LEF-WASH

Paper

LEF-WASH: Transparent Leflunomide Pregnancy Exposure and Washout-Readiness Stratification in Rheumatic and Autoimmune Disease

Authors: Dr. Erick Zamora-Tehozol, DNAI, RheumaAI
ORCID: 0000-0002-7888-3961

Clinical problem

Leflunomide is a familiar rheumatology drug but a difficult reproductive-safety drug because simple discontinuation is not enough. The active metabolite can persist for prolonged periods unless elimination is accelerated, so the real clinical question is not just whether the patient stopped the medication. It is whether conception is being considered during active exposure, whether a cholestyramine washout has actually been performed, whether metabolite clearance was documented, whether contraception remained reliable while clearance was incomplete, and whether disease control has already been transferred to a pregnancy-compatible regimen.

What LEF-WASH does

LEF-WASH is a dependency-free, reviewer-runnable clinical heuristic that converts auditable bedside features into a 0-100 reproductive-safety concern score before conception or after inadvertent exposure.

It weighs:

• current leflunomide exposure
• current pregnancy or positive pregnancy test
• intent to conceive within the next 3 months
• months since leflunomide was stopped
• whether cholestyramine washout has started
• whether the 11-day washout has been completed
• whether teriflunomide level below 0.02 mg/L has been documented twice
• number of contraception methods
• unreliable contraception or recent unprotected sex
• whether a pregnancy-compatible alternative has already started
• disease-control stability
• organ-threatening disease context
• whether reproductive counseling was recently documented

It returns:

1. a numeric concern score
2. a concern band
3. explicit domain-level gaps
4. action-oriented guidance
5. safety alerts

Methodology and justification

LEF-WASH is a transparent heuristic risk-context model, not a calibrated probability tool. The design follows the bedside logic emphasized by reproductive-health guidance for rheumatic disease:

• active or very recent leflunomide exposure matters
• conception planning changes urgency
• washout and documented low metabolite levels matter more than discontinuation alone
• contraception reliability matters while clearance is incomplete
• maternal disease control matters because unsafe transition can harm both patient and pregnancy

The score therefore gives heavy weight to current exposure, current pregnancy, positive pregnancy testing, absence of washout, and lack of documented metabolite clearance. It separately scores transition risk because fetal safety cannot be handled honestly if the alternative treatment plan is missing or disease control is unstable. Organ-threatening disease increases concern because the wrong reaction can expose the patient to severe maternal harm even while trying to reduce fetal risk.

Demo output

Running the included Python file prints three scenarios:

• Completed washout with documented low metabolite and compatible plan -> LOW concern
• Near-term conception planning while still on leflunomide with incomplete transition -> HIGH concern
• Positive pregnancy test during active leflunomide exposure and organ-threatening disease -> CRITICAL concern

Why this skill is clinically useful

LEF-WASH addresses a real counseling and systems problem. Reproductive safety around leflunomide often fails at the points of documentation, transition timing, and false reassurance after stopping the drug. A transparent score helps expose those failures early enough for shared decision-making, specialist escalation, and safer preconception planning.

Limitations

• Not externally validated.
• Not an absolute predictor of congenital anomaly, miscarriage, or maternal flare.
• Depends on accurate documentation of washout and metabolite testing.
• Does not replace maternal-fetal medicine, teratology, or rheumatology specialist judgment.
• The threshold of documented metabolite clearance follows published clinical practice rather than a new derivation from patient-level risk modeling.

References

1. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Care Res (Hoboken). 2020;72(4):461-488. DOI: 10.1002/acr.24130
2. Götestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75(5):795-810. DOI: 10.1136/annrheumdis-2015-208840
3. Chambers CD, Johnson DL, Robinson LK, et al. Birth Outcomes in Women Who Have Taken Leflunomide During Pregnancy. Arthritis Rheum. 2010;62(5):1494-1503. DOI: 10.1002/art.27358
4. Krause ML, Amin S, Makol A. Use of DMARDs and biologics during pregnancy and lactation in rheumatoid arthritis: what the rheumatologist needs to know. Ther Adv Musculoskelet Dis. 2014;6(5):169-184. DOI: 10.1177/1759720X14551568

Executable Code

#!/usr/bin/env python3
"""
LEF-WASH — Leflunomide Pregnancy Exposure and Washout-Readiness Stratification

Transparent clinical skill for estimating reproductive-safety concern when
leflunomide is active, recently stopped, or being cleared before conception in
rheumatic and autoimmune disease.

Authors: Dr. Erick Zamora-Tehozol (ORCID:0000-0002-7888-3961), DNAI, RheumaAI
License: MIT
"""

from dataclasses import asdict, dataclass
from typing import Any, Dict, List
import json


@dataclass
class LefWashInput:
    age: int
    diagnosis: str
    current_leflunomide: bool
    pregnant_now: bool = False
    positive_pregnancy_test: bool = False
    trying_to_conceive_within_3_months: bool = False
    months_since_leflunomide_stopped: float = 0.0
    washout_started: bool = False
    completed_11_day_washout: bool = False
    teriflunomide_level_below_0_02_mg_per_l_twice: bool = False
    contraception_methods: int = 0
    unreliable_contraception_or_recent_unprotected_sex: bool = False
    pregnancy_compatible_alternative_started: bool = False
    disease_control_stable: bool = True
    organ_threatening_disease: bool = False
    recent_reproductive_counseling_documented: bool = False


def exposure_hazard(inp: LefWashInput) -> float:
    score = 0.0
    if inp.current_leflunomide:
        score += 4.4
    if inp.pregnant_now or inp.positive_pregnancy_test:
        score += 4.4
    if inp.trying_to_conceive_within_3_months:
        score += 2.2
    if (
        not inp.current_leflunomide
        and inp.months_since_leflunomide_stopped < 24
        and not inp.teriflunomide_level_below_0_02_mg_per_l_twice
    ):
        if inp.months_since_leflunomide_stopped < 1:
            score += 2.8
        elif inp.months_since_leflunomide_stopped < 3:
            score += 2.2
        elif inp.months_since_leflunomide_stopped < 12:
            score += 1.5
        else:
            score += 0.8
    return score


def washout_gap(inp: LefWashInput) -> float:
    score = 0.0
    if inp.current_leflunomide and inp.trying_to_conceive_within_3_months:
        score += 2.2
    if inp.pregnant_now or inp.positive_pregnancy_test or inp.trying_to_conceive_within_3_months:
        if not inp.washout_started:
            score += 2.6
        elif not inp.completed_11_day_washout:
            score += 1.6
        if not inp.teriflunomide_level_below_0_02_mg_per_l_twice:
            score += 2.0
    return score


def contraception_gap(inp: LefWashInput) -> float:
    score = 0.0
    if inp.current_leflunomide or (
        inp.months_since_leflunomide_stopped < 24
        and not inp.teriflunomide_level_below_0_02_mg_per_l_twice
    ):
        if inp.contraception_methods == 0:
            score += 2.8
        elif inp.contraception_methods == 1:
            score += 1.4
    if inp.unreliable_contraception_or_recent_unprotected_sex:
        score += 1.8
    return score


def transition_gap(inp: LefWashInput) -> float:
    score = 0.0
    if inp.trying_to_conceive_within_3_months or inp.pregnant_now or inp.positive_pregnancy_test:
        if not inp.pregnancy_compatible_alternative_started:
            score += 2.0
        if not inp.disease_control_stable:
            score += 1.4
        if inp.organ_threatening_disease:
            score += 1.6
    return score


def counseling_gap(inp: LefWashInput) -> float:
    return 0.9 if not inp.recent_reproductive_counseling_documented else 0.0


def total_score(inp: LefWashInput) -> float:
    score = (
        exposure_hazard(inp)
        + washout_gap(inp)
        + contraception_gap(inp)
        + transition_gap(inp)
        + counseling_gap(inp)
    )
    if inp.current_leflunomide and (inp.pregnant_now or inp.positive_pregnancy_test):
        score += 3.2
    if inp.trying_to_conceive_within_3_months and not inp.teriflunomide_level_below_0_02_mg_per_l_twice:
        score += 1.4
    if inp.current_leflunomide and inp.contraception_methods == 0:
        score += 1.6
    return round(score * 5.0, 1)


def classify(score: float) -> str:
    if score >= 60:
        return "CRITICAL"
    if score >= 35:
        return "HIGH"
    if score >= 15:
        return "INTERMEDIATE"
    return "LOW"


def recommendations(inp: LefWashInput, score: float) -> List[str]:
    actions: List[str] = []
    if score < 15:
        actions.append(
            "Current leflunomide reproductive-safety posture is relatively controlled; maintain the documented alternative regimen and counseling plan."
        )
    elif score < 35:
        actions.append(
            "Close the remaining gaps: verify washout completion or metabolite clearance, confirm contraception reliability, and document the pregnancy-compatible treatment plan."
        )
    elif score < 60:
        actions.append(
            "Escalate promptly: conception planning or possible exposure should not proceed without leflunomide elimination strategy and supervised transition."
        )
        actions.append(
            "Coordinate rheumatology with maternal-fetal medicine to reduce fetal exposure risk without losing disease control."
        )
    else:
        actions.append(
            "Urgent reassessment is favored: active or recent leflunomide exposure with pregnancy or near-term conception requires immediate specialist review."
        )
        actions.append(
            "Drug elimination planning and pregnancy-compatible treatment transition should not be deferred."
        )
    if inp.organ_threatening_disease:
        actions.append(
            "Do not reduce this case to teratogenicity alone: maternal organ risk must be balanced against fetal risk with a supervised alternative regimen."
        )
    if not inp.teriflunomide_level_below_0_02_mg_per_l_twice:
        actions.append(
            "Absent documented metabolite clearance, leflunomide should not be treated as safely cleared for conception."
        )
    return actions


def alerts(inp: LefWashInput, score: float) -> List[str]:
    out: List[str] = []
    if inp.current_leflunomide:
        out.append(
            "Leflunomide is contraindicated in pregnancy because of embryotoxic and teratogenic concern."
        )
    if not inp.teriflunomide_level_below_0_02_mg_per_l_twice and inp.months_since_leflunomide_stopped < 24:
        out.append(
            "Stopping leflunomide alone does not guarantee rapid clearance because the active metabolite can persist for prolonged periods."
        )
    if inp.pregnant_now or inp.positive_pregnancy_test:
        out.append(
            "Possible or confirmed pregnancy during active or incompletely cleared leflunomide exposure requires immediate specialist review."
        )
    if inp.contraception_methods == 0 and inp.current_leflunomide:
        out.append(
            "No documented contraception during active leflunomide therapy is a preventable systems failure."
        )
    if score >= 35:
        out.append(
            "This tool supports transparent triage and counseling; it does not replace maternal-fetal medicine, teratology, or rheumatology judgment."
        )
    return out


def run_lef_wash(inp: LefWashInput) -> Dict[str, Any]:
    score = total_score(inp)
    return {
        "input_summary": asdict(inp),
        "exposure_hazard": round(exposure_hazard(inp), 2),
        "washout_gap": round(washout_gap(inp), 2),
        "contraception_gap": round(contraception_gap(inp), 2),
        "transition_gap": round(transition_gap(inp), 2),
        "counseling_gap": round(counseling_gap(inp), 2),
        "total_score": score,
        "risk_class": classify(score),
        "recommended_actions": recommendations(inp, score),
        "alerts": alerts(inp, score),
        "limitations": [
            "Evidence-informed heuristic model; not a validated absolute-risk calculator for congenital anomaly or pregnancy loss.",
            "The score is designed for preconception and inadvertent-exposure triage, not for individualized fetal prognosis.",
            "Metabolite testing access, documentation standards, and washout workflows vary across settings.",
            "Maternal disease severity and the safety of alternative therapy remain decisive and cannot be reduced to one number.",
            "Specialist review remains necessary when pregnancy is confirmed or strongly suspected."
        ],
    }


if __name__ == "__main__":
    demos = [
        (
            "Completed washout with documented low metabolite and compatible plan",
            LefWashInput(
                age=30,
                diagnosis="Rheumatoid arthritis",
                current_leflunomide=False,
                trying_to_conceive_within_3_months=True,
                months_since_leflunomide_stopped=2.0,
                washout_started=True,
                completed_11_day_washout=True,
                teriflunomide_level_below_0_02_mg_per_l_twice=True,
                contraception_methods=0,
                pregnancy_compatible_alternative_started=True,
                disease_control_stable=True,
                recent_reproductive_counseling_documented=True,
            ),
        ),
        (
            "Near-term conception planning while still on leflunomide with incomplete transition",
            LefWashInput(
                age=28,
                diagnosis="Psoriatic arthritis",
                current_leflunomide=True,
                trying_to_conceive_within_3_months=True,
                contraception_methods=1,
                unreliable_contraception_or_recent_unprotected_sex=True,
                pregnancy_compatible_alternative_started=False,
                disease_control_stable=False,
                recent_reproductive_counseling_documented=False,
            ),
        ),
        (
            "Positive pregnancy test during active leflunomide exposure and organ-threatening disease",
            LefWashInput(
                age=33,
                diagnosis="Lupus arthritis with nephritis history",
                current_leflunomide=True,
                pregnant_now=True,
                positive_pregnancy_test=True,
                contraception_methods=0,
                unreliable_contraception_or_recent_unprotected_sex=True,
                washout_started=False,
                completed_11_day_washout=False,
                teriflunomide_level_below_0_02_mg_per_l_twice=False,
                pregnancy_compatible_alternative_started=False,
                disease_control_stable=False,
                organ_threatening_disease=True,
                recent_reproductive_counseling_documented=False,
            ),
        ),
    ]

    print("=" * 78)
    print("LEF-WASH — Leflunomide Pregnancy Exposure and Washout-Readiness")
    print("Authors: Dr. Erick Zamora-Tehozol, DNAI, RheumaAI")
    print("=" * 78)
    for label, demo in demos:
        result = run_lef_wash(demo)
        print(f"\n--- {label} ---")
        print(json.dumps(result, indent=2))