- Email: [email protected]
Conversion to Positive Latent Tuberculosis Infection Status is Low in Hidradenitis Suppurativa Patients Taking Biologic Medications
Journal Pre-proof Conversion to Positive Latent Tuberculosis Infection Status is Low in Hidradenitis Suppurativa Patients Taking Biologic Medications Ariana Ellis, BS, Urmi Khanna, MD, AbdulAziz Galadari, MD, Anthony P. Fernandez, MD, PhD PII:
S0190-9622(20)30055-4
DOI:
https://doi.org/10.1016/j.jaad.2020.01.012
Reference:
YMJD 14134
To appear in:
Journal of the American Academy of Dermatology
Received Date: 8 July 2019 Revised Date:
27 December 2019
Accepted Date: 8 January 2020
Please cite this article as: Ellis A, Khanna U, Galadari A, Fernandez AP, Conversion to Positive Latent Tuberculosis Infection Status is Low in Hidradenitis Suppurativa Patients Taking Biologic Medications, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/ j.jaad.2020.01.012. 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 on behalf of the American Academy of Dermatology, Inc.
1
1 2 3 4 5
Conversion to Positive Latent Tuberculosis Infection Status is Low in Hidradenitis Suppurativa Patients Taking Biologic Medications Ariana Ellis, BS1,3, Urmi Khanna, MD3, AbdulAziz Galadari, MD3, Anthony P. Fernandez, MD, PhD2,3 1
Northeast Ohio Medical University, Rootstown, Ohio, USA Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA 3 Department of Dermatology, Cleveland Clinic, Cleveland, Ohio, USA 2
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
Corresponding Author: Anthony P. Fernandez, MD, PhD Assistant Clinical Professor, Cleveland Clinic Lerner College of Medicine W.D. Steck Chair of Clinical Dermatology Director of Medical and Inpatient Dermatology Staff Dermatologist and Dermatopathologist Departments of Dermatology and Pathology Cleveland Clinic 9500 Euclid Avenue; A61 Cleveland, Ohio 44195 Telephone: 216-445-8776 Fax: 216-636-0711 Email: [email protected] Authors’ Contributions: All authors contributed to the preparation of this manuscript. Conflict of interest: A.P.F. receives research support from Mallinckrodt, Corbus, Pfizer and Novartis and honorarium from AbbVie, Novartis, UCB, and Mallinckrodt for consulting, advisory board participation, and speaking. The other authors have no conflicts of interest to disclose. Funding: This article has no funding source Prior presentations: None IRB statement: This study was approved by Cleveland Clinic’s Institutional Review Board Manuscript: 500 words References: 5 Tables: 2 Figures: 0
Keywords: Hidradenitis Suppurativa, latent tuberculosis, biologics, TNF inhibitors, Quantiferon
2
42 43
To the Editor: Hidradenitis suppurativa (HS) is a chronic inflammatory disease that affects
44
intertriginous areas. Adalimumab is FDA-approved for HS treatment, but other TNF-α inhibitors
45
(TNFIs) may be effective1. Tuberculosis (TB) reactivation risk is well-known in patients taking
46
TNFIs, and latent tuberculosis infection (LTBI) screening prior to TNFI initiation is
47
recommended. Several organizations additionally recommend annual LTBI screening in patients
48
taking biologics2. However, value of serial LTBI screening in low-risk populations is
49
questionable3. There is limited data regarding incidence of LTBI conversion in HS patients
50
treated with biologics4,5. Given this, and because other biologics are being studied as HS
51
treatments, we reviewed LTBI screening results in HS patients on biologics to assess value of
52
serial testing.
53
After IRB approval, we identified HS patients treated for ≥3 months with a biologic and
54
≥2 documented LTBI test results from 2007-2019. Patients without HS, lacking biologic
55
exposure for >3 months, and/or with <2 LTBI test results were excluded. For patients with
56
positive or indeterminate QFT results, retrospective review of medical records was performed.
57
Analysis included calculating means, overall counts, and percentages.
58
One hundred seventy HS patients met our inclusion criteria. Associated chronic
59
inflammatory conditions in our HS population are noted in Table 1. Seventy-two patients were
60
treated with >1 biologic, with an average 1.7 unique biologics per patient. The most frequently
61
prescribed biologics were TNFIs. While treated with biologics, 64.7% of patients also received
62
>1 other immunosuppressive agent.
63 64
The cohort had 521 QFT tests, averaging 3.06 tests per patient. Of 170 patients, 143 (84.1%) had only negative QFT results, 18 (10.6%) had ≥1 indeterminate result, and 9 (5.3%)
3
65
had ≥1 positive result (Table 1). Four patients (2.4%) converted from initial negative QFT to
66
positive. Two of four converters had documented TB risk factors (Table 2). Only 4/9 patients
67
with positive QFTs were treated for LTBI, 3 of whom were converters. Of 5 patients not treated
68
for LTBI, 3 had follow-up negative tuberculin skin tests, 1 was previously treated for LTBI, and
69
1 was previously treated for active TB as an adolescent. No patient developed active TB.
70
TB reactivation risk in patients receiving TNFIs is well established5. Despite this, only 4
71
patients (2.4%) in our cohort converted to a positive QFT following biologic initiation. Other
72
studies have described a low percentage of QFT conversion in psoriasis patients on TNFIs
73
(0.4%)3. While LTBI screening prior to biologic initiation is important due to reactivation risk,
74
our results suggest routine serial LTBI testing of HS patients in low-risk areas taking biologics
75
may be unnecessary. False positive and indeterminate test results in this population may lead to
76
further testing, referrals, unnecessary treatment/adverse events, and excessive healthcare costs.
77
Alternatively, focusing repeat LTBI screening in patients accumulating new TB exposure risk
78
factors may be a superior strategy. Additional research is needed to improve LTBI screening
79
guidelines for HS patients receiving biologic therapy. Improved LTBI screening guidelines in
80
HS and other patients already on stable biologic therapy can be utilized by individual institutions
81
to develop protocols balancing risk-benefit of LTBI testing with healthcare costs.
82 83 84 85 86 87
Word Count: 500
4
88
References:
89 90
1. Savage KT, Flood KS, Porter ML, Kimball AB. TNF-α inhibitors in the treatment of
91
hidradenitis suppurativa. Ther Adv Chronic Dis. 2019. Doi: 10:2040622319851640.
92
2. Doherty SD, Van Voorhees A, Lebwohl MG, et al. National Psoriasis Foundation consensus
93
statement on screening for latent tuberculosis infection in patients with psoriasis treated with
94
systemic and biologic agents. J Am Acad Dermatol. 2008;59(2):209–17. Doi:
95
10.1016/j.jaad.2008.03.023.
96
3. Chung J, Aronson AB, Srikantha R, et al. Low conversion rate of QuantiFERON-TB Gold
97
screening tests in patients treated with tumor necrosis factor inhibitors: A retrospective cohort
98
study identifying an important practice gap. J Am Acad Dermatol. 2018; 79(1):169-171. Doi:
99
10.1016/j.jaad.2018.03.025.
100
4. Goletti D, Petrone L, Ippolito G, et al. Preventive therapy for tuberculosis in rheumatological
101
patients undergoing therapy with biological drugs. Expert Rev Anti Infect Ther. 2018; 16(6):501-
102
12. Doi: 10.1080/14787210.2018.1483238.
103
5. Zhang Z, Fan W, Yang G, et al. Risk of tuberculosis in patients treated with TNF-a
104
antagonists: a systematic review and meta-analysis of randomized controlled trials. BMJ Open.
105
2017; 7(3):e012567. Doi: 10.1136/bmjopen-2016-012567.
106 107 108 109
5
110
Table 1. Patient Characteristics Total number of patients Average age (years) of first chronic inflammatory disease diagnosis age of (mean) Gender (%) Female Male Biologic (%)a Adalimumab Infliximab Etanercept Ustekinumab Vedolizumab Abatacept Rituximab Certolizumab Ixekizumab Secukinumab Golimumab Guselkumab Tocilizumab Anakinra Canakinumab Tofacitinib Chronic Inflammatory Diseease Diagnoses in addition to HS (%)a Inflammatory Bowel Disease Psoriasis Rheumatoid Arthritis Ankylosing Spondylitis Juvenile Idiopathic Arthritis Systemic Lupus Erythematosus Dermatomyositis SAPHO Syndrome Uveitis Bechet’s Disease Felty’s Syndrome Immunosuppressive Agents taken concomitantly with a biologic (%)a Prednisone <20mg daily Prednisone ≥20mg daily Methotrexate Azathioprine Sulfasalazine Leflunamide Dapsone Hydroxychloroquine Mycophenolate Mofetil Mercaptopurine Cyclosporine QFT results Categories (%)b Negative Indeterminate Positive
170 34.1
111 (65.3) 59 (34.7) 108 (38.3) 47 (16.7) 47 (16.7) 19 (6.7) 12 (4.3) 11 (3.9) 8 (2.8) 7 (2.5) 6 (2.1) 6 (2.1) 4 (1.4) 2 (0.7) 2 (0.7) 1 (0.4) 1 (0.4) 1 (0.4) 55 (37.4) 51 (34.7) 25 (17.0) 3 (2.0) 3 (2.0) 3 (2.0) 2 (1.4) 2 (1.4) 1 (0.7) 1 (0.7) 1 (0.7)
79 (51.0) 15 (9.7) 28 (18.1) 7 (4.5) 7 (4.5) 6 (3.9) 6 (3.9) 4 (2.6) 1 (0.6) 1 (0.6) 1 (0.6) 143 (84.1) 18 (10.6) 9 (5.3)
6
111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134
a
Total number of biologics (biologics were initiated for HS or associated chronic inflammatory conditions), additional chronic inflammatory disease diagnoses, and immunosuppressive agents exceeds number of patients because some patients received more than 1 biologic, diagnosis or additional immunosuppressive agent b QuantiFERON-TB Gold (QFT;Qiagen; Hilden, Germany) was utilized in our cohort for all LTBI tests. Only LTBI tests performed at Cleveland Clinic laboratories were available for review based on our search. A patient was categorized as negative if all QFT results were negative, indeterminate if ≥1 indeterminate QFT result, and positive if they had ≥1 positive QFT result
7
135
Table 2. Hidradenitis Suppurativa patients who converted from negative to positive QFT while taking a biologic medication.
136 137 138 139 140 Patient #
Age at HS Diagnosis (years)
Gender
Biologic at time of conversion or most recent
Previous Biologics Taken
Concurrent medications at time of conversion
Treatment
Additional medical conditions requiring biologic therapy
Risk Factors for TBa
Duration of therapy prior to conversion (months)
1
33
M
Ustekinumab
Adalimumab Etanercept
None
Isoniazid
Psoriasis
Incarceration
84
2
60
F
Infliximabb
None
None
None, history of treated active TB
Rheumatoid Arthritis, Inflammatory Bowel Disease, Uveitis
92
3
25
M
Infliximab
None
None
Isoniazide
Inflammatory Bowel Disease
History of treatment for active pulmonary tuberculosisc None
4
59
M
Adalimumab
None
None
Rifampin, Isoniazid
None
None
10
141 142 143 144 145 146 147 148
a
84
Risk factors for TB: Immigration from/travel to high-risk TB area, occupational exposure, history of latent TB, exposure to persons with TB, chronic diseases associated with immunocompromised state (COPD, HIV, Hepatitis B/C, hematologic malignancy, etc), immunosuppressed state due to non-biologic medications. b Positive conversion was 2 years after stopping treatment with Infliximab, and just prior to initiating a new biologic therapy c Chest X-Ray showed stable post-inflammatory scarring with stable imaging over previous 6 years.
8
149 150
Abbreviations:
151
HS: Hidradenitis Suppurativa
152
TNFI: Tumor necrosis factor alpha inhibitors
153
LTBI: Latent tuberculosis infection
154
IRB: Institutional Review Board
155
QFT: QuantiFERON-TB Gold
156
S0190-9622(20)30055-4
DOI:
https://doi.org/10.1016/j.jaad.2020.01.012
Reference:
YMJD 14134
To appear in:
Journal of the American Academy of Dermatology
Received Date: 8 July 2019 Revised Date:
27 December 2019
Accepted Date: 8 January 2020
Please cite this article as: Ellis A, Khanna U, Galadari A, Fernandez AP, Conversion to Positive Latent Tuberculosis Infection Status is Low in Hidradenitis Suppurativa Patients Taking Biologic Medications, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/ j.jaad.2020.01.012. 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 on behalf of the American Academy of Dermatology, Inc.
1
1 2 3 4 5
Conversion to Positive Latent Tuberculosis Infection Status is Low in Hidradenitis Suppurativa Patients Taking Biologic Medications Ariana Ellis, BS1,3, Urmi Khanna, MD3, AbdulAziz Galadari, MD3, Anthony P. Fernandez, MD, PhD2,3 1
Northeast Ohio Medical University, Rootstown, Ohio, USA Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA 3 Department of Dermatology, Cleveland Clinic, Cleveland, Ohio, USA 2
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
Corresponding Author: Anthony P. Fernandez, MD, PhD Assistant Clinical Professor, Cleveland Clinic Lerner College of Medicine W.D. Steck Chair of Clinical Dermatology Director of Medical and Inpatient Dermatology Staff Dermatologist and Dermatopathologist Departments of Dermatology and Pathology Cleveland Clinic 9500 Euclid Avenue; A61 Cleveland, Ohio 44195 Telephone: 216-445-8776 Fax: 216-636-0711 Email: [email protected] Authors’ Contributions: All authors contributed to the preparation of this manuscript. Conflict of interest: A.P.F. receives research support from Mallinckrodt, Corbus, Pfizer and Novartis and honorarium from AbbVie, Novartis, UCB, and Mallinckrodt for consulting, advisory board participation, and speaking. The other authors have no conflicts of interest to disclose. Funding: This article has no funding source Prior presentations: None IRB statement: This study was approved by Cleveland Clinic’s Institutional Review Board Manuscript: 500 words References: 5 Tables: 2 Figures: 0
Keywords: Hidradenitis Suppurativa, latent tuberculosis, biologics, TNF inhibitors, Quantiferon
2
42 43
To the Editor: Hidradenitis suppurativa (HS) is a chronic inflammatory disease that affects
44
intertriginous areas. Adalimumab is FDA-approved for HS treatment, but other TNF-α inhibitors
45
(TNFIs) may be effective1. Tuberculosis (TB) reactivation risk is well-known in patients taking
46
TNFIs, and latent tuberculosis infection (LTBI) screening prior to TNFI initiation is
47
recommended. Several organizations additionally recommend annual LTBI screening in patients
48
taking biologics2. However, value of serial LTBI screening in low-risk populations is
49
questionable3. There is limited data regarding incidence of LTBI conversion in HS patients
50
treated with biologics4,5. Given this, and because other biologics are being studied as HS
51
treatments, we reviewed LTBI screening results in HS patients on biologics to assess value of
52
serial testing.
53
After IRB approval, we identified HS patients treated for ≥3 months with a biologic and
54
≥2 documented LTBI test results from 2007-2019. Patients without HS, lacking biologic
55
exposure for >3 months, and/or with <2 LTBI test results were excluded. For patients with
56
positive or indeterminate QFT results, retrospective review of medical records was performed.
57
Analysis included calculating means, overall counts, and percentages.
58
One hundred seventy HS patients met our inclusion criteria. Associated chronic
59
inflammatory conditions in our HS population are noted in Table 1. Seventy-two patients were
60
treated with >1 biologic, with an average 1.7 unique biologics per patient. The most frequently
61
prescribed biologics were TNFIs. While treated with biologics, 64.7% of patients also received
62
>1 other immunosuppressive agent.
63 64
The cohort had 521 QFT tests, averaging 3.06 tests per patient. Of 170 patients, 143 (84.1%) had only negative QFT results, 18 (10.6%) had ≥1 indeterminate result, and 9 (5.3%)
3
65
had ≥1 positive result (Table 1). Four patients (2.4%) converted from initial negative QFT to
66
positive. Two of four converters had documented TB risk factors (Table 2). Only 4/9 patients
67
with positive QFTs were treated for LTBI, 3 of whom were converters. Of 5 patients not treated
68
for LTBI, 3 had follow-up negative tuberculin skin tests, 1 was previously treated for LTBI, and
69
1 was previously treated for active TB as an adolescent. No patient developed active TB.
70
TB reactivation risk in patients receiving TNFIs is well established5. Despite this, only 4
71
patients (2.4%) in our cohort converted to a positive QFT following biologic initiation. Other
72
studies have described a low percentage of QFT conversion in psoriasis patients on TNFIs
73
(0.4%)3. While LTBI screening prior to biologic initiation is important due to reactivation risk,
74
our results suggest routine serial LTBI testing of HS patients in low-risk areas taking biologics
75
may be unnecessary. False positive and indeterminate test results in this population may lead to
76
further testing, referrals, unnecessary treatment/adverse events, and excessive healthcare costs.
77
Alternatively, focusing repeat LTBI screening in patients accumulating new TB exposure risk
78
factors may be a superior strategy. Additional research is needed to improve LTBI screening
79
guidelines for HS patients receiving biologic therapy. Improved LTBI screening guidelines in
80
HS and other patients already on stable biologic therapy can be utilized by individual institutions
81
to develop protocols balancing risk-benefit of LTBI testing with healthcare costs.
82 83 84 85 86 87
Word Count: 500
4
88
References:
89 90
1. Savage KT, Flood KS, Porter ML, Kimball AB. TNF-α inhibitors in the treatment of
91
hidradenitis suppurativa. Ther Adv Chronic Dis. 2019. Doi: 10:2040622319851640.
92
2. Doherty SD, Van Voorhees A, Lebwohl MG, et al. National Psoriasis Foundation consensus
93
statement on screening for latent tuberculosis infection in patients with psoriasis treated with
94
systemic and biologic agents. J Am Acad Dermatol. 2008;59(2):209–17. Doi:
95
10.1016/j.jaad.2008.03.023.
96
3. Chung J, Aronson AB, Srikantha R, et al. Low conversion rate of QuantiFERON-TB Gold
97
screening tests in patients treated with tumor necrosis factor inhibitors: A retrospective cohort
98
study identifying an important practice gap. J Am Acad Dermatol. 2018; 79(1):169-171. Doi:
99
10.1016/j.jaad.2018.03.025.
100
4. Goletti D, Petrone L, Ippolito G, et al. Preventive therapy for tuberculosis in rheumatological
101
patients undergoing therapy with biological drugs. Expert Rev Anti Infect Ther. 2018; 16(6):501-
102
12. Doi: 10.1080/14787210.2018.1483238.
103
5. Zhang Z, Fan W, Yang G, et al. Risk of tuberculosis in patients treated with TNF-a
104
antagonists: a systematic review and meta-analysis of randomized controlled trials. BMJ Open.
105
2017; 7(3):e012567. Doi: 10.1136/bmjopen-2016-012567.
106 107 108 109
5
110
Table 1. Patient Characteristics Total number of patients Average age (years) of first chronic inflammatory disease diagnosis age of (mean) Gender (%) Female Male Biologic (%)a Adalimumab Infliximab Etanercept Ustekinumab Vedolizumab Abatacept Rituximab Certolizumab Ixekizumab Secukinumab Golimumab Guselkumab Tocilizumab Anakinra Canakinumab Tofacitinib Chronic Inflammatory Diseease Diagnoses in addition to HS (%)a Inflammatory Bowel Disease Psoriasis Rheumatoid Arthritis Ankylosing Spondylitis Juvenile Idiopathic Arthritis Systemic Lupus Erythematosus Dermatomyositis SAPHO Syndrome Uveitis Bechet’s Disease Felty’s Syndrome Immunosuppressive Agents taken concomitantly with a biologic (%)a Prednisone <20mg daily Prednisone ≥20mg daily Methotrexate Azathioprine Sulfasalazine Leflunamide Dapsone Hydroxychloroquine Mycophenolate Mofetil Mercaptopurine Cyclosporine QFT results Categories (%)b Negative Indeterminate Positive
170 34.1
111 (65.3) 59 (34.7) 108 (38.3) 47 (16.7) 47 (16.7) 19 (6.7) 12 (4.3) 11 (3.9) 8 (2.8) 7 (2.5) 6 (2.1) 6 (2.1) 4 (1.4) 2 (0.7) 2 (0.7) 1 (0.4) 1 (0.4) 1 (0.4) 55 (37.4) 51 (34.7) 25 (17.0) 3 (2.0) 3 (2.0) 3 (2.0) 2 (1.4) 2 (1.4) 1 (0.7) 1 (0.7) 1 (0.7)
79 (51.0) 15 (9.7) 28 (18.1) 7 (4.5) 7 (4.5) 6 (3.9) 6 (3.9) 4 (2.6) 1 (0.6) 1 (0.6) 1 (0.6) 143 (84.1) 18 (10.6) 9 (5.3)
6
111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134
a
Total number of biologics (biologics were initiated for HS or associated chronic inflammatory conditions), additional chronic inflammatory disease diagnoses, and immunosuppressive agents exceeds number of patients because some patients received more than 1 biologic, diagnosis or additional immunosuppressive agent b QuantiFERON-TB Gold (QFT;Qiagen; Hilden, Germany) was utilized in our cohort for all LTBI tests. Only LTBI tests performed at Cleveland Clinic laboratories were available for review based on our search. A patient was categorized as negative if all QFT results were negative, indeterminate if ≥1 indeterminate QFT result, and positive if they had ≥1 positive QFT result
7
135
Table 2. Hidradenitis Suppurativa patients who converted from negative to positive QFT while taking a biologic medication.
136 137 138 139 140 Patient #
Age at HS Diagnosis (years)
Gender
Biologic at time of conversion or most recent
Previous Biologics Taken
Concurrent medications at time of conversion
Treatment
Additional medical conditions requiring biologic therapy
Risk Factors for TBa
Duration of therapy prior to conversion (months)
1
33
M
Ustekinumab
Adalimumab Etanercept
None
Isoniazid
Psoriasis
Incarceration
84
2
60
F
Infliximabb
None
None
None, history of treated active TB
Rheumatoid Arthritis, Inflammatory Bowel Disease, Uveitis
92
3
25
M
Infliximab
None
None
Isoniazide
Inflammatory Bowel Disease
History of treatment for active pulmonary tuberculosisc None
4
59
M
Adalimumab
None
None
Rifampin, Isoniazid
None
None
10
141 142 143 144 145 146 147 148
a
84
Risk factors for TB: Immigration from/travel to high-risk TB area, occupational exposure, history of latent TB, exposure to persons with TB, chronic diseases associated with immunocompromised state (COPD, HIV, Hepatitis B/C, hematologic malignancy, etc), immunosuppressed state due to non-biologic medications. b Positive conversion was 2 years after stopping treatment with Infliximab, and just prior to initiating a new biologic therapy c Chest X-Ray showed stable post-inflammatory scarring with stable imaging over previous 6 years.
8
149 150
Abbreviations:
151
HS: Hidradenitis Suppurativa
152
TNFI: Tumor necrosis factor alpha inhibitors
153
LTBI: Latent tuberculosis infection
154
IRB: Institutional Review Board
155
QFT: QuantiFERON-TB Gold
156