Professor and Chair of the Department of Dermatology and Professor of Internal Medicine in the Division of Rheumatic Diseases and in the Peter O'Donnell Jr. School of Public Health at UT Southwestern Medical Center in Dallas

Joseph Merola, MD, MMSc

Joints, Weight, and Mental Health: Ixekizumab + Tirzepatide for PsA, With Joseph Merola, MD

Combination treatment with ixekizumab (Taltz) and tirzepatide (Zepbound) produced superior joint outcomes compared with ixekizumab alone in a population of patients with difficult-to-treat 

Joseph F. Merola, MD, MMSc, FAAD, professor and chair of the Department of Dermatology and professor of internal medicine in the Division of Rheumatic Diseases and in the Peter O'Donnell Jr. School of Public Health at UT Southwestern Medical Center in Dallas, presented these findings, from the TOGETHER-PsA trial, as a late-breaking oral at the 

2026 American Academy of Dermatology (AAD) Annual Meeting

 held in Denver, Colorado, from March 27-31. The results were simultaneously published in 

TOGETHER-PsA (NCT06588296) was a 52-week, randomized, open-label, assessor-blinded phase 3b trial enrolling 271 adults with active PsA and obesity (BMI ≥30 kg/m²) or overweight (BMI 27–29.9 kg/m²) with at least 1 weight-related comorbidity. The trial population reflected the clinical reality that an estimated 65–82% of patients with PsA in the United States meet overweight or obese criteria. Participants had a mean age of 55.0 years (SD, 11.9), mean baseline weight of 106.1 kg (SD, 24.8), and mean BMI of 37.6 kg/m² (SD, 7.6). Both arms received diet and exercise counseling; patients were randomized 1:1 to ixekizumab plus tirzepatide or ixekizumab alone.

Merola emphasized several features of the enrollment that distinguished TOGETHER-PsA from earlier PsA trials. Approximately 70% of participants were women — a group he noted is historically harder to treat in PsA — and more than 60% had prior exposure to at least 1 advanced therapy, with at least 20% having received 2 or more prior treatments. A substantial proportion carried BMI levels in the class III obesity range. Despite this treatment-experienced, high-burden population, the combination arm still demonstrated meaningful separation from monotherapy across multiple endpoints.

The composite primary endpoint — simultaneous achievement of ACR50 and ≥10% weight reduction at week 36 — was met by 31.7% of patients on combination therapy versus 0.8% on ixekizumab alone (

 <.001). On ACR50 alone, combination therapy achieved 33.5% versus 20.4% (

 = .02). Merola highlighted the early onset of separation between arms — detectable by week 4, before clinically meaningful weight loss had accrued — as mechanistically provocative, suggesting tirzepatide may act through direct modulation of the adipokine and cytokine milieu that drives psoriatic inflammation rather than exclusively through weight reduction. Consistent improvements were observed across joint inflammation, pain, physical function, and health-related quality of life.

Among the secondary findings Merola called out specifically, the improvement in the SF-36 mental component score (MCS) stood out as clinically meaningful. Mental health measures frequently remain static across PsA clinical trial programs — either because they are not collected, or because the data are not highlighted on the assumption they will not change. In TOGETHER-PsA, the MCS did improve, a finding Merola attributed to the multidomain nature of the intervention: simultaneous improvement in skin, joints, and body weight appears to carry a psychological benefit that single-domain therapy may not replicate. He raised the additional possibility, acknowledged as speculative, that reduced systemic inflammation may itself carry direct central nervous system effects. On safety, the combination regimen was well tolerated. GI adverse events led to discontinuation in 2.9% of patients in the combination arm versus 1.0% on ixekizumab monotherapy — a rate Merola cited as reassuring, noting that the great majority of patients remained on treatment and derived benefit across multiple domains.

“This is not something where patients are running for the hills because of GI side effects, just the opposite. The vast majority of patients stayed in this study and saw multiple benefits. I think that's important to highlight,” Merola emphasized.

Merola also addressed the question of who should prescribe GLP-1/GIP receptor agonists in this setting. He framed the minimum expectation as ensuring dermatologists and rheumatologists initiate the conversation with patients about concurrent use, leaving the prescribing decision to individual clinician comfort — whether that means owning the prescription directly or co-managing with endocrinology or primary care. Week 52 data from TOGETHER-PsA and the companion TOGETHER-PsO skin trial are forthcoming.

Merola’s disclosures include Amgen, Astra-Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Abbvie, Dermavant, Eli Lilly, Moonlake, Novartis, Janssen, Oruka, UCB, Sanofi, Regeneron, Sun Pharma, Galderma, Biogen and Pfizer.

Merola JF, et al. Ixekizumab with tirzepatide achieved greater disease control than ixekizumab alone in adults with psoriatic arthritis and overweight or obesity: results from a randomized clinical trial. 

Eli Lilly and Company. Phase 3b data presented at AAD Annual Meeting show Lilly's Taltz (ixekizumab) plus Zepbound (tirzepatide) delivered superior efficacy for adults with psoriatic arthritis and obesity. Press release. March 28, 2026. 

https://investor.lilly.com/news-releases/news-release-details/phase-3b-data-presented-aad-annual-meeting-show-lillys-taltz

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The combination showed efficacy in a predominantly female, treatment-experienced, high-BMI population.


Evolving Research Landscape Drives Progress in CLE at AAD 2026

Cutaneous lupus erythematosus (CLE) is a disease whose therapeutic stagnation has stood in stark contrast to the scientific progress made in understanding its underlying biology. Over the past two decades, advances in immunology have illuminated the central role of plasmacytoid dendritic cells, type I interferon signaling, and innate immune dysregulation in driving the skin inflammation, tissue injury, and scarring that define the disease.¹ That growing mechanistic clarity has not only reframed how clinicians think about CLE pathophysiology but has begun to translate into a new generation of rationally designed therapeutic candidates targeting the specific immunological pathways responsible for disease activity.

Litifilimab is perhaps the clearest example of that translation. Its development as a BDCA2-targeting monoclonal antibody was predicated on the understanding that pDC-driven type I interferon production is a proximal driver of lupus pathogenesis, and its two positive Phase 2 trials in CLE represent the most advanced clinical validation of that mechanistic hypothesis to date.² The progress made in CLE is also inseparable from broader advances in lupus research, where a deepening understanding of immune dysregulation across the spectrum of disease has created shared scientific infrastructure that benefits both systemic and cutaneous manifestations.

For patients who have lived with inadequate treatment options for generations, the convergence of scientific understanding and clinical evidence now underway represents a genuine inflection point. In this final segment, Joseph Merola, MD, MMSc, and Victoria Werth, MD, reflect on how the field's evolving understanding of CLE pathophysiology has shaped the current moment in drug development, and what the trajectory of innovation suggests for the future of care in this long-underserved disease.

Furie R, Werth VP, Merola JF, et al. Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus. 

 2019;129(3):1359-1371. doi:10.1172/JCI124466

Biogen Inc. Biogen announces second positive Phase 2 litifilimab trial in cutaneous lupus erythematosus at 2026 American Academy of Dermatology Annual Meeting, showing a significant reduction in skin disease activity. Published March 28, 2026. 

https://investors.biogen.com/news-releases/news-release-details/biogen-announces-second-positive-phase-2-litifilimab-trial

Experts reflect on how advances in understanding CLE have fueled drug development and what the trajectory of innovation holds for the field.

AMETHYST Phase 3 and Remaining Questions Surrounding Litifilimab in CLE

Cutaneous lupus erythematosus (CLE) remains one of dermatology's most consequential unmet needs. Despite its prevalence, chronicity, and capacity for permanent disfigurement, no targeted therapy has ever been approved for the disease, and the clinical trial landscape has historically been sparse. That context makes the emerging litifilimab program not only scientifically significant but unusually anticipated — 2 positive Phase 2 trials in a condition where positive Phase 2 data alone represent a meaningful advance.

With consistent efficacy signals established across the LILAC and AMETHYST Part A studies, attention now turns to AMETHYST Part B, the phase 3 portion of the phase 2/3 trial, which is currently ongoing with results remaining blinded. Part B will be critical in several respects. 

It will need to confirm the efficacy signal observed in Part A in a larger, more powered population, establish the durability of response beyond the 24-week controlled period examined in Phase 2, and provide the robust safety dataset that will ultimately inform regulatory review. Importantly, AMETHYST was designed with a globally representative enrollment strategy, with 74% women and 33% non-white participants in Part A, reflecting the demographic realities of CLE. Whether that representation is maintained and whether the efficacy signal holds across subgroups defined by disease subtype, severity, and background therapy will be among the most closely watched questions as Phase 3 data mature.¹

For clinicians who have long managed CLE with tools borrowed from adjacent indications, the prospect of a purpose-built, mechanism-driven therapy with a Phase 3 program underway is a substantive shift in the trajectory of the field. The Breakthrough Therapy Designation granted to litifilimab by the FDA adds further momentum, signaling regulatory recognition of both the unmet need and the strength of the existing evidence base.

In this segment, Joseph Merola, MD, MMSc, and Victoria Werth, MD, share what they are most anticipating from the AMETHYST Phase 3 program, which data points will be most informative for clinical practice, and what approval of a first targeted therapy for CLE would mean for patients who have been waiting decades for a better option.

Experts share what they anticipate most from the ongoing AMETHYST Phase 3 program and what approval of a first targeted therapy would mean for patients.

Potential of Targeting BDCA2 in Cutaneous Lupus Erythematosus Management

Cutaneous lupus erythematosus (CLE) is driven by a complex interplay of innate and adaptive immune dysregulation, with plasmacytoid dendritic cells (pDCs) occupying a central role in disease pathogenesis. Activated pDCs produce substantial quantities of type I interferon and other pro-inflammatory cytokines and chemokines that perpetuate skin inflammation, drive keratinocyte injury, and contribute to the irreversible tissue damage that defines the most severe presentations of the disease. For a patient population that has long been managed with broadly immunosuppressive agents carrying significant toxicity profiles, a therapy designed to interrupt this pathway at its source represents a meaningful mechanistic departure from the standard of care.

Litifilimab targets BDCA2, a receptor selectively expressed on pDCs. Binding of litifilimab to BDCA2 suppresses pDC activation and downstream production of type I interferon and associated inflammatory mediators, offering a targeted approach to interrupting the immunological cascade thought to underlie CLE pathology. The specificity of this mechanism is clinically relevant: by acting on pDCs rather than broadly suppressing immune function, litifilimab has the potential to attenuate disease-driving inflammation while preserving broader immune competence.

That mechanistic rationale is now supported by a pair of positive Phase 2 trials. In the phase 2 portion of the AMETHYST study, litifilimab demonstrated a statistically significant 11.8% higher rate of clear or almost clear skin versus placebo at Week 16 (14.7% vs 2.9%; 95% CI: 1.39, 22.27; P < .05), with separation from placebo observed as early as Week 4. At Week 24, 40.8% of litifilimab-treated participants achieved a CLASI-50 response compared with 21% receiving placebo, and 1 in 6 participants in the litifilimab group achieved a CLASI score of 0 to 3, indicating no or minimal disease activity, compared with none in the placebo group. These results are consistent with the earlier LILAC Phase 2 study and collectively represent the only investigational program with positive efficacy data across multiple CLE trials to date.¹

In this segment, Joseph Merola, MD, MMSc, and Victoria Werth, MD, examine how the mechanism of action of litifilimab maps onto the immunopathology of CLE, what the AMETHYST results reveal about the durability and depth of response, and what these findings may mean for patients who have exhausted current treatment options.

Drenkard C, Barbour KE, Greenlund KJ, Lim SS. The burden of living with cutaneous lupus erythematosus. 

 2022;9:897987. doi:10.3389/fmed.2022.897987

Experts explore how litifilimab's BDCA2-targeting mechanism maps onto CLE pathophysiology.

Joseph Merola, MD, MMSc

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