Efficacy and safety of dual-targeted therapy with tofacitinib and TNF inhibitors in refractory spondyloarthritis: a case series from a tertiary care center

Abstract

Spondyloarthritis (SpA) is a complex inflammatory disease involving multiple cytokine pathways, including tumor necrosis factor-α (TNF-α) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. Despite advances in biologic and targeted synthetic therapies, up to 40% of patients with SpA remain refractory to monotherapy. This case series from a tertiary care center in India evaluated the efficacy and safety of dual-targeted therapy (DTT) combining tofacitinib, a JAK inhibitor, with TNF inhibitors in four patients with refractory SpA and psoriatic arthritis (PsA). All four patients had longstanding disease (mean duration 11.5 years) and had failed at least one prior biologic. Case 1 (PsA): Long-standing disease (24 years) failed optimized adalimumab; following DTT, disease activity in psoriatic arthritis (DAPSA) score improved from high disease activity (36) to low disease activity (8). Case 2 (SpA): Refractory to two TNF inhibitors; after adding tofacitinib, the Ankylosing Spondylitis Disease Activity Score incorporating C-reactive protein (ASDAS-CRP) score improved from very high activity (3.7) to low disease activity (1.7). Case 3 (SpA): Presented with very high ASDAS-CRP (3.8); rapid clinical response and laboratory remission (ASDAS-CRP, 1.6) were achieved within months of starting DTT. Case 4 (SpA): Failed adalimumab monotherapy; the addition of tofacitinib led to an improvement in ASDAS-CRP from 3.5 to 1.7. No serious adverse events or significant laboratory abnormalities were observed over 5–18 months. DTT combines extracellular TNF-α blockade with intracellular JAK-STAT inhibition. This addresses the pathway redundancy and compensatory mechanisms in refractory SpA. Our findings add to the emerging real-world evidence supporting DTT therapy as a promising option for patients with refractory SpA. Our real-world findings demonstrate improved disease control and safety when monotherapy fails. Future prospective studies are essential to optimize the selection, dosing, and long-term safety of DTT.

Plain language summary

Combining two different anti-inflammatory drugs helps patients with hard-to-treat inflammatory spine and joint disease.

Spondyloarthritis is a chronic condition causing inflammation in the spine and joints, leading to pain, stiffness, and reduced movement. Some patients also develop psoriatic arthritis, which affects both the skin and joints. While modern treatments have improved outcomes, approximately one-third of patients continue to have active disease despite trying multiple medications. Current treatments typically target one inflammatory pathway at a time. TNF inhibitors block a specific protein (tumor necrosis factor) that drives inflammation, while JAK inhibitors (like tofacitinib) prevent inflammatory signals from working inside immune cells. When one treatment fails, doctors usually switch to a different single medication rather than combining two. This study from an Indian hospital examined four patients whose arthritis remained severe despite trying conventional medications and at least one biologic drug. Instead of switching to another single therapy, doctors prescribed a combination of tofacitinib with a TNF inhibitor (adalimumab or etanercept). The idea was that blocking inflammation at two different points might work better than targeting just one pathway. All four patients improved significantly. Their disease activity scores dropped from high to low levels, blood tests showed reduced inflammation, and two patients achieved complete disease remission. The combination was well-tolerated, with no serious side effects observed during follow-ups lasting 5 to 18 months. These results suggest that using two targeted therapies together—one blocking inflammation outside cells and another blocking signals inside cells—may benefit patients who haven’t responded to standard treatments. This “dual therapy” approach addresses the complex nature of inflammatory arthritis, where multiple inflammatory pathways work together to cause disease. While this small study shows promise, larger research trials are needed to confirm these findings, identify which patients would benefit.

Keywords

dual-targeted therapy refractory spondyloarthritis spondyloarthritis TNF inhibitors tofacitinib

Introduction

Spondyloarthritis (SpA) encompasses a heterogeneous group of chronic inflammatory disorders characterized by axial and peripheral arthritis, enthesitis, and extra-articular manifestations.¹ The pathogenesis of SpA involves multiple interconnected inflammatory pathways, including tumor necrosis factor (TNF)-α, the interleukin (IL)-23/IL-17 axis, and Janus kinase (JAK)-signal transducer and activator of transcription (JAK-STAT) signaling, creating a complex cytokine network that drives disease progression.²

Conventional synthetic DMARDs, such as methotrexate, sulfasalazine, and leflunomide, have limited efficacy in axial disease but are frequently used to treat peripheral joint synovitis. The advent of biological therapies targeting specific pathways has revolutionized the management of SpA. TNF inhibitors (TNFi) remain the first-line biological therapy, whereas IL-17 inhibitors (IL-17i) have shown efficacy, particularly in patients with concomitant psoriasis. More recently, JAK inhibitors such as tofacitinib have been approved for SpA.³

Despite these therapeutic advances, up to 30%–40% of patients exhibit inadequate or partial response to monotherapy with biologics or targeted synthetic DMARDs.⁴ Current ASAS-EULAR management recommendations advocate switching to alternative pathway inhibitors (from TNFi to IL-17i or JAK inhibitors) in cases of treatment failure. However, these guidelines do not address the potential for combining different pathway blockades simultaneously to achieve more comprehensive cytokine inhibition.^3,4

Given the multiple pathways involved in SpA pathogenesis, dual-targeted therapy (DTT) combining agents with complementary mechanisms has emerged as a promising approach for refractory cases.⁵ The combination of tofacitinib (targeting JAK-STAT signaling) with adalimumab (blocking TNF-α) theoretically offers synergistic effects by simultaneously inhibiting extracellular TNF-mediated inflammation and intracellular cytokine cascades. However, real-world evidence for this specific combination remains limited, particularly in resource-constrained settings, such as India.

This case series evaluated the efficacy and safety of DTT with tofacitinib and TNFi in four patients with refractory SpA with peripheral arthritis at a tertiary care center in India, providing insights into its potential role in managing complex cases in which standard sequential therapy approaches have failed.

Materials and methods

This case series was prepared in accordance with the CARE (CAse REport) guidelines and followed the relevant EQUATOR reporting standards. This study was conducted at a tertiary care center in Mumbai, India, involving patients managed between 2024 and 2026.

Patients were included based on a clinical diagnosis of refractory disease, defined here as persistent high disease activity despite failure to respond to at least one biological agent. Case 1 was classified as PsA according to the CASPAR criteria.⁶ Cases 2, 3, and 4 were classified as axial spondyloarthritis (axSpA) with peripheral involvement according to the ASAS classification criteria.³

The decision to initiate DTT was based on clinical judgment in “difficult-to-manage” cases where standard sequential monotherapy was financially or clinically unfeasible. Clinical outcomes were evaluated using the Ankylosing Spondylitis Disease Activity Score incorporating C-reactive protein (ASDAS-CRP), the Disease Activity in Psoriatic Arthritis (DAPSA) score, and objective measures including the Tender Joint Count and Swollen Joint Count.

Case descriptions

Case 1

A 44-year-old woman with psoriasis since age 20 developed psoriatic arthritis (PsA) in 2020 involving the left ankle and knee. Initial treatment with methotrexate (10 mg/week) and sulfasalazine (500 mg twice daily) produced only partial relief.

From March 2022, she was started on adalimumab 40 mg every 2 weeks with methotrexate 15 mg/week. Over the next 2 years, methotrexate was escalated to 25 mg/week and adalimumab optimized, but she continued to experience active skin disease and intermittent joint flares. The baseline DAPSA score was 36 (high disease activity) despite therapy, representing an inadequate response to anti-TNF treatment.

In April 2024, tofacitinib 5 mg twice daily was added to ongoing methotrexate and adalimumab treatment. Within 2 months, joint symptoms improved markedly, and the DAPSA score improved to 14 (moderate activity), indicating a significant clinical response. By December 2024 (8 months) and June 2025 (14 months), she maintained good articular control with DAPSA scores between 8 and 10 (low disease activity), although cutaneous psoriasis persisted. No significant laboratory abnormalities or adverse events were observed.

Case 2

A 56-year-old woman developed inflammatory low back pain at the age of 48 years and was diagnosed with non-radiographic axSpA in 2017 based on MRI evidence of bilateral sacroiliitis and HLA-B27 positivity. In 2018, she developed asymmetrical, predominantly large-joint inflammatory arthritis (knee > ankle > hip).

She was treated with NSAIDs, methotrexate (up to 25 mg/week), and sulfasalazine (3 g/day) for 3 years with only partial benefit. Adalimumab (40 mg every 2 weeks) was started in October 2021, but despite concurrent methotrexate and sulfasalazine, she continued to have right knee arthritis and elevated CRP (>25 mg/L) and high ASDAS-CRP (3.5–3.7). Left knee synovectomy was performed in July 2022. She was switched to etanercept in January 2023; however, disease activity persisted despite repeated intra-articular steroid injections through February 2024, representing anti-TNF failure after approximately 30 months of biologic therapy. In March 2024, tofacitinib 5 mg twice daily was added to methotrexate, sulfasalazine, and etanercept. By April 2024 (6 weeks), the knee swelling had markedly improved. ESR and CRP levels normalized by June 2024, and ASDAS-CRP decreased to 2.0 at 3 months and 1.7 at 1 year (low disease activity). Spinal mobility also improved in the patient. Through September 2025 (18 months), the response remained stable without adverse events or laboratory abnormalities.

Case 3

A 51-year-old man with HLA-B27-positive spondyloarthritis presented in 2016 with polyarticular inflammatory arthritis. He received methotrexate (up to 25 mg subcutaneously), sulfasalazine (1 g twice daily), leflunomide (10 mg), and intermittent steroids without adequate control. He was lost to follow-up between 2017 and 2024. In June 2024, he presented with polyarthritis and dactylitis. Tofacitinib 5 mg twice daily was started but was insufficient; in July 2024, adalimumab (40 mg every 2 weeks) was added. After three doses, the patient still had active disease with CRP 98 mg/L and ASDAS-CRP 3.8 (very high disease activity). Combination therapy with adalimumab plus tofacitinib (11 mg OD) was continued from September 2024. By November 2024, he showed 80% clinical improvement, with a CRP level of 2.7 mg/L and an ASDAS-CRP score of 1.6 (indicating low disease activity). By March 2025, he had no active synovitis and maintained laboratory remission with no adverse events.

Case 4

A 62-year-old HLA-B27-positive male presented in 2019 with inflammatory back pain and peripheral arthritis. Initial therapy with methotrexate (25 mg), leflunomide (10–20 mg), and sulfasalazine (3 g/day) provided partial benefit. In January 2021, he had a flare and received adalimumab, but discontinued after three injections and was lost to follow-up. In January 2025, he returned with a 1-month flare (polyarthritis, dactylitis; CRP 57 mg/L). He was restarted on adalimumab 40 mg every 2 weeks, sulfasalazine 1 g twice daily, and a tapering prednisolone, but showed a limited response after six doses (ASDAS-CRP 3.5). In March 2025, tofacitinib (5 mg twice daily) was added to adalimumab. By May 2025, the CRP level had become negative, and the ASDAS-CRP had improved to 1.8 (low disease activity). By August 2025, he remained clinically and biochemically improved (CRP 4.2 mg/L, ASDAS-CRP ~1.7) with stable renal and liver parameters.

Discussion

This case series presents four patients with refractory SpA and PsA who received DTT combining tofacitinib and anti-TNF agents. All patients had long-standing disease refractory to conventional synthetic DMARDs and at least one biologic agent (Table 1). Upon initiation of combination therapy, all patients demonstrated marked clinical improvement with substantial reductions in disease activity scores (ASDAS-CRP) and inflammatory markers, achieving sustained remission or low disease activity over the follow-up period. Importantly, no serious adverse events were observed in this cohort, underscoring the potential safety and efficacy of this therapeutic strategy in difficult-to-treat populations with limited treatment options (Table 2).

Table 1.

Baseline demographics and clinical features.

Case	Age/sex	Diagnosis	HLA-B27	Disease duration	Major manifestations	Prior DMARDs	Prior biologics
1	44/F	PsA	Neg	24 years	Skin, L. ankle/knee arthritis	MTX, SSAZ	Adalimumab
2	56/F	Axial and peripheral SpA	Pos	8 years	IBP, large joint oligoarthritis	MTX, SSAZ	Adalimumab, Etanercept
3	51/M	Axial and peripheral SpA	Pos	8 years	Polyarthritis, dactylitis	MTX, SSAZ, LEF	Adalimumab
4	62/M	Axial and peripheral SpA	Pos	6 years	IBP, polyarthritis, dactylitis	MTX, SSAZ, LEF	Adalimumab

F, female; IBP, inflammatory back pain; LEF, leflunomide; M, male; MTX, methotrexate; Neg, negative; Pos, positive; PsA, psoriatic arthritis; SpA, spondyloarthritis; SSAZ, sulfasalazine.

Table 2.

Treatment timeline and outcome.

Case	DTT start	DTT regimen	Baseline				Last Follow up				Articular response	Adverse events	Follow-up (months)
Case	DTT start	DTT regimen	Disease activity	TJC	SJC	CRP (mg/L)	Disease activity	TJC	SJC	CRP (mg/L)	Articular response	Adverse events	Follow-up (months)
1	April 2024	Tofacitinib + Adalimumab	36 (DAPSA)	8	8	35	8 (DAPSA)	2	2	7	Marked sustained	None	14
2	March 2024	Tofacitinib + Etanercept	3.7 (ASDAS-CRP)	6	6	25	1.7 (ASDAS-CRP)	1	1	3	Marked sustained	None	18
3	Sep 2024	Tofacitinib + Adalimumab	3.8 (ASDAS-CRP)	13	13	98	1.6 (ASDAS-CRP)	0	0	3	Complete remission	None	6
4	Mar 2025	Tofacitinib + Adalimumab	3.5 (ASDAS-CRP)	11	11	57	1.7 (ASDAS-CRP)	0	0	4	Complete remission	None	5

ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score incorporating C-reactive protein; DAPSA, Disease Activity in Psoriatic Arthritis score; DTT, dual-targeted treatment; SJC, swollen joint count; TJC, tender joint count.

The mechanistic rationale for combining anti-TNF therapy with tofacitinib lies in their complementary actions on critical, yet distinct, inflammatory pathways in SpA and PsA. TNF-α is a pivotal pro-inflammatory cytokine that binds TNF receptors, triggering the NF-κB and MAPK signaling cascades, which promote synovial inflammation and joint damage.^7,8 Anti-TNF biologics neutralize TNF-α, blocking extracellular inflammatory signals. Conversely, tofacitinib, a selective JAK inhibitor, interrupts intracellular cytokine signaling by inhibiting the JAK-STAT pathway associated with cytokines like IL-6, IL-23, and interferon-γ. Many of these cytokines act downstream or in parallel to TNF-α, contributing to persistent inflammation.³ Dual inhibition addresses cytokine redundancy and compensatory pathways, enhancing the suppression of inflammatory networks underlying refractory diseases, with anti-TNF inhibiting extracellular signals and tofacitinib modulating intracellular pathways.

Supporting evidence for dual therapy in patients with SpA and PsA comes from multiple sources. Chang and Wang⁹ demonstrated that tofacitinib combined with biologic DMARDs in ankylosing spondylitis patients who had an inadequate response to biologics resulted in significant improvements in ASDAS-CRP and BASDAI scores within 12 weeks, with minimal adverse events and excellent tolerability. Similarly, a multicenter Spanish cohort evaluating 36 different dual-targeted combinations in 33 patients with active musculoskeletal disease demonstrated remission or low disease activity in 58.3% of cases, with SpA patients showing superior response rates (71% remission/low activity).¹⁰ These combinations included tofacitinib plus adalimumab regimens similar to our series, validating the efficacy of JAK inhibitor-TNF blocker dual therapy in refractory spondyloarthropathies. This approach is further supported by De Marco et al.,¹¹ who utilized dual targeting (TNFi and anti-IL-12/23) to manage tissue-specific refractory PsA. Case reports in refractory rheumatoid arthritis further illustrate the potential for sustained remission with such combinations.¹²

Extending beyond rheumatology, DTT has shown promise in refractory inflammatory bowel disease (IBD), where overlapping cytokine networks drive gut inflammation. Systematic reviews document clinical benefit with regimens combining TNF inhibitors and JAK inhibitors or other biologics, though with careful attention to infection risk and patient selection.¹³

Significantly, the recent systematic review and meta-analysis by Lignou et al. encompassing 1200 patients across immune mediated inflammatory diseases—including SpA, PsA, RA, and IBD—provides strong support for DTT. They found significant clinical improvements and remission rates with double biologic or targeted synthetic DMARD combinations, and an acceptable safety profile, with adverse events similar to those of monotherapy regimens.¹⁴ Infection risks necessitate vigilant monitoring, but the data affirm the promise of multidimensional cytokine blockade in refractory disease.

Limitations

While current ASAS-EULAR management recommendations advocate for switching to an alternative pathway monotherapy in cases of treatment failure for axSpA³ and the updated 2023 EULAR PsA management recommendations suggest a similar sequential switch.¹⁵ However, in resource-constrained settings, the significant cost disparity between newer biological classes and generic JAK inhibitors makes adding a targeted synthetic a more practical and feasible choice for achieving clinical goals.

This study has several other limitations. The small sample size and retrospective design limit the generalizability and strength of the conclusions. In addition, the follow-up duration was limited, precluding the assessment of long-term outcomes and rare adverse events.

Conclusion

Our experience with these four patients demonstrates that combining tofacitinib with anti-TNF agents leads to good therapeutic control of recalcitrant SpA/PsA. This combination addresses the molecular complexity and compensatory inflammatory pathways fundamental to SpA and PsA persistence. Prospective studies on recalcitrant SpA/PsA are warranted to refine patient selection, dosing, and long-term safety monitoring.

Supplemental Material

sj-docx-1-tab-10.1177_1759720X261449890 – Supplemental material for Efficacy and safety of dual-targeted therapy with tofacitinib and TNF inhibitors in refractory spondyloarthritis: a case series from a tertiary care center

Supplemental material, sj-docx-1-tab-10.1177_1759720X261449890 for Efficacy and safety of dual-targeted therapy with tofacitinib and TNF inhibitors in refractory spondyloarthritis: a case series from a tertiary care center by Aashish Agrawal, Sandeep Sriram Yadav and Canchi Balakrishnan in Therapeutic Advances in Musculoskeletal Disease

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Sandeep Sriram Yadav

Supplemental material

Supplemental material for this article is available online.

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