Blau syndrome treated with a combination of Tripterygium wilfordii and corticosteroids: a case description

Introduction

Blau syndrome is an uncommon autosomal dominant autoinflammatory disorder resulting from gain-of-function mutations in the NOD2 gene, which encodes a protein comprised of innate immune responses (1). First described in 1985, this condition is characterized by a classic triad of granulomatous dermatitis, arthritis, and uveitis (2). Additionally, patients may present with fever, hepatosplenomegaly, lymphadenopathy, and involvement of blood vessels and the cardiac, urinary, and central nervous systems (3,4). In this report, we describe a patient who was diagnosed with Blau syndrome due to the presence of the classic triad (granulomatous dermatitis, symmetric arthritis, and uveitis) and NOD2 gene mutation. The patient received low-dose prednisone and Tripterygium wilfordii (T. wilfordii), and the disease was stable. Clinically, symptoms typically manifest in early childhood, and if left untreated, the majority of patients develop serious consequences, including blindness, joint deformity, and visceral involvement (3,5). Due to its rarity and variable presentation, Blau syndrome poses significant diagnostic and therapeutic challenges.

Current treatment strategies for Blau syndrome primarily involve immunosuppressive agents, including corticosteroids, methotrexate, and biologic therapies targeting tumor necrosis factor alpha (TNF-α) (3,6). T. wilfordii, a traditional Chinese herb, has been used for treating various inflammatory and autoimmune disorders, including rheumatoid arthritis (7), primary Sjogren syndrome (8), and psoriasis (6). Extracts from T. wilfordii, known as “Tripterygium glycosides”, are considered one of the most effective herbal treatments in traditional Chinese medicine. In China, Tripterygium glycosides are available in tablet form and have been shown to efficiently resolve symptoms and improve quality of life in individuals with autoimmune disorders (7).

In this report, we report a 57-year-old patient with Blau syndrome who was successfully treated with low-dose corticosteroids and T. wilfordii. This case highlights the potential efficacy of T. wilfordii as an adjunctive therapy for Blau syndrome and underscores the need for further research into its mechanisms of action and clinical applications.

Case presentation

A 57-year-old male farmer reported 50 years of polyarticular swelling, pain, and deformity; a 5-year history of rash; a 5-month history of blurred vision; and worsening symptoms over the previous 2 months at July 2024. The patient had experienced multiple joint swelling and pain for over 50 years, which gradually progressed to joint enlargement, deformity, and limited range of motion. Despite these symptoms, he did not seek medical treatment. Five years prior, he developed a rash primarily on his hands, which later spread to his lower limbs and trunk. The rash resolved with significant postinflammatory hyperpigmentation and skin desquamation. Five months prior to presentation, the patient experienced ocular redness and blurred vision. Two months prior admitted the hospital, his symptoms worsened, prompting him to seek medical attention.

The patient’s medical history included hypertension and long-term treatment with levamlodipine at 2.5 mg/day. There were also notable for joint deformities in his mother and daughter, as well as a rash in his granddaughter. During physical examination, he displayed multiple erythematous skin-colored papules merging into plaques across his arms, legs, back, and abdomen (Figure 1A,1B). He also had swelling and tenderness in the left ankle and right elbow joints, with deformities in multiple joints of both hands and feet (Figure 2A,2B).

Figure 1 Rash on the torso (A,B) of the patient who was admitted to the hospital without prior treatment.

Figure 2 Bilateral toe deformity, bilateral ankle swelling, and bilateral rashes on both lower limbs (A,B) of the patients who was admitted to the hospital without prior treatment.

Laboratory tests indicated the following: white blood cell (WBC) count, 13.1×10⁹/L [normal range, (4–10)×10⁹/L], C-reactive protein (CRP), 69.6 mg/L (normal range, <4 mg/L); and erythrocyte sedimentation rate (ESR), 87 mm/h (normal range, <20 mm/h). Tests for serum cytokine indicated normal levels for interleukin (IL)-2/4/8/10 and interferon (IFN)-γ, along with elevated levels of IL-6 (29.22 pg/mL; normal range, <12 pg/mL) and TNF-α (7.3 pg/mL; normal range, <5.6 pg/mL). The levels of certain immunoglobulins were elevated, including immunoglobulin G (IgG) (26.0 g/L; normal range, 7–16 g/L) and immunoglobulin A (IgA) (8.23 g/L; normal range, 0.7–4 g/L), while the levels of immunoglobulin M (IgM) were normal (0.9 g/L; normal range, 0.4–2.3 g/L). Rheumatoid factor, anticitrullinated protein antibody, antinuclear antibody, allergen, and T-lymphocyte spot test for tuberculosis (T-SPOT) tests were all negative. Bone marrow biopsy results were within normal limits.

Wrist magnetic resonance imaging (MRI) indicated deformity of the distal ulna and radius on the right side, with osteoarthritic changes in the distal ulna, radius, and proximal carpal bones, consistent with Madelung deformity (Figure 3). Hand joint ultrasound revealed bone erosion in the interphalangeal joint, a small amount of interphalangeal joint effusion and synovial hyperplasia, and tenosynovitis of the flexor tendon (Figure 4).

Figure 3 Magnetic resonance imaging of wrist joint. The morphological changes of the distal radius (red arrow) and the distal ulna (yellow arrow) (A), bone hyperplasia and hypertrophy (green arrow) (B), articular surface injury of the distal radius with slight bone marrow edema under the articular surface (white arrow) (C), and dorsal subluxation of the distal ulna (blue arrow) (D) were consistent with Madelong deformity.

Figure 4 Ultrasound images of the right interphalangeal joint. (A) Signs of bone erosion in the interphalangeal joint (red arrow). (B) Thickening of the tendon sheath of the flexor tendon (green arrow).

Biopsy of skin from the left leg indicated granulomatous inflammation in the superficial dermis without caseous necrosis (Figure 5). Special stains, including Gram, acid-fast (Ziehl-Neelsen), and Fite stains, negatively stained the bacteria and mycobacteria.

Figure 5 Biopsy results indicating granulomatous inflammation in the superficial dermis without caseous necrosis (HE staining, ×20). HE, hematoxylin-eosin.

Ophthalmological evaluation revealed uveitis. Given the presence of arthritis, uveitis, and noncaseating granulomas on the skin biopsy, a genetic test was conducted on the patient, his daughter, and granddaughter. A mutation in codon 1000 C>T (protein R334W) in the NOD2 gene was identified. Treatment was initiated with prednisolone at 20 mg/day and Tripterygium glycosides at 40 mg/day.

At a follow-up visit 4 weeks later, inflammatory markers, including WBC (6.9×10⁹/L), CRP (4.5 mg/L), ESR (14.1 mm), IL-2/4/6/8/10, TNF-α, and IFN-γ, appeared to have normalized. Significant improvement was observed in joint swelling, pain, and rash (Figure 6). Ophthalmological re-evaluation showed marked improvement in uveitis and alleviation of blurred vision. At 8-month follow-up, the patient discontinued corticosteroids and continued Tripterygium glycosides at 40 mg/day, and the disease remained stable. All procedures in this study were performed in accordance with the ethical standards of the relevant institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 6 Rash on the torso of the patient after treatment for 1 month.

Discussion

Blau syndrome is an uncommon autosomal dominant autoinflammatory disorder resulting from the NOD2 gene mutation which is positioned on chromosome 16q12.1-13 and encodes a protein of 1040 amino acids consisting of three domains: caspase activation and recruitment domain (CARD), a nucleotide-binding oligomerization domain (NOD/NACHT), and leucine-rich repeats (LRRs) (9). Matsuda et al. (3) examined 50 cases of Blau syndrome, among whom 32 cases had sporadic NOD2 mutations and 18 had familial mutations from nine unrelated families. In all the 50 patients, 15 different NOD2 mutations were found, two mutations (p.W490S and D512V) of the 15 were previously unreported.

NOD2 is a member of the NOD-like receptor (NLR) family and has a high expression in antigen-presenting cells—including monocytes and macrophages—and in intestinal Paneth cells (9). Upon binding to its ligand, muramyl dipeptide (MDP), NOD2 stimulates nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, initiating the transcription of inflammatory genes (10). This leads to the upregulation of pr-inflammatory cytokines and a persistent, excessive inflammatory response, ultimately resulting in granulomatous inflammation (11). Additionally, interferon gamma (IFN-γ) can act as an initiating signal, inducing NF-κB stimulation and producing proinflammatory cytokines, such as IL-6/8 and TNF-α, in macrophages carrying Blau syndrome–associated mutations through the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway (12).

Treatment strategies for Blau syndrome primarily involve immunosuppressive agents, such as corticosteroids, methotrexate, and biologic therapies targeting TNF-α (3,13). In Matsuda et al.’s study (3) of 50 Blau syndrome cases, 26 patients were administered biologics following diagnosis, all of which were TNF-α agents. Among these patients, three received biologics alone, while the others received a combination of biologics and methotrexate or prednisolone. Ueki et al. (12) discovered that tofacitinib, a type of Janus kinase inhibitor, inhibited the IFN-γ-based induction of NOD2 expression, thus regulating the generation of pro-inflammatory cytokines. This suggests that tofacitinib could be a potential treatment for Blau syndrome, as it inhibits NOD2 expression, which is responsible for the autoinflammation that is observed in this condition. Jensen et al. (1) reported a case of Blau syndrome treated with a combination prednisone, methotrexate, and hydroxychloroquine, which resolved the symptoms of rash and arthritis. In our case, the patient, who had rash, arthritis, and uveitis, was treated with a low dose of prednisone in combination with Tripterygium glycosides, which induced disease remission after 1 month.

T. wilfordii, a traditional Chinese herb, has been widely used in treating various inflammatory and autoimmune conditions, including rheumatoid arthritis (13) and systemic lupus erythematosus (14). Tripterygium glycosides and their active components, including triptolide and celastrol, have demonstrated potent anti-inflammatory and immunomodulatory effects in preclinical studies (8). These compounds suppress proinflammatory cytokine generation, suppress T-cell stimulation, and modulate NF-κB signaling pathways (15), which are implicated in the pathogenesis of Blau syndrome. Despite its promising therapeutic potential, the use of T. wilfordii to manage Blau syndrome has not been extensively studied, and reports of its clinical application remain scarce.

In our case, T. wilfordii was used to treat a patient with Blau syndrome, supporting its potential as a therapeutic option for this challenging condition. Considering the long disease course, the patient’s financial status, relatively older age, and infection risk, we chose T. wilfordii as the disease-modifying antirheumatic drug. After 8 months of follow-up from admitted the hospital (July 2024), given the potential hepatotoxicity and nephrotoxicity associated with T. wilfordii, the patient’s liver function, renal function, and a complete blood count were monitored at baseline and monthly thereafter, and were found to be normal.

T. wilfordii may represent a potential alternative treatment for Blau syndrome, although further studies are needed to determine its noninferiority to methotrexate. By reporting the clinical course, treatment response, and safety profile in this patient, we hope to add to the growing amount of data supporting the application of T. wilfordii in autoinflammatory disorders and encourage further research into its mechanisms and efficacy.

Certain limitations to this the case report should be noted. (I) This report is of only a single case, the findings cannot be extensively generalized. (II) The initial improvement occurred under a combination of prednisone and Tripterygium glycosides, obscuring Tripterygium’s specific early contribution. (III) There were no comparisons of Tripterygium glycosides to standard therapies (such as methotrexate and biologics). Finally, (IV) the proposed mechanism (NF-κB/cytokine suppression) linking Tripterygium to Blau syndrome pathogenesis is plausible but remains speculative and based solely on a single clinical case; further molecular analysis should be conducted to verify this potential mechanism.

Acknowledgments

The authors express appreciation to the patient for his dedication to this research.

Footnote

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-660/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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