- Email: [email protected]
Treatment of severe lichen planus with the JAK inhibitor tofacitinib
Journal Pre-proof Treatment of severe lichen planus with the JAK inhibitor tofacitinib William Damsky, MD, PhD, Alice Wang, BS, Brianna Olamiju, BA, Danielle Peterson, MD, Anjela Galan, MD, Brett King, MD, PhD PII:
S0091-6749(20)30120-2
DOI:
https://doi.org/10.1016/j.jaci.2020.01.031
Reference:
YMAI 14398
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 4 December 2019 Revised Date:
14 January 2020
Accepted Date: 21 January 2020
Please cite this article as: Damsky W, Wang A, Olamiju B, Peterson D, Galan A, King B, Treatment of severe lichen planus with the JAK inhibitor tofacitinib, Journal of Allergy and Clinical Immunology (2020), doi: https://doi.org/10.1016/j.jaci.2020.01.031. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
Treatment of severe lichen planus with the JAK inhibitor tofacitinib William Damsky MD, PhD1, Alice Wang BS1, Brianna Olamiju BA1, Danielle Peterson MD1, Anjela Galan MD1,2, Brett King MD, PhD1,* 1
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
2
*Author to whom correspondence should be addressed: Brett King MD, PhD 333 Cedar St, LCI 501, PO Box 208059, New Haven, CT 06520 Phone: 203-785-4092, Fax: 203-785-7637, Email: [email protected] Format: Letter to the Editor Words: 933 Figure/Table: 1 References: 6 Keywords: lichen planus, erosive lichen planus, JAK inhibitor, tofacitinib Capsule Summary: Lichen planus (LP) is frequently difficult to treat. Here we show that JAK-STAT signaling is activated in LP and that treatment with a JAK inhibitor, tofacitinib, was effective in 3 patients with recalcitrant erosive LP. Funding: This work was supported by the Ranjini and Ajay Poddar Fund for Dermatologic Diseases Research (BK). WD is supported by the Dermatology Foundation. Disclosures: WD has research funding from Pfizer, but it did not support this work. WD is a consultant for Eli Lilly. BAK is an investigator for Concert Pharmaceuticals Inc, Eli Lilly and Company, and Pfizer Inc. BAK is a consultant to and/or has served on advisory boards for Aclaris Therapeutics, Arena Pharmaceuticals, Bristol-Meyers Squibb, Concert Pharmaceuticals Inc, Dermavant Sciences, Eli Lilly and Company, and Pfizer Inc; he is on speakers bureau for Pfizer Inc, Regeneron and Sanofi Genzyme.
46
To the Editor,
47 48
Lichen planus (LP) is an inflammatory skin disease that affects cutaneous and/or
49
mucosal sites and is difficult to treat. Histologically, LP is characterized by a T cell
50
predominate lymphocytic response at the dermal-epidermal junction. Classic cutaneous
51
LP manifests as pruritic, flat-topped papules. Oral involvement in LP is common,
52
manifesting as reticulated white patches involving the buccal mucosa. Erosive lichen
53
planus (ELP) is a severe variant of LP that preferentially affects mucosal sites including
54
the mouth and/or genitals leading to painful ulcers and sometimes scarring.
55 56
ELP has a negative impact on normal daily function and can make speaking, eating, or
57
brushing one’s teeth a challenge, due to pain. There are no U.S. Food and Drug
58
Administration approved therapies for either LP or ELP. When severe, patients are often
59
treated with systemic corticosteroids; however, disease often recurs following cessation
60
and corticosteroids are inappropriate for chronic administration. Steroid-sparing agents
61
have failed to demonstrate reproducible efficacy in LP/ELP1. New molecularly targeted
62
therapies are direly needed.
63 64
The molecular pathogenesis of LP is not completely understood; however, Janus kinase
65
– signal transducer and activator of transcription (JAK-STAT) dependent cytokines such
66
as interferon gamma (IFN-γ) are postulated to play a role in disease pathogenesis. In
67
fact, Shao and colleagues recently demonstrated using in vitro approaches that T cell
68
directed anti-keratinocyte responses are enhanced by IFN-γ due to its activation of the
69
JAK-STAT pathway in keratinocytes2. They showed that a JAK1/2 inhibitor, baricitinib,
70
suppressed allogenic T cell responses against keratinocytes in vitro.
71 72
While JAK inhibitors have not been evaluated in LP in the clinic, the JAK inhibitor
73
tofacitinib was used to treat 10 patients with lichen planopilaris, a scarring alopecia that
74
has some histologic features that are similar to LP3. Other authors have also previously
75
postulated that JAK inhibition might be useful more broadly in LP4.
76 77
Based in part on the above data and in part on the success of JAK inhibition in the
78
treatment of other recalcitrant inflammatory skin diseases4, 5, we treated 3 patients with
79
recalcitrant ELP with tofacitinib, a JAK1/3 inhibitor. The patients ranged from 57-78
80
years old (Fig. 1, A and B). The duration of uncontrolled ELP ranged from 0.5-22 years.
81
Biopsies in all cases showed ELP, and other etiologies were excluded. Collectively
82
these patients had previously failed treatment with other commonly used medications
83
including prednisone, acitretin, methotrexate, mycophenolate mofetil, and cyclosporine
84
(Fig. 1B).
85 86
Patient 1 had severe, painful oral involvement leading to difficulty eating and speaking.
87
He also had ocular and penile involvement. Patient 2, in addition to severe, painful oral
88
involvement, leading to difficulty eating, had severe, painful vaginal and urethral
89
involvement, leading to disabling functional impairment. She required periodic
90
mechanical urethral dilation to preserve urinary function. Patient 3 had severe oral
91
involvement.
92 93
Tofacitinib 5mg twice daily was initiated with each patient’s verbal informed consent and
94
objective change in clinical disease activity was tracked using a validated scoring
95
system for oral ELP6. Marked improvement was noted in all 3 patients while taking
96
tofacitinib (Fig. 1C). Due to the severity of disease in Patient 1 and because he had not
97
responded to treatment with prednisone 60mg daily, a combination of tofacitinib and
98
methotrexate and prednisone 10mg daily were initially used and lead to dramatic
99
remission of both symptoms and clinically apparent disease (Fig. 1, A and C). At his
100
request, a trial off of tofacitinib and methotrexate was performed and the painful
101
erosions recurred, even with prednisone 10mg daily. Re-initiation of tofacitinib
102
monotherapy led again to improvement. Patients 2 and 3 experienced complete or near-
103
complete remission of their previously long-standing and refractory ELP with tofacitinib
104
monotherapy (Fig. 1C). Patient 2 noted the ability to eat and swallow without pain and
105
was able to brush her teeth without bleeding. Patient 3 noted the ability to eat without
106
pain and, strikingly, her speech normalized because she was again able to move her
107
lips and tongue without pain. Tofacitinib was well tolerated and there were no adverse
108
effects in these patients.
109 110
In their work, Shao et al. showed that in LP, STAT1 activation occurs in lesional
111
keratinocytes. We used phospho-STAT1 immunohistochemistry to evaluate STAT1
112
activation in biopsies from these 3 patients as well as de-identified biopsies from other
113
patients with LP/ELP. In total, we examined 11 cases of LP and 20 cases of ELP; the
114
latter included 8 cases of oral ELP, 6 cases of vulvovaginal ELP, and 5 cases of penile
115
ELP (see Supplemental Data). We found that all cases of LP and ELP showed
116
activation of STAT1 in keratinocytes, consistent with the effect of IFN-γ as proposed by
117
Shao et al. (Fig. 1, D and E). We also found excess IFN-γ production by lymphocytes in
118
ELP (Fig. 1D). Levels of activated STAT1 staining were slightly higher in ELP than LP
119
(Fig. 1D). Significant STAT1 activation was also observed in infiltrating lymphocytes.
120
Levels of STAT1 activation in keratinocytes observed in the 3 patients treated with
121
tofacitinib were comparable to biopsies from other patients included in this analysis.
122 123
These data illustrate the promise that JAK inhibitors hold for treatment of LP/ELP.
124
Tofacitinib, a JAK1/3 inhibitor was effective in all 3 of our patients. Whether or not a
125
JAK1/2 inhibitor, such as baricitinib, which was used in the pre-clinical Shao et al. study
126
might be equally or more effective remains to be determined. The efficacy of JAK
127
inhibitors in LP/ELP may involve suppression of JAK-STAT signaling in both
128
keratinocytes and lymphocytes. Our limited data suggests that continuous therapy is
129
required to maintain the therapeutic benefit. Together, our data as well as that of other
130
investigators provide both strong mechanistic rationale and clinical evidence for the
131
efficacy of JAK inhibitors in patients with LP and underscore the need for larger clinical
132
studies.
133 134
William Damsky MD, PhD1, Alice Wang BA1, Brianna Olamiju BA1, Danielle Peterson
135
MD1, Anjela Galan MD1,2, Brett King MD, PhD1,*
136
1
137
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
138 139 140 141
References
142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179
1.
2.
3. 4. 5. 6.
Schwager Z, Stern M, Cohen J, Femia A. Clinical epidemiology and treatment of lichen planus: A retrospective review of 2 tertiary care centers. J Am Acad Dermatol 2019; 81:1397-9. Shao S, Tsoi LC, Sarkar MK, Xing X, Xue K, Uppala R, et al. IFN-gamma enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus. Sci Transl Med 2019; 11. Yang CC, Khanna T, Sallee B, Christiano AM, Bordone LA. Tofacitinib for the treatment of lichen planopilaris: A case series. Dermatol Ther 2018; 31:e12656. Di Lernia V. Targeting the IFN-gamma/CXCL10 pathway in lichen planus. Med Hypotheses 2016; 92:60-1. Damsky W, King BA. JAK inhibitors in dermatology: The promise of a new drug class. J Am Acad Dermatol 2017; 76:736-44. Escudier M, Ahmed N, Shirlaw P, Setterfield J, Tappuni A, Black MM, et al. A scoring system for mucosal disease severity with special reference to oral lichen planus. Br J Dermatol 2007; 157:765-70.
180 181 182 183 184 185 186
Fig. 1 Tofacitinib leads to dramatic improvement in erosive lichen planus (ELP).
187
(A) Clinical photographs of Patients 1-3. Shown are pre-treatment (prior to initiation of
188
tofacitinib) and during-treatment images. The during-treatment photos from Patient 1
189
reflect a combination of tofacitinib and methotrexate. This patient was also continuously
190
taking prednisone 10 mg per day throughout. Patients 2 and 3 were treated with
191
tofacitinib monotherapy. (B) Baseline characteristics of patients. F: female, M: male,
192
DIF: direct immunofluorescence, IIF: indirect immunofluorescence, ELISA: quantitative
193
measurement of BP180, BP230, DSG1, and DSG3 antibodies in serum, B: diagnosis
194
supported by biopsy at this site, PR: partial response, NR: no response. (C) Percentage
195
improvement from baseline ELP severity score6 over time with tofacitinib therapy.
196
*Tofacitinib and methotrexate discontinued. **Tofacitinib monotherapy re-initiated. (D)
197
Representative phospho-STAT1 immunohistochemistry (TYR701) in lesional and
198
control tissue. Insets: Representative in situ hybridization to detect IFNG production. (E)
199
Quantification of keratinocyte phospho-STAT1 staining levels (see Supplemental Data)
200
*** p < 0.0001, ** p = 0.0011. Quantification of staining in biopsies from Patient 1 (blue),
201
Patient 2 (red) and patient 3 (green) are shown. Shown are the mean and [standard
202
deviation] for each condition. VV: vulvovaginal, Pen: penile.
203 204 205 206 207 208
209
Supplementary Materials for Treatment of severe lichen planus with the JAK inhibitor tofacitinib William Damsky, Alice Wang, Brianna Olamiju, Danielle Peterson, Anjela Galan, Brett King This file includes: Supplementary Experimental Methods Supplementary Table 1
Supplemental Experimental Methods
Prior to initiating tofacitinib in these patients, the risks of the medication were discussed. As is always the case in Dr. King’s clinic, a long discussion was had with the patients (and, when possible, their families) regarding their disease, JAK inhibitors and their potential adverse effects, and the patients were informed that tofacitinib would be used “off-label” for their lichen planus. Prior to initiation of tofacitinib, patients provided verbal informed consent. Skin biopsies were identified at random by searching the Yale Dermatopathology database and de-identified prior to any analysis. Research involving human specimens was reviewed and approved by the Yale Institutional Review Board (IRB). Basic charactersitics of the patients from which the biopsies were retained and are listed in the table below (Supplementary Table 1). All patients were felt to have lichen planus based on correlation of the clinical impression provided on the biopsy requisition plus typical histopathological findings of lichen planus. For normal skin, tips from skin cancer excisions were utilized (5 cases) and were also de-identified. For biopsies from the three patients treated with tofacitinib, the biopsies were de-identified/coded prior to any analysis being performed. For immunohistochemsitry antigen retrieval was performed using pH 6.0 citrate buffer. The phospho-STAT1 (TYR701) antibody was obtained from Cell Signaling Technology (58D6). Primary antibody was detected using ImmPRESS peroxidase reagent kit (Vector) and DAB chromogen substrate (Vector). Slides were counterstained with hematoxylin. For in situ hybridization, the IFNG probe was obtained from Advanced Cell Diagnostics (Hs-IFNG Cat #310501). The probe was hybridized to the tissue and
detected using the RNAScope kit (Advanced Cell Diagnostics) according to the manufacturer’s instructions. For quantification of phospho-STAT1 activity, three areas with active interface change were analyzed for each case (resulting in 3 data points for each case). The percentage of keratinocytes in the lower half of the epidermis (out 20 cells at the dermal-epidermal junction) showing nuclear STAT1 staining were counted per area (i.e. 3 areas x 20 keratinocytes each per case). Keratinocytes were identified based on their epithelioid morphology and location. The percentage of positive keratinocytes for each was to create Figure 1E.
Statistical significance was evaluated using an unpaired student’s t-test. Graphpad Prism software was used for the statistics and to calculate the mean and standard deviation.
Classic LP Age Sex 48 F 40 M 29 M 38 M 50 F 63 F 34 F 35 M 30 M 66 M 58 M ELP (Oral) Age Sex 67 F 43 M 34 F 57 F 41 F 71 M Patient #1 Patient #3 ELP (Vulvovaginal) 23 F 36 F 36 F 64 F 79 F Patient #2 ELP (Penile) 27 M 24 M 53 M 46 M Patient #1
Anatomic site leg arm lower leg arm hip wrist forearm lower leg forearm shoulder leg Anatomic site palate buccal mucosa buccal mucosa buccal mucosa buccal mucosa buccal mucosa vermillion lip buccal mucosa vulva vulva vulva vulva vulva vaginal penile shaft penis penis penis Penile sulcus
Supplementary Table 1. Basic characteristics of LP biopsies used for immunohistochemical case series.
S0091-6749(20)30120-2
DOI:
https://doi.org/10.1016/j.jaci.2020.01.031
Reference:
YMAI 14398
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 4 December 2019 Revised Date:
14 January 2020
Accepted Date: 21 January 2020
Please cite this article as: Damsky W, Wang A, Olamiju B, Peterson D, Galan A, King B, Treatment of severe lichen planus with the JAK inhibitor tofacitinib, Journal of Allergy and Clinical Immunology (2020), doi: https://doi.org/10.1016/j.jaci.2020.01.031. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
Treatment of severe lichen planus with the JAK inhibitor tofacitinib William Damsky MD, PhD1, Alice Wang BS1, Brianna Olamiju BA1, Danielle Peterson MD1, Anjela Galan MD1,2, Brett King MD, PhD1,* 1
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
2
*Author to whom correspondence should be addressed: Brett King MD, PhD 333 Cedar St, LCI 501, PO Box 208059, New Haven, CT 06520 Phone: 203-785-4092, Fax: 203-785-7637, Email: [email protected] Format: Letter to the Editor Words: 933 Figure/Table: 1 References: 6 Keywords: lichen planus, erosive lichen planus, JAK inhibitor, tofacitinib Capsule Summary: Lichen planus (LP) is frequently difficult to treat. Here we show that JAK-STAT signaling is activated in LP and that treatment with a JAK inhibitor, tofacitinib, was effective in 3 patients with recalcitrant erosive LP. Funding: This work was supported by the Ranjini and Ajay Poddar Fund for Dermatologic Diseases Research (BK). WD is supported by the Dermatology Foundation. Disclosures: WD has research funding from Pfizer, but it did not support this work. WD is a consultant for Eli Lilly. BAK is an investigator for Concert Pharmaceuticals Inc, Eli Lilly and Company, and Pfizer Inc. BAK is a consultant to and/or has served on advisory boards for Aclaris Therapeutics, Arena Pharmaceuticals, Bristol-Meyers Squibb, Concert Pharmaceuticals Inc, Dermavant Sciences, Eli Lilly and Company, and Pfizer Inc; he is on speakers bureau for Pfizer Inc, Regeneron and Sanofi Genzyme.
46
To the Editor,
47 48
Lichen planus (LP) is an inflammatory skin disease that affects cutaneous and/or
49
mucosal sites and is difficult to treat. Histologically, LP is characterized by a T cell
50
predominate lymphocytic response at the dermal-epidermal junction. Classic cutaneous
51
LP manifests as pruritic, flat-topped papules. Oral involvement in LP is common,
52
manifesting as reticulated white patches involving the buccal mucosa. Erosive lichen
53
planus (ELP) is a severe variant of LP that preferentially affects mucosal sites including
54
the mouth and/or genitals leading to painful ulcers and sometimes scarring.
55 56
ELP has a negative impact on normal daily function and can make speaking, eating, or
57
brushing one’s teeth a challenge, due to pain. There are no U.S. Food and Drug
58
Administration approved therapies for either LP or ELP. When severe, patients are often
59
treated with systemic corticosteroids; however, disease often recurs following cessation
60
and corticosteroids are inappropriate for chronic administration. Steroid-sparing agents
61
have failed to demonstrate reproducible efficacy in LP/ELP1. New molecularly targeted
62
therapies are direly needed.
63 64
The molecular pathogenesis of LP is not completely understood; however, Janus kinase
65
– signal transducer and activator of transcription (JAK-STAT) dependent cytokines such
66
as interferon gamma (IFN-γ) are postulated to play a role in disease pathogenesis. In
67
fact, Shao and colleagues recently demonstrated using in vitro approaches that T cell
68
directed anti-keratinocyte responses are enhanced by IFN-γ due to its activation of the
69
JAK-STAT pathway in keratinocytes2. They showed that a JAK1/2 inhibitor, baricitinib,
70
suppressed allogenic T cell responses against keratinocytes in vitro.
71 72
While JAK inhibitors have not been evaluated in LP in the clinic, the JAK inhibitor
73
tofacitinib was used to treat 10 patients with lichen planopilaris, a scarring alopecia that
74
has some histologic features that are similar to LP3. Other authors have also previously
75
postulated that JAK inhibition might be useful more broadly in LP4.
76 77
Based in part on the above data and in part on the success of JAK inhibition in the
78
treatment of other recalcitrant inflammatory skin diseases4, 5, we treated 3 patients with
79
recalcitrant ELP with tofacitinib, a JAK1/3 inhibitor. The patients ranged from 57-78
80
years old (Fig. 1, A and B). The duration of uncontrolled ELP ranged from 0.5-22 years.
81
Biopsies in all cases showed ELP, and other etiologies were excluded. Collectively
82
these patients had previously failed treatment with other commonly used medications
83
including prednisone, acitretin, methotrexate, mycophenolate mofetil, and cyclosporine
84
(Fig. 1B).
85 86
Patient 1 had severe, painful oral involvement leading to difficulty eating and speaking.
87
He also had ocular and penile involvement. Patient 2, in addition to severe, painful oral
88
involvement, leading to difficulty eating, had severe, painful vaginal and urethral
89
involvement, leading to disabling functional impairment. She required periodic
90
mechanical urethral dilation to preserve urinary function. Patient 3 had severe oral
91
involvement.
92 93
Tofacitinib 5mg twice daily was initiated with each patient’s verbal informed consent and
94
objective change in clinical disease activity was tracked using a validated scoring
95
system for oral ELP6. Marked improvement was noted in all 3 patients while taking
96
tofacitinib (Fig. 1C). Due to the severity of disease in Patient 1 and because he had not
97
responded to treatment with prednisone 60mg daily, a combination of tofacitinib and
98
methotrexate and prednisone 10mg daily were initially used and lead to dramatic
99
remission of both symptoms and clinically apparent disease (Fig. 1, A and C). At his
100
request, a trial off of tofacitinib and methotrexate was performed and the painful
101
erosions recurred, even with prednisone 10mg daily. Re-initiation of tofacitinib
102
monotherapy led again to improvement. Patients 2 and 3 experienced complete or near-
103
complete remission of their previously long-standing and refractory ELP with tofacitinib
104
monotherapy (Fig. 1C). Patient 2 noted the ability to eat and swallow without pain and
105
was able to brush her teeth without bleeding. Patient 3 noted the ability to eat without
106
pain and, strikingly, her speech normalized because she was again able to move her
107
lips and tongue without pain. Tofacitinib was well tolerated and there were no adverse
108
effects in these patients.
109 110
In their work, Shao et al. showed that in LP, STAT1 activation occurs in lesional
111
keratinocytes. We used phospho-STAT1 immunohistochemistry to evaluate STAT1
112
activation in biopsies from these 3 patients as well as de-identified biopsies from other
113
patients with LP/ELP. In total, we examined 11 cases of LP and 20 cases of ELP; the
114
latter included 8 cases of oral ELP, 6 cases of vulvovaginal ELP, and 5 cases of penile
115
ELP (see Supplemental Data). We found that all cases of LP and ELP showed
116
activation of STAT1 in keratinocytes, consistent with the effect of IFN-γ as proposed by
117
Shao et al. (Fig. 1, D and E). We also found excess IFN-γ production by lymphocytes in
118
ELP (Fig. 1D). Levels of activated STAT1 staining were slightly higher in ELP than LP
119
(Fig. 1D). Significant STAT1 activation was also observed in infiltrating lymphocytes.
120
Levels of STAT1 activation in keratinocytes observed in the 3 patients treated with
121
tofacitinib were comparable to biopsies from other patients included in this analysis.
122 123
These data illustrate the promise that JAK inhibitors hold for treatment of LP/ELP.
124
Tofacitinib, a JAK1/3 inhibitor was effective in all 3 of our patients. Whether or not a
125
JAK1/2 inhibitor, such as baricitinib, which was used in the pre-clinical Shao et al. study
126
might be equally or more effective remains to be determined. The efficacy of JAK
127
inhibitors in LP/ELP may involve suppression of JAK-STAT signaling in both
128
keratinocytes and lymphocytes. Our limited data suggests that continuous therapy is
129
required to maintain the therapeutic benefit. Together, our data as well as that of other
130
investigators provide both strong mechanistic rationale and clinical evidence for the
131
efficacy of JAK inhibitors in patients with LP and underscore the need for larger clinical
132
studies.
133 134
William Damsky MD, PhD1, Alice Wang BA1, Brianna Olamiju BA1, Danielle Peterson
135
MD1, Anjela Galan MD1,2, Brett King MD, PhD1,*
136
1
137
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
138 139 140 141
References
142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179
1.
2.
3. 4. 5. 6.
Schwager Z, Stern M, Cohen J, Femia A. Clinical epidemiology and treatment of lichen planus: A retrospective review of 2 tertiary care centers. J Am Acad Dermatol 2019; 81:1397-9. Shao S, Tsoi LC, Sarkar MK, Xing X, Xue K, Uppala R, et al. IFN-gamma enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus. Sci Transl Med 2019; 11. Yang CC, Khanna T, Sallee B, Christiano AM, Bordone LA. Tofacitinib for the treatment of lichen planopilaris: A case series. Dermatol Ther 2018; 31:e12656. Di Lernia V. Targeting the IFN-gamma/CXCL10 pathway in lichen planus. Med Hypotheses 2016; 92:60-1. Damsky W, King BA. JAK inhibitors in dermatology: The promise of a new drug class. J Am Acad Dermatol 2017; 76:736-44. Escudier M, Ahmed N, Shirlaw P, Setterfield J, Tappuni A, Black MM, et al. A scoring system for mucosal disease severity with special reference to oral lichen planus. Br J Dermatol 2007; 157:765-70.
180 181 182 183 184 185 186
Fig. 1 Tofacitinib leads to dramatic improvement in erosive lichen planus (ELP).
187
(A) Clinical photographs of Patients 1-3. Shown are pre-treatment (prior to initiation of
188
tofacitinib) and during-treatment images. The during-treatment photos from Patient 1
189
reflect a combination of tofacitinib and methotrexate. This patient was also continuously
190
taking prednisone 10 mg per day throughout. Patients 2 and 3 were treated with
191
tofacitinib monotherapy. (B) Baseline characteristics of patients. F: female, M: male,
192
DIF: direct immunofluorescence, IIF: indirect immunofluorescence, ELISA: quantitative
193
measurement of BP180, BP230, DSG1, and DSG3 antibodies in serum, B: diagnosis
194
supported by biopsy at this site, PR: partial response, NR: no response. (C) Percentage
195
improvement from baseline ELP severity score6 over time with tofacitinib therapy.
196
*Tofacitinib and methotrexate discontinued. **Tofacitinib monotherapy re-initiated. (D)
197
Representative phospho-STAT1 immunohistochemistry (TYR701) in lesional and
198
control tissue. Insets: Representative in situ hybridization to detect IFNG production. (E)
199
Quantification of keratinocyte phospho-STAT1 staining levels (see Supplemental Data)
200
*** p < 0.0001, ** p = 0.0011. Quantification of staining in biopsies from Patient 1 (blue),
201
Patient 2 (red) and patient 3 (green) are shown. Shown are the mean and [standard
202
deviation] for each condition. VV: vulvovaginal, Pen: penile.
203 204 205 206 207 208
209
Supplementary Materials for Treatment of severe lichen planus with the JAK inhibitor tofacitinib William Damsky, Alice Wang, Brianna Olamiju, Danielle Peterson, Anjela Galan, Brett King This file includes: Supplementary Experimental Methods Supplementary Table 1
Supplemental Experimental Methods
Prior to initiating tofacitinib in these patients, the risks of the medication were discussed. As is always the case in Dr. King’s clinic, a long discussion was had with the patients (and, when possible, their families) regarding their disease, JAK inhibitors and their potential adverse effects, and the patients were informed that tofacitinib would be used “off-label” for their lichen planus. Prior to initiation of tofacitinib, patients provided verbal informed consent. Skin biopsies were identified at random by searching the Yale Dermatopathology database and de-identified prior to any analysis. Research involving human specimens was reviewed and approved by the Yale Institutional Review Board (IRB). Basic charactersitics of the patients from which the biopsies were retained and are listed in the table below (Supplementary Table 1). All patients were felt to have lichen planus based on correlation of the clinical impression provided on the biopsy requisition plus typical histopathological findings of lichen planus. For normal skin, tips from skin cancer excisions were utilized (5 cases) and were also de-identified. For biopsies from the three patients treated with tofacitinib, the biopsies were de-identified/coded prior to any analysis being performed. For immunohistochemsitry antigen retrieval was performed using pH 6.0 citrate buffer. The phospho-STAT1 (TYR701) antibody was obtained from Cell Signaling Technology (58D6). Primary antibody was detected using ImmPRESS peroxidase reagent kit (Vector) and DAB chromogen substrate (Vector). Slides were counterstained with hematoxylin. For in situ hybridization, the IFNG probe was obtained from Advanced Cell Diagnostics (Hs-IFNG Cat #310501). The probe was hybridized to the tissue and
detected using the RNAScope kit (Advanced Cell Diagnostics) according to the manufacturer’s instructions. For quantification of phospho-STAT1 activity, three areas with active interface change were analyzed for each case (resulting in 3 data points for each case). The percentage of keratinocytes in the lower half of the epidermis (out 20 cells at the dermal-epidermal junction) showing nuclear STAT1 staining were counted per area (i.e. 3 areas x 20 keratinocytes each per case). Keratinocytes were identified based on their epithelioid morphology and location. The percentage of positive keratinocytes for each was to create Figure 1E.
Statistical significance was evaluated using an unpaired student’s t-test. Graphpad Prism software was used for the statistics and to calculate the mean and standard deviation.
Classic LP Age Sex 48 F 40 M 29 M 38 M 50 F 63 F 34 F 35 M 30 M 66 M 58 M ELP (Oral) Age Sex 67 F 43 M 34 F 57 F 41 F 71 M Patient #1 Patient #3 ELP (Vulvovaginal) 23 F 36 F 36 F 64 F 79 F Patient #2 ELP (Penile) 27 M 24 M 53 M 46 M Patient #1
Anatomic site leg arm lower leg arm hip wrist forearm lower leg forearm shoulder leg Anatomic site palate buccal mucosa buccal mucosa buccal mucosa buccal mucosa buccal mucosa vermillion lip buccal mucosa vulva vulva vulva vulva vulva vaginal penile shaft penis penis penis Penile sulcus
Supplementary Table 1. Basic characteristics of LP biopsies used for immunohistochemical case series.