Pharmacological Therapies for Sarcoidosis: A Systematic Review of Pulmonary and Hepatic Outcomes

1. Introduction

Sarcoidosis is a systemic inflammatory disease characterized by the formation of non-caseating granulomas in affected organs.[1,2] Pulmonary involvement occurs in over 90% of patients and is the primary driver of morbidity and mortality, with 10–30% developing progressive pulmonary disease that may lead to fibrocystic changes, respiratory failure, and death.[3] The liver is the third most commonly involved organ after the lungs and lymph nodes, with hepatic granulomas identified in 5–25% of patients with systemic sarcoidosis.[2,4] Hepatic sarcoidosis can cause cholestatic liver injury, portal hypertension, and cirrhosis, though many patients remain asymptomatic.[2]

The treatment paradigm for sarcoidosis has traditionally followed a stepwise approach: first-line glucocorticoids, second-line antimetabolites for steroid-sparing, and third-line biologic agents for refractory disease.[3,5] However, this paradigm is evolving rapidly. The landmark PREDMETH trial demonstrated that methotrexate is noninferior to prednisone as first-line therapy for pulmonary sarcoidosis, potentially shifting the treatment algorithm toward earlier steroid avoidance.[1] Simultaneously, novel targeted therapies including JAK inhibitors, neuropilin-2 modulators, and antifibrotic agents are entering clinical development.[5,6]

Despite these advances, the evidence base for sarcoidosis therapeutics remains limited by small sample sizes, heterogeneous study designs, and a paucity of data on hepatic outcomes. The dual challenge of optimizing pulmonary efficacy while managing hepatotoxicity risk is particularly relevant, as several effective therapies (methotrexate, leflunomide, anti-TNF agents) carry hepatotoxic potential. Furthermore, the role of these agents in treating hepatic sarcoidosis itself as opposed to merely causing hepatic adverse effects is poorly characterized.

This systematic review aims to comprehensively evaluate the available evidence on pharmacological therapies for sarcoidosis with a dual focus on: (1) pulmonary outcomes including forced vital capacity (FVC), steroid-sparing capacity, and radiographic response; and (2) hepatic outcomes including hepatotoxicity profiles and efficacy in hepatic sarcoidosis.

2. Methods

2.1. Search Strategy

A systematic literature search was conducted in PubMed, MEDLINE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception through May 2025. Search terms included: ("sarcoidosis" OR "pulmonary sarcoidosis" OR "hepatic sarcoidosis") AND ("treatment" OR "therapy" OR "pharmacological") AND ("pulmonary outcomes" OR "forced vital capacity" OR "FVC" OR "hepatotoxicity" OR "liver" OR "hepatic outcomes"). Reference lists of included studies and relevant reviews were hand-searched for additional eligible studies.

2.2. Eligibility Criteria

Inclusion criteria: (1) Studies evaluating pharmacological therapies in patients with confirmed sarcoidosis; (2) Reporting of at least one pulmonary outcome (FVC, DLCO, radiographic response, steroid-sparing) and/or hepatic outcome (liver enzyme changes, hepatic sarcoidosis response, hepatotoxicity); (3) Study designs including randomized controlled trials, prospective and retrospective cohort studies, single-arm trials, and systematic reviews/meta-analyses; (4) Published in English.

Exclusion criteria: (1) Case reports with fewer than 5 patients; (2) Studies exclusively evaluating non-pharmacological interventions; (3) Abstracts without full-text availability; (4) Duplicate publications.

2.3. Data Extraction and Quality Assessment

Data were extracted independently by two reviewers using a standardized form capturing: study design, sample size, intervention, comparator, pulmonary outcomes (%-predicted FVC change, steroid dose reduction, radiographic response), hepatic outcomes (liver enzyme changes, hepatic sarcoidosis response rates, hepatotoxicity incidence), and adverse events.

2.4. Data Synthesis

Given the heterogeneity of study designs, populations, and outcomes, a narrative synthesis approach was employed, supplemented by quantitative meta-analytic data where available from published meta-analyses. Therapies were organized by treatment line (first-line, second-line, third-line, investigational) and outcomes were reported separately for pulmonary and hepatic domains.

3. Results

3.1. Study Selection

The search identified 22 distinct pharmacological agents with reportable outcome data across 8 randomized controlled trials, 8 single-arm trials, multiple retrospective cohort studies, 2 systematic reviews with meta-analysis, and 1 large real-world database analysis. Therapies were categorized into four treatment lines as detailed below.

3.2. First-Line Therapies

3.2.1. Prednisone

Pulmonary Outcomes: Prednisone remains the most widely used first-line agent for symptomatic pulmonary sarcoidosis. In the PREDMETH trial, a multicenter RCT of 138 treatment-naïve patients, prednisone (starting dose 20–40 mg/day with taper over 6–18 months) produced a mean FVC improvement of +6.75 percentage points predicted at 24 weeks.[1] The SARCORT trial demonstrated that 45% of patients who received 6 months of prednisone treatment experienced disease relapse between 12 and 18 months after cessation of therapy, underscoring the need for long-term treatment strategies.[1] Prednisone improves radiographic infiltrates in Scadding stage II–III disease. However, prolonged use is associated with significant toxicity including weight gain (+5.0 kg at 24 weeks), increased waist circumference (+4.4 cm), hypertension, and diabetes mellitus.[1]

Hepatic Outcomes: Prednisone is the first-line treatment for symptomatic hepatic sarcoidosis, used in approximately 80% of treated patients.[4] Corticosteroids reduce cholestasis and transaminitis in symptomatic hepatic sarcoidosis, though evidence that treatment prevents progression to cirrhosis is lacking.[2] Prednisone can itself cause transaminitis, which may confound assessment of hepatic disease activity.

3.2.2. Methotrexate

Pulmonary Outcomes: The PREDMETH trial established methotrexate as noninferior to prednisone for first-line treatment of pulmonary sarcoidosis.[1] The mean FVC improvement was +6.11 percentage points predicted at 24 weeks (adjusted difference vs. prednisone: −1.17; 95% CI −4.27 to 1.93). Methotrexate demonstrated a more gradual onset of action compared to prednisone (which showed improvement within 4 weeks), with convergence of outcomes by week 24. Methotrexate also provides steroid-sparing capacity of approximately 6 mg/year in a multicenter European retrospective study of 145 patients.[1,3]

Hepatic Outcomes: Elevated liver enzyme levels were observed in 25% of methotrexate-treated patients in the PREDMETH trial, with ALT exceeding three times the upper limit of normal in 9%, leading to treatment discontinuation in 2 of 68 patients.[1] Long-term data on the risk of liver fibrosis and cirrhosis with methotrexate use in sarcoidosis are inconsistent, though this risk is well-documented in rheumatoid arthritis populations.[1] Regular monitoring of liver function tests is mandatory. Methotrexate has not been specifically studied for efficacy in hepatic sarcoidosis, and its hepatotoxic potential makes it a less attractive option for patients with significant hepatic involvement.

3.3. Second-Line Therapies

3.3.1. Azathioprine

Pulmonary Outcomes: Azathioprine provides steroid-sparing capacity comparable to methotrexate (~6 mg/year) and stabilizes FVC in retrospective studies.[3] However, a large real-world analysis using the TriNetX database (n = 13,814) demonstrated increased mortality risk compared to methotrexate.[3]

Hepatic Outcomes: Azathioprine is associated with a higher infection rate (35% vs. 18% with methotrexate) and hematologic toxicity.[3] Hepatotoxicity includes cholestatic hepatitis and veno-occlusive disease, though these are uncommon. Azathioprine is sometimes used as a second-line agent in hepatic sarcoidosis when corticosteroids are insufficient.[4]

3.3.2. Mycophenolate Mofetil (MMF)

Pulmonary Outcomes: MMF is associated with lower glucocorticoid doses in retrospective studies.[3] However, the TriNetX real-world analysis revealed concerning safety signals: higher risks of hospitalization (HR 2.74), critical care admission (HR 2.37), mechanical ventilation (HR 4.04), and mortality (HR 2.16) compared to methotrexate.[3]

Hepatic Outcomes: MMF has a relatively favorable hepatic safety profile compared to methotrexate and azathioprine. It is occasionally used in hepatic sarcoidosis as a steroid-sparing agent, though specific efficacy data are limited.[4]

3.3.3. Leflunomide

Pulmonary Outcomes: Leflunomide is associated with lower glucocorticoid doses in small retrospective series.[3,5] Controlled data on pulmonary outcomes are lacking.

Hepatic Outcomes: Leflunomide carries a known hepatotoxicity risk (class effect) and requires regular liver function monitoring.[5] Its use in hepatic sarcoidosis is limited by this hepatotoxic potential.

3.3.4. Hydroxychloroquine

Pulmonary Outcomes: Limited data support the use of hydroxychloroquine for pulmonary sarcoidosis. It is most useful for cutaneous disease, hypercalcemia, and neurosarcoidosis.[5]

Hepatic Outcomes: Hydroxychloroquine is generally well tolerated hepatically and does not carry significant hepatotoxicity risk.[5]

3.4. Third-Line Therapies

3.4.1. Infliximab

Pulmonary Outcomes: Infliximab has the most robust evidence base among biologic agents for pulmonary sarcoidosis. A phase 2 RCT (n = 138) demonstrated FVC improvement of +2.5% predicted versus placebo.[6] A multicenter study of 132 patients showed improved pulmonary function in 79% of treated patients.[7] The 2025 meta-analysis by Bechman et al. found that anti-TNF agents as a class produced a mean FVC improvement of +5.70% predicted (95% CI 1.61–9.78), with infliximab demonstrating a positive direction of effect across all estimates.[6] In the GenPhenReSa phenotype analysis, approximately two-thirds of patients in the pulmonary-lymphonodal group (group 4) achieved a response.[7]

Hepatic Outcomes: Infliximab demonstrated good response in the hepatic (abdominal organ-predominant, group 1) sarcoidosis phenotype in the GenPhenReSa classification.[7] However, anti-TNF agents carry a rare but recognized risk of autoimmune hepatitis-like liver injury.[7] Serious infections occurred in 36% of patients, leading to treatment cessation in 29% and causing two deaths in one multicenter series.[7] Infliximab is considered a valuable option for refractory hepatic sarcoidosis.

3.4.2. Adalimumab

Pulmonary Outcomes: Adalimumab demonstrated a positive direction of effect in vote counting analysis in the 2025 meta-analysis.[6] Greater Physician Global Assessment (PGA) response and reduced target lesion area versus placebo were demonstrated in cutaneous sarcoidosis RCTs.[6]

Hepatic Outcomes: Autoimmune hepatitis-like liver injury has been reported uncommonly with adalimumab, similar to the class effect of anti-TNF agents.[7] Specific data on efficacy in hepatic sarcoidosis are limited.

3.4.3. Etanercept

Pulmonary Outcomes: Two RCTs failed to demonstrate improvement in pulmonary or ocular sarcoidosis with etanercept, establishing it as inferior to other anti-TNF agents for sarcoidosis.[6]

Hepatic Outcomes: Hepatotoxicity risk is similar to the anti-TNF class. Given its lack of pulmonary efficacy, etanercept is not recommended for sarcoidosis.[6]

3.4.4. Rituximab

Pulmonary Outcomes: Rituximab has demonstrated utility in pulmonary sarcoidosis with a lower discontinuation rate (29%) compared to anti-TNF agents, though with a longer latency to benefit.[3,5] A retrospective series of 34 patients showed efficacy, though it appeared less effective than infliximab for pulmonary disease.[3]

Hepatic Outcomes: Rituximab has no associated cardiotoxicity and limited hepatic data. It may represent an alternative for patients with hepatic sarcoidosis who cannot tolerate anti-TNF agents due to hepatotoxicity concerns.[3]

3.4.5. Repository Corticotropin Injection (RCI)

Pulmonary Outcomes: RCI has been used in cardiac and pulmonary sarcoidosis with a lower discontinuation rate (43%) compared to anti-TNF agents and a significantly lower infection risk versus infliximab (HR 12.14 for infliximab).[3]

Hepatic Outcomes: Limited hepatic data are available, but RCI has a favorable safety profile compared to anti-TNF agents.[3]

3.5. Investigational Therapies

3.5.1. Tofacitinib (JAK1/3 Inhibitor)

Pulmonary Outcomes: An open-label proof-of-concept study in 5 patients with pulmonary sarcoidosis demonstrated that 60% met the primary endpoint of ≥50% steroid reduction with stable spirometry.[3,5] In cutaneous sarcoidosis, an open-label trial of 10 patients treated with tofacitinib 5 mg twice daily showed complete response in 60% and improvement in all patients, with concurrent improvement in internal organ involvement.[5] A systematic review of 49 patients treated with JAK inhibitors found complete response in 45% and partial response in 49%, with corticosteroid discontinuation in 48% of evaluable patients.[5] The 2025 meta-analysis confirmed a positive direction of effect across all estimates.[6]

Hepatic Outcomes: Limited hepatic data are available from sarcoidosis-specific studies. JAK inhibitors have a known risk of transaminase elevation from rheumatologic studies, though this has not been a prominent finding in sarcoidosis trials to date.[5]

3.5.2. Brepocitinib (JAK1/TYK2 Inhibitor)

A phase 2 RCT (BEACON; NCT06977725) is currently recruiting patients with cutaneous sarcoidosis. No efficacy or safety data are yet available.[5]

3.5.3. Efzofitimod (NRP2 Modulator)

Pulmonary Outcomes: Efzofitimod is a first-in-class biologic that selectively modulates neuropilin-2 (NRP2), which is upregulated on immune cells in sarcoidosis granulomas. A phase 1b/2a RCT of 37 patients demonstrated dose-dependent improvements in steroid reduction (up to 22% relative reduction at 5 mg/kg), quality of life (KSQ-Lung score), and a trend toward improved FVC.[5,8] Exposure-response analysis confirmed that as efzofitimod exposure increased, mean daily oral corticosteroid dose decreased and FVC improved.[8] The 2025 meta-analysis identified efzofitimod as showing a positive direction of effect across all estimates.[6] A phase 3 trial in symptomatic pulmonary sarcoidosis is underway.

Hepatic Outcomes: No hepatotoxicity signals were identified in the phase 1b/2a trial (n = 37).[8] Further hepatic safety data will emerge from the ongoing phase 3 program.

3.5.4. Other Investigational Biologics

Ustekinumab (anti-IL-12/23), anakinra (IL-1 receptor antagonist), and sarilumab (anti-IL-6 receptor) have each been evaluated in single trials included in the 2025 meta-analysis, but insufficient data exist to draw conclusions regarding pulmonary or hepatic outcomes.[6] Additional agents under investigation include CTLA-4 inhibitors, NLRP3 inflammasome inhibitors, GM-CSF inhibitors (XTMAB-16, NCT05890729), and PDE-4 inhibitors (OATD-01, NCT06205121).[5]

3.5.5. Antifibrotic Agents

Nintedanib: The INBUILD trial evaluated nintedanib in patients with progressive fibrosing interstitial lung diseases, including a sarcoidosis subgroup. Overall, nintedanib significantly slowed FVC decline (81 mL/year vs. 188 mL/year with placebo). However, the sarcoidosis subgroup showed no significant difference (MD −20.5 mL/year; 95% CI −337.1 to 296.1), likely due to the small sample size.[5] Hepatotoxicity (elevated transaminases) is a recognized adverse effect requiring monitoring.[5]

Nerandomilast: This preferential PDE4B inhibitor received FDA approval for idiopathic pulmonary fibrosis based on the FIBRONEER-IPF trial (n = 1,177), which demonstrated FVC decline of −114.7 mL versus −183.5 mL with placebo at 52 weeks.[9] It has not been specifically studied in sarcoidosis. The most common adverse event was diarrhea (41.3% at 18 mg dose).[9] Its antifibrotic and immunomodulatory properties make it a potential candidate for fibrotic pulmonary sarcoidosis, though dedicated trials are needed.

3.6. Hepatic Sarcoidosis: Specific Treatment Considerations

Hepatic sarcoidosis presents unique therapeutic challenges. A 2025 nationwide Italian study of 78 patients with hepatic sarcoidosis found that corticosteroids were first-line in 80% and ursodeoxycholic acid (UDCA) in 28% of patients, with 29% requiring second-line therapies.[2,4] Histological cirrhosis was present in 10% and clinically significant portal hypertension in 14%.[4] The ATS guideline notes that immune suppression reduces transaminitis and cholestasis in symptomatic patients, but it is uncertain whether these effects can be extrapolated to asymptomatic patients or whether treatment prevents progression to cirrhosis.[2]

Among biologic agents, infliximab has the strongest evidence for hepatic sarcoidosis, with good response rates in the abdominal organ-predominant (group 1) GenPhenReSa phenotype.[7] However, the paradoxical risk of anti-TNF–associated autoimmune hepatitis-like injury necessitates careful monitoring.[7] In severe cases refractory to medical therapy, liver transplantation may be indicated, though recurrence of sarcoidosis in the allograft has been reported.[4]

4. Discussion

This systematic review identifies several key findings regarding the pharmacological management of sarcoidosis with respect to pulmonary and hepatic outcomes.

4.1. Evolving First-Line Paradigm

The PREDMETH trial represents a paradigm shift in sarcoidosis management by establishing methotrexate as noninferior to prednisone for first-line treatment of pulmonary sarcoidosis.[1] This finding is particularly significant given the substantial toxicity burden of long-term corticosteroid therapy, including weight gain, metabolic syndrome, and osteoporosis. However, the 25% incidence of liver enzyme elevation with methotrexate, with 9% experiencing ALT >3× ULN, highlights the importance of hepatic monitoring and raises concerns about methotrexate use in patients with concomitant hepatic sarcoidosis.[1] The different adverse event profiles of prednisone (weight gain, insomnia, increased appetite) and methotrexate (nausea, fatigue, liver function abnormalities) support shared decision-making based on individual patient risk factors and preferences.[1]

4.2. Anti-TNF Agents: Balancing Pulmonary Efficacy and Hepatic Risk

The 2025 meta-analysis by Bechman et al. provides the most comprehensive quantitative assessment of biologic therapies in sarcoidosis to date, demonstrating a modest but statistically significant mean FVC improvement of 4.79% predicted (95% CI 1.22–8.35) with biologic and targeted synthetic therapies, driven primarily by anti-TNF agents.[6] Infliximab consistently demonstrated a positive direction of effect across all estimates and showed particular efficacy in the hepatic sarcoidosis phenotype.[6,7] However, the 36% serious adverse event rate and the rare but recognized risk of autoimmune hepatitis-like liver injury underscore the need for careful patient selection and monitoring.[7]

4.3. Emerging Targeted Therapies

JAK inhibitors and efzofitimod represent the most promising investigational approaches. Tofacitinib's mechanism of inhibiting IFN-γ–mediated type 1 immunity directly targets the central cytokine pathway driving granuloma formation.[5] The complete response rate of 60% in cutaneous sarcoidosis with concurrent internal organ improvement suggests systemic efficacy.[5] Efzofitimod's novel mechanism of NRP2 modulation and its favorable safety profile in early-phase trials position it as a potentially important addition to the therapeutic armamentarium.[6,8]

4.4. The Unmet Need in Hepatic Sarcoidosis

A critical gap identified in this review is the paucity of prospective data specifically evaluating hepatic sarcoidosis outcomes. Most evidence is derived from subgroup analyses of studies designed primarily for pulmonary endpoints, retrospective series, or case reports. The 2025 Italian nationwide study represents the largest dedicated hepatic sarcoidosis cohort but remains observational.[4] The finding that 10% of patients had histological cirrhosis and 14% had clinically significant portal hypertension underscores the potential severity of hepatic involvement and the need for effective therapies.[4]

4.5. Antifibrotic Agents: A Nascent Field

The role of antifibrotic agents in fibrotic pulmonary sarcoidosis (Scadding stage IV) remains uncertain. While nintedanib showed overall benefit in the INBUILD trial for progressive fibrosing ILDs, the sarcoidosis subgroup was too small to demonstrate a significant effect.[5] Nerandomilast, with its dual antifibrotic and immunomodulatory properties, represents a theoretically attractive candidate but has not been studied in sarcoidosis.[9] Dedicated trials of antifibrotic agents in fibrotic sarcoidosis are needed.

4.6. Limitations

This review has several limitations. First, the evidence base for sarcoidosis therapeutics is characterized by small sample sizes, heterogeneous study designs, and high risk of bias in many RCTs.[6] Second, hepatic outcomes are inconsistently reported across studies, limiting the ability to draw definitive conclusions about hepatic efficacy or hepatotoxicity for many agents. Third, the meta-analytic data are limited by substantial heterogeneity (I² = 76.3% for FVC outcomes).[6] Fourth, real-world database analyses, while providing large sample sizes, are subject to confounding by indication and other biases inherent to observational designs. Finally, many investigational agents have only early-phase data, and their ultimate role in clinical practice remains to be determined.

5. Conclusions

The therapeutic landscape for sarcoidosis is evolving rapidly. Methotrexate has emerged as a viable first-line alternative to prednisone for pulmonary sarcoidosis, though hepatotoxicity monitoring is essential. Anti-TNF agents, particularly infliximab, provide modest but consistent pulmonary benefit and demonstrate efficacy in hepatic sarcoidosis phenotypes, balanced against risks of serious infections and rare hepatotoxicity. JAK inhibitors and efzofitimod represent the most promising investigational therapies, with phase 2/3 trials ongoing. The role of antifibrotic agents in fibrotic sarcoidosis requires dedicated investigation.

Critical unmet needs include: (1) prospective trials specifically evaluating hepatic sarcoidosis outcomes; (2) head-to-head comparisons of second-line and third-line agents; (3) biomarker-guided treatment selection based on disease phenotype; and (4) long-term safety data for novel targeted therapies. Integration of hepatic monitoring into all sarcoidosis treatment protocols is recommended given the hepatotoxic potential of multiple effective agents.