Tofacitinib was the first Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitor approved to treat certain rheumatologic conditions (e.g. rheumatoid arthritis).1 However, the US Food and Drug Administration (FDA) did not extend similar approval to dermatologic conditions due to safety concerns and a lack of large clinical trials in dermatologic patients.2 Nevertheless, tofacitinib is used off-label for dermatologic diseases recalcitrant to FDA-approved therapies.3 Reports of adverse events (AE) from tofacitinib stem primarily from studies of rheumatology populations, with limited real-world data available in dermatology patients.3
We conducted an institutional review board (IRB)-approved retrospective study of 606 patients treated with systemic JAK inhibitors at NYU Langone Health from 1/1/13–7/1/22. Patients with ≥2 consecutive tofacitinib prescriptions for dermatologic or rheumatologic indications (by ICD9/10 codes) were included (Supplementary Table 1). We reviewed charts for AEs during the period the patient was prescribed tofacitinib (505 total person-years). Serious infections were defined as requiring hospitalization and/or intravenous antibiotics. Cardiac adverse events (CAE) included major adverse cardiovascular events (MACE) and venous thromboembolism (VTE). AEs were validated by physician chart review (TK for all; MG for CAE). Incidence rates were calculated using the epi.conf function (RStudio).
Of the 306 patients who met inclusion criteria (Supplementary Figure 1), 57 were dermatology and 249 were rheumatology patients (Supplementary Figure 2). The most common diagnoses in the dermatology and rheumatology cohorts were alopecia areata and rheumatoid arthritis, respectively. Dermatology patients were younger than rheumatology patients and demonstrated significantly lower prevalence of hypertension, obesity, and use of additional immunosuppressive agents (Table 1).
Table 1:
Demographics and patient characteristics
| Characteristic | Overall, N = 3061 | Dermatology, N = 571 | Rheumatology, N = 2491 | p-value2 |
|---|---|---|---|---|
| Sex | <0.001 * | |||
| Male | 92 (30%) | 28 (49%) | 64 (26%) | |
| Female | 214 (70%) | 29 (51%) | 185 (74%) | |
| Age in years 3 | 55.9 (16.3) | 33.5 (16.8) | 58.3 (14.4) | <0.001 * |
| Race | ||||
| White | 200 (65%) | 38 (67%) | 162 (65%) | 0.82 |
| Black/African American | 30 (9.8%) | 4 (7.0%) | 26 (10%) | 0.43 |
| Asian | 8 (2.6%) | 1 (1.8%) | 7 (2.8%) | >0.99 |
| Other Race | 46 (15%) | 4 (7.0%) | 42 (17%) | 0.061 |
| Prefer not to say race | 5 (1.6%) | 4 (7.0%) | 1 (0.4%) | 0.005 * |
| Unknown | 17 (5.6%) | 6 (11.%) | 11 (4.4%) | 0.10 |
| Ethnicity | ||||
| Hispanic or Latino | 7 (2.3%) | 0 (0%) | 7 (2.8%) | 0.36 |
| Not Hispanic or Latino | 196 (64%) | 22 (39%) | 174 (70%) | <0.001 * |
| Other Ethnicity | 21 (6.9%) | 1 (1.8%) | 20 (8.0%) | 0.14 |
| Smoking History | 0.77 | |||
| Current/Active Smoker | 12 (4.1%) | 1 (2.0%) | 11 (4.5%) | |
| Former Smoker | 82 (28%) | 15 (31%) | 67 (27%) | |
| Never Smoker | 202 (68%) | 33 (67%) | 169 (68%) | |
| Comorbidities | ||||
| Obesity | 97 (33%) | 10 (20%) | 87 (36%) | 0.033 * |
| COPD | 16 (5.3%) | 0 (0%) | 16 (6.5%) | 0.086 |
| Hypertension | 109 (36%) | 11 (19%) | 98 (40%) | 0.003 * |
| Diabetes Mellitus | 42 (14%) | 4 (7.1%) | 38 (15%) | 0.11 |
| CKD | 16 (5.2%) | 0 (0%) | 16 (6.5%) | 0.049 |
| Corticosteroid Use | 150 (50%) | 13 (23%) | 137 (55%) | <0.001 * |
| ≥2 Immunosuppressive Medications | 86 (28%) | 4 (7.0%) | 82 (33%) | <0.001 * |
|
Tofacitinib
Maintenance Dosages |
<0.001 * | |||
| 5mg | 3 (1.0%) | 1 (1.8%) | 2 (0.8%) | |
| 10 mg | 88 (29%) | 42 (74%) | 46 (18%) | |
| 11 mg | 205 (67%) | 7 (12%) | 198 (80%) | |
| 15 mg | 6 (2.0%) | 5 (8.8%) | 1 (0.4%) | |
| 20 mg | 2 (0.7%) | 1 (1.8%) | 1 (0.4%) | |
| Time on Tofacitinib | ||||
| Duration in months 4 | 26.0 (23.0) | 26.7 (24.0) | 22.8 (18) | 0.26 |
significant at p < 0.05
n (%) unless otherwise noted; percentages may not add up to exactly 100% due to rounding of certain values
Wilcoxon test for continuous data; Pearson’s Chi-squared test or Fisher’s exact test (for counts < 5) for categorical data
median (standard deviation)
median (interquartile range)
COPD - Chronic Obstructive Pulmonary Disease
CKD - Chronic Kidney Disease
Age, comorbidities and smoking history recorded at time of initiation of tofacitinib.
There were 152 infection events (Table 2). Rheumatology and dermatology patients had similar overall infection rates (2.52 [2.10, 3.00] vs. 2.43 [1.57, 3.59] per 12 person-months). The incidence rate of serious infections trended higher in the rheumatology cohort (0.54 [0.35, 0.78] vs. 0.10 [0.002, 0.54] per 12 person-months). The most common cause of serious infection, bacterial pneumonia, occurred exclusively in the rheumatology cohort (Supplementary Tables 2 & 3).
Table 2:
Incidence of infection, cardiac adverse events and malignancies in rheumatology vs. dermatology patients treated with tofacitinib
| Adverse Events | Rheumatology patients (N = 249) [person-months = 5035] | Dermatology patients (N = 57) [person-months = 1029] | ||
|---|---|---|---|---|
|
| ||||
| Events | IR (per 12-person months) [95% CI] | Events | IR (per 12-person months) [95% CI] | |
|
| ||||
| Any infection | 127 | 2.52 [2.10, 3.00] | 25 | 2.43 [1.57, 3.59] |
| Serious infection | 27 | 0.54 [0.35, 0.78] | 1 | 0.10 [0.002, 0.54] |
| Non-serious infection | 100 | 1.99 [1.62, 2.42] | 24 | 2.33 [1.49, 3.47] |
| Herpes simplex | 9 | 0.18 [0.08, 0.34] | 6 | 0.58 [0.21, 1.27] |
| Zoster/ Shingles | 10 | 0.20 [0.10, 0.37] | 3 | 0.29 [0.06, 0.85] |
| CAE* | 4 | 0.08 [0.02, 0.20] | 0 | - |
| Myocardial infarction | 1 | 0.02 [0.00, 0.11] | 0 | - |
| Pulmonary embolism | 0 | 0 [0, 0.07] | 0 | - |
| Deep vein thrombosis | 3 | 0.06 [0.01, 0.17] | 0 | - |
| Stroke | 1 | 0.02 [0.0005, 0.11] | 0 | - |
| Malignancy | 13 | 0.26 [0.14, 0.44] | 2 | 0.19 [0.02, 0.70] |
| Excluding NMSC | 5 | 0.01 [0.03, 0.23] | 1 | 0.10 [0.002, 0.54] |
| NMSC | 8 | 0.16 [0.07, 0.31] | 1 | 0.10 [0.002, 0.54] |
Specific Cardiovascular Adverse Events (CAE) may not add up to 4 as some patients experienced multiple events. Only first event counted in total number.
IR - Incidence Rate
CI - Confidence Interval
CAE - Cardiovascular Adverse Event
NMSC - Nonmelanoma Skin Cancer
Five CAEs occurred, 2 MACE and 3 VTE in the rheumatology cohort, with none in the dermatology cohort (Table 2, Supplementary Tables 3 & 4). Malignancy events occurred at similar rates in the two cohorts with non-melanoma skin cancer being the most prevalent malignancy type (Table 2, Supplementary Table 3). Of lab abnormalities occurring 1–3 months after tofacitinib initiation, lymphopenia, neutropenia, neutrophilia, and hypercholesterolemia occurred significantly more often in the rheumatology compared to the dermatology cohort (Supplementary Table 5).
Our results demonstrate that dermatology patients prescribed tofacitinib differ significantly in baseline characteristics compared to rheumatology patients. Dermatology patients may be less likely to experience CAE and serious infections, though direct comparison of these two populations is challenging given the extent to which they differ in demographics and risk factors. The increased CAE rates observed in the rheumatology cohort are likely due to known cardiovascular risk factors observed in this group including older age, obesity, and hypertension (Supplementary Table 4).
Improved understanding of the JAK-STAT inhibitor side effect profile in dermatology patients is essential for therapeutic decision making.4 Extrapolating safety data from rheumatologic studies may be insufficient for appropriate counseling of dermatology patients.5 Study limitations include its retrospective nature and single-center design. This study supports the need for larger, prospective studies on patients taking tofacitinib and other JAK inhibitors for dermatologic indications.
Supplementary Material
Acknowledgements:
TK is supported in part by an NIH T32AR064184 award. MG is supported in part by an NIH K23HL152013 award and unrestricted Pfizer research grants to study JAK inhibitors and cardiovascular risk. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Footnotes
Conflicts of Interest: Dr. Lo Sicco is a current investigator for Pfizer. She is a consultant for Pfizer and Aquis. Dr. Garshick reports consultant fees from Horizon Therapeutics, Abbvie, BMS and Kiniksa. Drs. Karagounis, Betensky, Klein, Karim, Liu, and Carli Needle, Ambika Nohria, Jessica Gjonaj, and Jinal Shah have no conflicts of interest.
IRB Approval Status: Obtained, study exempt from full IRB review.
Patient Consent: Not applicable
Prior Presentation: None
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