- Email: [email protected]
Systemic Inflammation Gone Awry: PASH Syndrome and Temporomandibular Joint Ankylosis
DIAGNOSTIC DILEMMA Thomas J. Marrie, MD, Section Editor
Systemic Inflammation Gone Awry: PASH Syndrome and Temporomandibular Joint Ankylosis Jeffrey J. Wargo, MD, Brian T. Emmer, MD, PhD Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.
PRESENTATION
ASSESSMENT
The development of new symptoms in a patient with hidradenitis suppurativa led to the recognition of a systemic autoinflammatory condition. A long battle with hidradenitis suppurativa and acne became even more difficult for a 24-year-old man who developed increasing pain and malodorous drainage from the chronic subcutaneous nodules on his axillae, groin, and buttocks, as well as new rapidly progressive ulcers on his legs. He had first been diagnosed with hidradenitis suppurativa at age 13 years. His skin lesions had been managed with hygiene, wound care, and topical and oral antibiotics. Despite this, lesions on his buttocks became especially severe, prompting excisional surgery with skin grafting and diverting loop ileostomy at age 21 years. Perioperative testing had revealed a fistula between a buttocks lesion and his rectum, which was managed conservatively. Computed tomography did not reveal radiographic features of inflammatory bowel disease. He had no personal or family history of inflammatory bowel disease. His recent medical care had been limited because of his incarceration until a few months previously. In addition to his worsening skin lesions, he also reported a history of progressive trismus. He had sustained facial trauma in a physical altercation 8 years ago but had normal jaw function until 2 years ago, when he developed progressive difficulty and pain with opening his mouth. He now was unable to open his mouth more than 1 to 2 inches, causing him difficulty with eating and speaking.
On admission, he had a temperature of 36.3 C, a blood pressure of 129/73 mm Hg, a heart rate of 86 beats/min, a respiratory rate of 14 breaths/min, and an oxygen saturation of 100% on room air. He appeared uncomfortable but not acutely ill. He had numerous tender nodules involving the axillae, face, medial thighs, and buttocks with extensive scarring, induration, and open sinus tracts draining purulent fluid (Figure 1). He also had bilateral lower-extremity large ulcerations with hyperpigmented and indurated margins in addition to hemorrhagic pustules and papules with early ulcer formation (Figures 2 and 3). He had substantial tenderness over his bilateral temporomandibular joints and was unable to open his mouth to more than a maximal inter-incisor opening of 4 mm. Laboratory analysis demonstrated elevated inflammatory markers (erythrocyte sedimentation rate 88 mm, C-reactive protein 4.0 mg/dL). He was treated with intravenous fluids, analgesics, and wound care. On the basis of a suspected bacterial superinfection of his hidradenitis suppurative lesions, broad-spectrum intravenous antibiotics with vancomycin and cefepime were administered. On the basis of the appearance of his lower-extremity ulcers, pyoderma gangrenosum was suspected, and punch biopsies were sent for analysis. To further evaluate his trismus, computed tomography of his maxillofacial bones was performed.
Funding: None. Conflict of Interest: None. Authorship: Both authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Jeffrey J. Wargo, MD, Department of Internal Medicine, University of Michigan Medical School, 1500 East Medical Center Dr, Ann Arbor, MI 48109. E-mail address: [email protected]
0002-9343/$ -see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjmed.2015.12.019
DIAGNOSIS Hidradenitis suppurativa is a chronic relapsing condition associated with follicular occlusion. It most commonly affects regions of skin containing a high density of folliculopilosebaceous units, such as the axilla, groin, and buttock. Presentation consists of recurrent, painful, inflamed odorous pustules and nodules, resulting in fibrous scars. Our patient’s pain improved with initial management. Skin biopsies of his leg ulcers revealed a superficial neutrophilic and granulomatous infiltrate with pustular exudate, consistent with pyoderma
e2
The American Journal of Medicine, Vol 129, No 4, April 2016
Figure 1 Tender nodules involving the axillae associated with extensive scarring, induration, and open sinus tracts.
gangrenosum with bacterial superinfection. Pyoderma gangrenosum characteristically evolves rapidly from an initial pustule or papule into a quickly expanding and painful ulcer with neutrophil-predominant infiltrates. It has been associated with several diseases, including inflammatory bowel disease, inflammatory arthritis, and hematologic malignancy. Less commonly, as in our patient, pyoderma gangrenosum is associated with acne and suppurative hidradenitis, a constellation of findings collectively described as pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) syndrome. Pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome is a recently described autoinflammatory disorder similar to but distinct from the previously recognized pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome.1 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome is an autosomal dominant hereditary disease caused by mutations in the PSTPIP1 gene on chromosome 15.2 Proline-serine-threonine phosphatase interacting protein 1 encodes a protein that appears to be involved in inflammasome formation and interleukin-1 b
activation through interaction with pyrin (mutations in which underlie familial Mediterranean fever).3 Targeted therapy of pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome with the interleukin-1 receptor antagonist anakinra has been reported.4 In contrast to pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome, the molecular pathogenesis of pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome remains unknown. On the basis of its clinical features and their similarity to other syndromes, pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome is suspected to be caused by dysregulation of inflammatory pathways. Pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome does not follow a strict Mendelian inheritance, and targeted exonic sequencing of proline-serine-threonine phosphatase interacting protein 1, MEFV, NLRP3, and TNFRSF1A did not identify candidate mutations.1 In regard to our patient’s diagnostic evaluation for trismus, maxillofacial computed tomography revealed diffuse nodular thickening of the skin and subcutaneous soft tissues of the face related to hidradenitis suppurative with associated severe degenerative changes and ankylosis of the bilateral temporomandibular joints (Figure 4). Temporomandibular joint ankylosis is characterized by fusion of the mandible with the fossa by bony or fibrotic tissue.5 It can be caused by many factors, including trauma, infection, inflammation,
Figure 2 Left lower extremity with large ulcerations with hyperpigmented and indurated margins.
Figure 3 Right lower-extremity hemorrhagic pustules and papules with early ulcer formation.
Wargo and Emmer
Systemic Inflammation Gone Awry
Figure 4 Normal temporomandibular joints. Ankylosis of temporomandibular joints.
e3 azathioprine, and plasmapheresis, have been used to treat pyoderma gangrenosum.10 For our patient’s temporomandibular joint ankylosis, he was scheduled for outpatient follow-up with oral and maxillofacial surgery to discuss bilateral gap arthroplasty and temporalis flap. The surgical management of temporomandibular joint ankylosis poses a significant challenge, because several different approaches have been associated with modest outcomes and high rates of recurrence.11
CONCLUSIONS arthritis, and congenital malformations. The cause of our patient’s temporomandibular joint ankylosis is unclear, with possible contributions from prior trauma and infected hidradenitis suppurative lesions. Of note, another case report described a patient who would otherwise exhibit features of pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome but who also developed inflammatory arthritis involving the axial spine (seronegative spondyloarthritis). The term “pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis syndrome” was proposed to describe this association.6
MANAGEMENT After confirmation of pyoderma gangrenosum on biopsy, intravenous methylprednisolone 100 mg daily for 3 days was initiated. This was transitioned to oral prednisone 60 mg daily thereafter with a plan to taper by 10 mg each week over 6 weeks. Wound care included daily gentle soap and water scrubs, topical mupirocin and clindamycin, and zinc oxide paste to serve as a barrier cream to prevent further skin breakdown. Antibiotics were transitioned to oral doxycycline and amoxicillin/clavulanic acid to complete an additional 4 weeks of therapy. His ulcer stabilized and started to improve within 1 week. After treatment of his acute infection and tapering of his steroids, he was recommended to initiate infliximab therapy. Observational studies have demonstrated promise for infliximab in the treatment of both pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome and pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis syndrome.6,7 More broadly, tumor necrosis factor-alpha antagonists may be used in the management of both isolated pyoderma gangrenosum and hidradenitis suppurativa. One randomized controlled trial of infliximab for the treatment of pyoderma gangrenosum included 30 patients receiving infliximab with a response rate of 69% versus 21% maintaining complete remission.8 Another open-label trial of 38 patients with moderate to severe hidradenitis suppurativa revealed a beneficial effect of infliximab by 8 weeks with a 50% or greater reduction in disease severity scores versus placebotreated patients.9 In addition to tumor necrosis factor-alpha antagonists, other immunomodulatory therapies, including cyclosporine, methotrexate, mycophenolate, tacrolimus,
Patients with pyoderma gangrenosum should be evaluated for associated conditions, including pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome, pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome, and pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis syndrome. Diagnosis is established by tissue biopsy and identification of each of the associated features of the syndrome. Wound care and immunomodulatory therapy are important components of treatment for these systemic autoinflammatory conditions.
References 1. Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)ea new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012;66:409-415. 2. Wise CA, Gillum JD, Seidman CE, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet. 2002;11:961-969. 3. Shoham NG, Centola M, Mansfield E, et al. Pyrin binds the PSTPIP1/ CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100:13501-13506. 4. Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens JJ. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology (Oxford). 2005;44:406-408. 5. Gundlach KK. Ankylosis of the temporomandibular joint. J Craniomaxillofac Surg. 2010;38:122-130. 6. Bruzzese V. Pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis: efficacy of anti a tumor necrosis factor therapy. J Clin Rheumatol. 2012;18:413-415. 7. Staub J, Pfannschmidt N, Strohal R, et al. Successful treatment of PASH syndrome with infliximab, cyclosporine and dapsone. J Eur Acad Dermatol Venereol. 2015;29:2243-2247. 8. Brooklyn TN, Dunnill MG, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomized, double blind, placebo controlled trial. Gut. 2006;55:505-509. 9. Grant A, Gonzalez T, Montgomery MO, Cardenas V, Kerdel FA. Infliximab therapy for patients with moderate to severe hidradenitis suppurativa: a randomized, double-blind, placebo-controlled crossover trial. J Am Acad Dermatol. 2010;62:205-217. 10. Reichrath J, Bens G, Bonowitz A, Tilgen W. Treatment recommendations for pyoderma gangrenosum: an evidence-based review of the literature based on more than 350 patients. J Am Acad Dermatol. 2005;53:273-283. 11. Al-Moraissi EA, El-Sharkawy TM, Mounair RM, El-Ghareeb TI. A systemic review and met-analysis of the clinical outcomes for various surgical modalities in the management of temporomandibular joint ankylosis. Int J Oral Maxillofac Surg. 2015;44: 470-482.
Systemic Inflammation Gone Awry: PASH Syndrome and Temporomandibular Joint Ankylosis Jeffrey J. Wargo, MD, Brian T. Emmer, MD, PhD Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.
PRESENTATION
ASSESSMENT
The development of new symptoms in a patient with hidradenitis suppurativa led to the recognition of a systemic autoinflammatory condition. A long battle with hidradenitis suppurativa and acne became even more difficult for a 24-year-old man who developed increasing pain and malodorous drainage from the chronic subcutaneous nodules on his axillae, groin, and buttocks, as well as new rapidly progressive ulcers on his legs. He had first been diagnosed with hidradenitis suppurativa at age 13 years. His skin lesions had been managed with hygiene, wound care, and topical and oral antibiotics. Despite this, lesions on his buttocks became especially severe, prompting excisional surgery with skin grafting and diverting loop ileostomy at age 21 years. Perioperative testing had revealed a fistula between a buttocks lesion and his rectum, which was managed conservatively. Computed tomography did not reveal radiographic features of inflammatory bowel disease. He had no personal or family history of inflammatory bowel disease. His recent medical care had been limited because of his incarceration until a few months previously. In addition to his worsening skin lesions, he also reported a history of progressive trismus. He had sustained facial trauma in a physical altercation 8 years ago but had normal jaw function until 2 years ago, when he developed progressive difficulty and pain with opening his mouth. He now was unable to open his mouth more than 1 to 2 inches, causing him difficulty with eating and speaking.
On admission, he had a temperature of 36.3 C, a blood pressure of 129/73 mm Hg, a heart rate of 86 beats/min, a respiratory rate of 14 breaths/min, and an oxygen saturation of 100% on room air. He appeared uncomfortable but not acutely ill. He had numerous tender nodules involving the axillae, face, medial thighs, and buttocks with extensive scarring, induration, and open sinus tracts draining purulent fluid (Figure 1). He also had bilateral lower-extremity large ulcerations with hyperpigmented and indurated margins in addition to hemorrhagic pustules and papules with early ulcer formation (Figures 2 and 3). He had substantial tenderness over his bilateral temporomandibular joints and was unable to open his mouth to more than a maximal inter-incisor opening of 4 mm. Laboratory analysis demonstrated elevated inflammatory markers (erythrocyte sedimentation rate 88 mm, C-reactive protein 4.0 mg/dL). He was treated with intravenous fluids, analgesics, and wound care. On the basis of a suspected bacterial superinfection of his hidradenitis suppurative lesions, broad-spectrum intravenous antibiotics with vancomycin and cefepime were administered. On the basis of the appearance of his lower-extremity ulcers, pyoderma gangrenosum was suspected, and punch biopsies were sent for analysis. To further evaluate his trismus, computed tomography of his maxillofacial bones was performed.
Funding: None. Conflict of Interest: None. Authorship: Both authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Jeffrey J. Wargo, MD, Department of Internal Medicine, University of Michigan Medical School, 1500 East Medical Center Dr, Ann Arbor, MI 48109. E-mail address: [email protected]
0002-9343/$ -see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjmed.2015.12.019
DIAGNOSIS Hidradenitis suppurativa is a chronic relapsing condition associated with follicular occlusion. It most commonly affects regions of skin containing a high density of folliculopilosebaceous units, such as the axilla, groin, and buttock. Presentation consists of recurrent, painful, inflamed odorous pustules and nodules, resulting in fibrous scars. Our patient’s pain improved with initial management. Skin biopsies of his leg ulcers revealed a superficial neutrophilic and granulomatous infiltrate with pustular exudate, consistent with pyoderma
e2
The American Journal of Medicine, Vol 129, No 4, April 2016
Figure 1 Tender nodules involving the axillae associated with extensive scarring, induration, and open sinus tracts.
gangrenosum with bacterial superinfection. Pyoderma gangrenosum characteristically evolves rapidly from an initial pustule or papule into a quickly expanding and painful ulcer with neutrophil-predominant infiltrates. It has been associated with several diseases, including inflammatory bowel disease, inflammatory arthritis, and hematologic malignancy. Less commonly, as in our patient, pyoderma gangrenosum is associated with acne and suppurative hidradenitis, a constellation of findings collectively described as pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) syndrome. Pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome is a recently described autoinflammatory disorder similar to but distinct from the previously recognized pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome.1 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome is an autosomal dominant hereditary disease caused by mutations in the PSTPIP1 gene on chromosome 15.2 Proline-serine-threonine phosphatase interacting protein 1 encodes a protein that appears to be involved in inflammasome formation and interleukin-1 b
activation through interaction with pyrin (mutations in which underlie familial Mediterranean fever).3 Targeted therapy of pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome with the interleukin-1 receptor antagonist anakinra has been reported.4 In contrast to pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome, the molecular pathogenesis of pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome remains unknown. On the basis of its clinical features and their similarity to other syndromes, pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome is suspected to be caused by dysregulation of inflammatory pathways. Pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome does not follow a strict Mendelian inheritance, and targeted exonic sequencing of proline-serine-threonine phosphatase interacting protein 1, MEFV, NLRP3, and TNFRSF1A did not identify candidate mutations.1 In regard to our patient’s diagnostic evaluation for trismus, maxillofacial computed tomography revealed diffuse nodular thickening of the skin and subcutaneous soft tissues of the face related to hidradenitis suppurative with associated severe degenerative changes and ankylosis of the bilateral temporomandibular joints (Figure 4). Temporomandibular joint ankylosis is characterized by fusion of the mandible with the fossa by bony or fibrotic tissue.5 It can be caused by many factors, including trauma, infection, inflammation,
Figure 2 Left lower extremity with large ulcerations with hyperpigmented and indurated margins.
Figure 3 Right lower-extremity hemorrhagic pustules and papules with early ulcer formation.
Wargo and Emmer
Systemic Inflammation Gone Awry
Figure 4 Normal temporomandibular joints. Ankylosis of temporomandibular joints.
e3 azathioprine, and plasmapheresis, have been used to treat pyoderma gangrenosum.10 For our patient’s temporomandibular joint ankylosis, he was scheduled for outpatient follow-up with oral and maxillofacial surgery to discuss bilateral gap arthroplasty and temporalis flap. The surgical management of temporomandibular joint ankylosis poses a significant challenge, because several different approaches have been associated with modest outcomes and high rates of recurrence.11
CONCLUSIONS arthritis, and congenital malformations. The cause of our patient’s temporomandibular joint ankylosis is unclear, with possible contributions from prior trauma and infected hidradenitis suppurative lesions. Of note, another case report described a patient who would otherwise exhibit features of pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome but who also developed inflammatory arthritis involving the axial spine (seronegative spondyloarthritis). The term “pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis syndrome” was proposed to describe this association.6
MANAGEMENT After confirmation of pyoderma gangrenosum on biopsy, intravenous methylprednisolone 100 mg daily for 3 days was initiated. This was transitioned to oral prednisone 60 mg daily thereafter with a plan to taper by 10 mg each week over 6 weeks. Wound care included daily gentle soap and water scrubs, topical mupirocin and clindamycin, and zinc oxide paste to serve as a barrier cream to prevent further skin breakdown. Antibiotics were transitioned to oral doxycycline and amoxicillin/clavulanic acid to complete an additional 4 weeks of therapy. His ulcer stabilized and started to improve within 1 week. After treatment of his acute infection and tapering of his steroids, he was recommended to initiate infliximab therapy. Observational studies have demonstrated promise for infliximab in the treatment of both pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome and pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis syndrome.6,7 More broadly, tumor necrosis factor-alpha antagonists may be used in the management of both isolated pyoderma gangrenosum and hidradenitis suppurativa. One randomized controlled trial of infliximab for the treatment of pyoderma gangrenosum included 30 patients receiving infliximab with a response rate of 69% versus 21% maintaining complete remission.8 Another open-label trial of 38 patients with moderate to severe hidradenitis suppurativa revealed a beneficial effect of infliximab by 8 weeks with a 50% or greater reduction in disease severity scores versus placebotreated patients.9 In addition to tumor necrosis factor-alpha antagonists, other immunomodulatory therapies, including cyclosporine, methotrexate, mycophenolate, tacrolimus,
Patients with pyoderma gangrenosum should be evaluated for associated conditions, including pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome, pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome, and pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis syndrome. Diagnosis is established by tissue biopsy and identification of each of the associated features of the syndrome. Wound care and immunomodulatory therapy are important components of treatment for these systemic autoinflammatory conditions.
References 1. Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)ea new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012;66:409-415. 2. Wise CA, Gillum JD, Seidman CE, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet. 2002;11:961-969. 3. Shoham NG, Centola M, Mansfield E, et al. Pyrin binds the PSTPIP1/ CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100:13501-13506. 4. Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens JJ. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology (Oxford). 2005;44:406-408. 5. Gundlach KK. Ankylosis of the temporomandibular joint. J Craniomaxillofac Surg. 2010;38:122-130. 6. Bruzzese V. Pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and axial spondyloarthritis: efficacy of anti a tumor necrosis factor therapy. J Clin Rheumatol. 2012;18:413-415. 7. Staub J, Pfannschmidt N, Strohal R, et al. Successful treatment of PASH syndrome with infliximab, cyclosporine and dapsone. J Eur Acad Dermatol Venereol. 2015;29:2243-2247. 8. Brooklyn TN, Dunnill MG, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomized, double blind, placebo controlled trial. Gut. 2006;55:505-509. 9. Grant A, Gonzalez T, Montgomery MO, Cardenas V, Kerdel FA. Infliximab therapy for patients with moderate to severe hidradenitis suppurativa: a randomized, double-blind, placebo-controlled crossover trial. J Am Acad Dermatol. 2010;62:205-217. 10. Reichrath J, Bens G, Bonowitz A, Tilgen W. Treatment recommendations for pyoderma gangrenosum: an evidence-based review of the literature based on more than 350 patients. J Am Acad Dermatol. 2005;53:273-283. 11. Al-Moraissi EA, El-Sharkawy TM, Mounair RM, El-Ghareeb TI. A systemic review and met-analysis of the clinical outcomes for various surgical modalities in the management of temporomandibular joint ankylosis. Int J Oral Maxillofac Surg. 2015;44: 470-482.