Are JAK Inhibitors Safe for Dermatological Use? A Comprehensive Review of Clinical Trials and Monitoring Strategies.

🔍 Key Finding

Oral JAK inhibitors demonstrated low rates of venous thromboembolism, major adverse cardiovascular events, and malignancy in dermatology clinical trials, comparable to placebo. Most patients experiencing serious adverse events had pre-existing risk factors for those specific events.

🔬 Methodology Overview

Design: Narrative review. Data Sources: PubMed (via Medline). Selection Criteria: Articles on clinical trials of JAK inhibitors in dermatology, focusing on FDA-approved JAK inhibitors and their safety profiles published from November 2011 to October 2022. Phase 3 randomized controlled trials and follow-up data were included. Search Terms: "phase 3 trials" AND "atopic dermatitis” OR “alopecia areata" OR "psoriasis” OR “vitiligo” AND "abrocitinib” OR “upadacitinib” OR “ruxolitinib" OR "baricitinib" OR "deucravacitinib." Analysis Approach: Qualitative synthesis of safety data from clinical trials, focusing on adverse events such as venous thromboembolism, major adverse cardiovascular events, malignancy, serious infections, and common adverse effects. Scope: Safety and tolerability of oral and topical JAK inhibitors in dermatological conditions including atopic dermatitis, alopecia areata, vitiligo, and psoriasis.

📊 Results

Here’s a summary of key findings from the provided research article, formatted as requested:

• Low VTE, MACE, and Malignancy Rates in Dermatology Trials: Oral JAK inhibitors demonstrated low rates of venous thromboembolism (0-0.5 %), major adverse cardiovascular events (0.1-0.6 %), and malignancy (0-0.9 % for NMSC, 0-0.7 % for non-NMSC) in dermatology-specific phase 3 clinical trials. These rates were generally comparable to, or in some cases lower than, placebo groups.
• Pre-existing Risk Factors Important: Most patients who experienced these serious adverse events had pre-existing risk factors for the specific event, highlighting the importance of baseline risk assessment.
• Common Adverse Events: The most frequent adverse events (> 5 % incidence) with oral JAK inhibitors included upper respiratory tract infections, nasopharyngitis, nausea, headache, and acne.
• Elevated CPK: A common laboratory abnormality observed was elevated creatine phosphokinase (CPK), occurring in ≤ 6 % of AD patients on upadacitinib or abrocitinib.
• Lipid Changes with Some JAK Inhibitors: Dose-related elevations in LDL and HDL cholesterol were observed with abrocitinib in AD and baricitinib in AA, while no significant lipid changes were seen with upadacitinib in AD, or deucravacitinib in psoriasis.
• Black Box Warning Context: The safety data should be interpreted in the context of the underlying patient population. Dermatology patients using JAK inhibitors tend to be younger and have fewer comorbidities compared to the rheumatoid arthritis patients in the studies that led to the FDA black box warning. Large cohort studies suggest that chronic inflammatory skin diseases themselves are not associated with increased VTE risk.

💡 Clinical Impact

This review summarizes the safety profile of JAK inhibitors in dermatology, finding low rates of serious complications like venous thromboembolism and malignancy in clinical trials. This information, along with suggested monitoring guidelines, can help dermatologists assess the risk-benefit ratio of JAK inhibitors for patients with atopic dermatitis, alopecia areata, psoriasis, and vitiligo, facilitating informed shared decision-making.

🤔 Limitations

• Limited long-term safety data: The ORAL Surveillance study primarily focused on tofacitinib in older RA patients with cardiovascular risk factors, making it difficult to generalize the findings to younger dermatology patients with different conditions. More long-term data specific to dermatologic use of JAK inhibitors are needed.
• Baseline risk and underlying disease: The paper highlights that the underlying diseases (RA, AD, etc.) themselves carry risks of VTE, MACE, and malignancy. It’s crucial to disentangle the risks attributable to JAK inhibitors from the pre-existing risks associated with these conditions.
• Limited data in specific populations: Data on the use of JAK inhibitors in pregnant or breastfeeding women, patients with severe organ failure, and those on other immunosuppressants are limited, making it difficult to assess the risk-benefit ratio in these groups.
• Short-term nature of some trials: Some trials only had 12- or 16-week follow-up periods, which may not be sufficient to capture the full range of potential adverse events, especially long-term complications like malignancy.
• Lack of head-to-head comparisons: The studies primarily compared JAK inhibitors to placebo, rather than to other established treatments for these dermatologic conditions. This makes it harder to determine the relative safety profile of JAK inhibitors compared to alternative therapies.
• Focus on adjudicated events: The paper primarily discusses adjudicated events, which are events deemed by a committee to be related to the treatment. This may underestimate the true incidence of adverse events experienced by patients, as some events may not be considered related by the adjudication committee.
• Potential for underreporting in real-world settings: The data presented are primarily from clinical trials, which may have stricter monitoring and reporting procedures than real-world clinical practice. This could lead to underreporting of adverse events in broader clinical use.

✨ What It Means For You

Dermatologists should carefully evaluate patient-specific risk factors for complications like venous thromboembolism, major adverse cardiovascular events, malignancy, and serious infections before prescribing JAK inhibitors. Pre-treatment screening and regular monitoring of laboratory values, including complete blood count, liver and kidney function, and lipid panel, are crucial for early detection and management of potential adverse events. Consider dose reduction or treatment cessation if significant laboratory abnormalities or adverse events occur.

Reference

Samuel C, Cornman H, Kambala A, Kwatra SG. A Review on the Safety of Using JAK Inhibitors in Dermatology: Clinical and Laboratory Monitoring. Dermatol Ther (Heidelb). 2023;13:729–749. https://doi.org/10.1007/s13555-023-00892-5