:10.1111/jdv.13052
Practice Points
- Tumor necrosis factor inhibitors, Janus kinase inhibitors, phosphodiesterase 4 inhibitors, and monoclonal antibodies have shown success in the treatment of folliculitis decalvans resistant to traditional therapies.
- The true etiology of folliculitis decalvans is still unknown, but possible factors include Staphylococcus aureus infection and an impaired host immune system, which may benefit from treatment with biologics and small molecule inhibitors.