Background: The skin is a central organ involved in systemic autoimmune diseases (AID). Next to T-cell activation, the formation of pathogenic B-cells and plasma cells as well as the emergence of autoantibodies is a crucial process in AID. While some patients with AID can be managed well by conventional immunosuppressants, others develop highly-treatment resistant disease and require new therapeutic concepts that tackle pathologic B-cell and plasma cell activation. T-cell engagers are a powerful therapeutic tool to deplete B-cell and plasma cells and may be efficacious to improve skin manifestations of systemic AID.

Methods: We evaluated the effect of the BCMA-directed T-cell engager teclistamab on cutaneous manifestations of highly treatment-resistant systemic AID. Skin activity was assessed using the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), and skin-related quality of life using the Dermatology Life Quality Index (DLQI), based on clinical findings and patient interviews before and after treatment.

Results: Three patients (two with dermatomyositis, one with systemic sclerosis) with treatment-resistant disease and cutaneous manifestations were treated with teclistamab. In both dermatomyositis patients, skin disease activity substantially decreased, and skin-related quality of life improved. In the patient with systemic sclerosis, digital ulcers resolved, skin fibrosis decreased, hair regrew and the skin-related quality of life normalized.

Conclusion: In this small case series, BCMA-directed T-cell engager therapy was associated with improvement of skin manifestations and skin-related quality of life in patients with highly treatment-refractory AID. Larger studies are required to systematically assess efficacy, safety, and durability of cutaneous responses to T-cell engagers.

T-Cell Engagers, connective tissue diseases, skin improvement

T-cell engagers are powerful biological drugs that have been developed to deeply deplete B-cells and plasma cells in the human body [1]. To accomplish this task, these protein-based drugs are characterized by two binding domains that allow them to (i) recognize target cells (e.g., B-cells or plasma cells) and (ii) engage and activate T-cells, which can then kill the target cells. T-cell engagers thereby use the intrinsic capacity of T-cells to kill, directing this effect to a certain immune cell lineage by binding to a respective cell lineage-specific surface antigen. While T-cell activation is usually accomplished by a CD3 binding domain of the engager, the binding to either CD19 or CD20 molecules, specifically expressed on B-cells allows the killing of B-cells. Other engagers combine CD3 binding with the recognition of B-cell maturation antigen (BCMA), which is expressed on plasma cells and B-cells allowing the additional elimination of plasma cells. Since deep killing of malignant B-cell is essential to achieve remission in hemato-oncologic patients, T-cell engagers have been developed to treat certain forms of lymphoma and leukemia as well as multiple myeloma [2, 3].

T-cell engagers do not distinguish between malignant and benign target cells, as long as they express the specific target antigen. Therefore, these agents are considered to play a role in the treatment of autoimmune disease (AID) allowing deep depletion of pathogenic B-cells and autoantibody producing plasma cells. Initial data suggest remarkable efficacy of T-cell engagers in various AID, such as rheumatoid arthritis, systemic sclerosis and autoimmune hemolytic anemia [4–7]. To date, T-cell engagers have not been tested in autoimmune skin diseases, such as pemphigus vulgaris and also no data exist if and how T-cell engagers influence cutaneous manifestations of systemic AID.

B-cell activation, plasma cell differentiation and autoantibody production are central features of AID. B-cell depletion by monoclonal antibodies like rituximab and inhibition of B-cell activation by monoclonal antibodies like belimumab are established strategies in the treatment of AID, supporting the role of B-cells in their pathogenesis. However, some patients with AID show resistance against conventional B-cell depletion with rituximab, which may be based on insufficient B-cell depletion in tissues or the fact that rituximab does not deplete plasmablasts and plasma cells that lack CD20 expression.

B-cell maturation antigen (BCMA) is a surface receptor selectively expressed on plasma blasts and mature plasma cells. T-cell engagers targeting BCMA effectively kill plasma cells by T-cell activation. This strategy is used in the treatment of multiple myeloma with three approved BCMA-directed T-cell engagers (teclistamab, elranatamab, and linvoseltamab). One of them, teclistamab, is a bispecific IgG4 antibody that binds BCMA and CD3 and has a proline-Alanine-alanine (PAA) mutation in its Fc-proportion to decrease Fc-receptor binding [8]. Teclistamab has been successfully used in patients with highly resistant AID [5]. Herein we present the first data on cutaneous manifestations in three patients with highly -resistant systemic AID that received the T-cell engager teclistamab.

Three patients with treatment-resistant systemic AID (two with dermatomyositis, one with systemic sclerosis) fulfilling respective classification criteria [9, 10] and presenting with active signs of cutaneous disease at baseline were assessed. Characteristics of the patients are described in Table 1.

Patient 1 was a Caucasian 24-year-old woman diagnosed with anti–melanoma differentiation-associated gene 5 (MDA5)–positive idiopathic inflammatory myositis (IIM) in November 2021, with symptom onset in June 2021. She presented with lung (progressive interstitial lung disease), joint (arthritis) and cutaneous disease manifestations. Cutaneous disease included painful ischemic ulcerations of the fingertips and periungual areas, as well as deep ulcerations over the metacarpophalangeal joints and elbows (Fig. 1). In addition, she exhibited hyperkeratotic, fissured lesions of the lateral and palmar aspects of the fingers consistent with mechanic’s hands, accompanied by characteristic palmar papules. Additional cutaneous manifestations of dermatomyositis included Gottron's papules (Fig. 1C), heliotrope periorbital erythema with eczematous changes (Fig. 1A, B), and a holster sign with poikilodermatous changes (Fig. 1D). Due to lung disease, arthritis as well as due to severe pain and functional impairment caused by the digital ulcerations, the patient was unable to continue her work as an office administrator. Previous therapies with methotrexate, azathioprine, upadacitinib, hydroxychloroquine, and rituximab had been ineffective.

Figure 1. 

Skin manifestations of patient 1 (anti–MDA5–positive dermatomyositis) before and after treatment with teclistamab. A) Facial skin involvement shown in frontal view at baseline (upper image), demonstrating heliotrope periorbital erythema with eczematous and erosive changes around the nasal bridge and eyelids (arrows), accompanied by poikilodermatous skin with prominent telangiectasias, consistent with a vasculopathic cutaneous phenotype characteristic of anti-MDA5–associated dermatomyositis, and marked improvement at follow-up 12 weeks after treatment (lower image). B) Lateral facial view showing heliotrope periorbital erythema with eczematous changes and marked photosensitivity at baseline (upper image, arrows), with substantial resolution at follow-up after treatment (lower image). C) Severe hand involvement at baseline (upper and lower left images) with painful nailfold capillary abnormalities (upper image), hyperkeratosis and erosions (arrows), as well as Gottron's papules (lower left image), resulting in functional impairment, with complete resolution after treatment (lower right image). D) Holster sign (arrow) presenting as livid erythema of the lateral thighs at baseline (upper image), reflecting inflammatory vasculopathic skin involvement and its resolution (lower image).

Shortly after initiation of teclistamab treatment, a marked and sustained improvement in cutaneous disease activity was noted, with the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) decreasing from a score of 22 at baseline to a score of 6, 3 months after therapy. Skin-related quality of life as assessed by DLQI decreasing from 18 to 0 after teclistamab. Cutaneous disease manifestations including heliotropic erythema, digital ulcerations, mechanic hands (periungual hyperkeratosis), Gottron's papules and Holster's sign resolved (Fig. 1, Table 1). Anti-MDA-5 autoantibodies seroconverted and remained negative until the last follow-up. Low-grade cytokine release syndrome (CRS; grade 2) occurred after teclistamab administration. No immune effector cell-associated neurotoxicity syndrome (ICANS) was recorded. With respect of infections, viral gastroenteritis occurred 12 weeks after teclistamab initiation of treatment with spontaneous resolution. The patient could restart her work after treatment. Her improvement of cutaneous manifestations after teclistamab treatment now lasts for 22 months without need for further treatment.

Patient 2 was an Asian 57-year-old woman diagnosed with anti-PL-7 antibody–positive idiopathic inflammatory myositis (IIIM), in November 2021, with symptom onset in June 2021. She presented with lung (progressive interstitial lung disease), muscle (myositis), joint (arthritis and enthesitis) and cutaneous disease. Cutaneous manifestations included heliotropic erythema with pruritic eczematous changes of the eyelids, livedo racemosa and diffuse alopecia (Fig. 2). Due to multi-organ involvement the patient was severely impaired in her daily activities. Previous therapies with azathioprine, hydroxychloroquine, methotrexate, mycophenolate mofetil, nintedanib, and rituximab had been ineffective to improve her disease.

Figure 2. 

Cutaneous manifestations of patient 2 (dermatomyositis) before and after teclistamab treatment. A) Frontal view showing periorbital erythema with pruritic eczematous eyelid changes and xerosis at baseline (upper image), with complete resolution at follow-up after 12 weeks (lower image); B) Inflammatory swelling of the hands due to arthritis and enthesitis at baseline (upper image), completely resolving after treatment (lower image); C) Livedo racemosa–like poikilodermatous skin changes at baseline (upper image) with complete resolution at follow-up (lower image).

After initiation of teclistamab treatment, cutaneous disease activity improved with CDASI decreasing from a score of 13 at baseline to a score of 2, 3 months after therapy. Skin-related quality of life as assessed by DLQI decreasing from 10 to 1 after teclistamab. Heliotropic erythema and livedo racemosa disappeared and hair showed marked regrowth after the control of disease activity of dermatomyositis. Anti-PL-7 antibodies levels did moderately decrease but did not seroconvert. Low-grade CRS (grade 2) but no ICANS occurred. Her improvement of cutaneous manifestations after teclistamab treatment lasted for 14 months. Thereafter, disease relapsed with recurrence of arthritis and tenosynovitis, hypergammaglobulinemia, and re-emergence of cutaneous manifestations including livedo reticularis and eczematous skin changes. The patient regained remission after initiation of treatment with the Janus kinase inhibitor baricitinib. Herpes zoster infection in the right second lumbar segment was recorded 3 months after initiation of baricitinib and was successfully treated with valacyclovir.

Patient 3 was a Caucasian 60-year-old man diagnosed with anti-PM-Scl75 and anti-PM-Scl100 positive systemic sclerosis with symptom onset in January 2021. He presented with lung (progressive interstitial lung disease) and cutaneous disease. Cutaneous manifestations included multiple digital ulcers and extensive calcinosis cutis affecting the elbows and both lower legs and diffuse alopecia (Fig. 3). In addition, the patient exhibited hypopigmented skin areas in a characteristic salt-and-pepper–like pattern, predominantly affecting fibrotic and scar-like regions of the skin (Fig. 3). These changes, often intermingled with hyperpigmented areas, are a typical and diagnostically relevant feature of diffuse cutaneous systemic sclerosis. Due to lung involvement and digital ulcers the patient was severely impaired in his daily activities. Previous therapies with cyclophosphamide, hydroxychloroquine, nintedanib, mycophenolate mofetil and rituximab had been ineffective to improve his disease.

Figure 3. 

Cutaneous and mucosal manifestations of advanced skin fibrosis in patient 3 (diffuse cutaneous systemic sclerosis) before and after teclistamab treatment. A) Characteristic mask-like face marked by rigid facial expression, tight and shiny skin, and reduced skin folding before treatment. The insert shows reduced oral aperture (microstomia) with restricted mouth opening, a shortened lingual frenulum, and sclerosis/fibrosis of the labial mucosa before treatment. Facial telangiectasias reflecting superficial dilated capillaries were present. In addition, fragile, brittle, and thinned scalp hair was noted, as well as salt-and-pepper–like pigmentation on the extensor surfaces of the fingers, consistent with advanced cutaneous fibrosis and calcifications. B) Early follow-up 2 weeks after teclistamab administration showing a transient worsening of diffuse eczematous and scaling skin changes, interpreted as a cutaneous turnover or clearance reaction, followed by early signs of skin renewal with subsequent improvement of eczematous lesions and beginning recovery of scalp hair density. C) Long-term follow-up 25 months after treatment demonstrating sustained cutaneous remission with marked softening of the skin, improved elasticity, increased oral aperture, normalization of skin coloration, reappearance of facial skin folds, and resolution of mask-like facies. Residual digital pits persisted but were reduced. Insert shows improved mouth opening. Lower image: Improved hand mobility with decreased tissue fibrosis, improved grip function, and absence of calcifications.

After initiation of teclistamab treatment, cutaneous disease activity improved with modified Rodnan skin score decreasing from a score of 34 at baseline to 11 at 40 months of follow-up. Also, his pulmonary function improved. Skin-related quality of life as assessed by DLQI decreasing from 17 to 0 after teclistamab. Digital ulcers healed, calcinosis regressed and hair showed marked regrowth after the control of disease activity of systemic sclerosis (Fig. 1C). In addition, hypopigmented skin areas decreased and virtually disappeared after the treatment. Anti-PM-Scl75 and anti-PM-Scl100 autoantibodies seroconverted after 6 months and remained negative until the last follow-up. No CRS, ICANS or any infection occurred. Improvement of cutaneous manifestations after teclistamab treatment now lasts for 18 months after the teclistamab course without any need for further treatment.

This case series shows the efficacy of plasma cell-directed T-cell engager treatment in cutaneous manifestations of systemic AID suggesting that the majority of the skin changes associated with these diseases are at least in part driven by the formation of pathologic plasma cells. Teclistamab is a BCMA-directed T-cell engager that potently kills plasma cells and is approved for the treatment of relapsed/refractory multiple myeloma. This characteristic makes teclistamab and other T-cell engagers interesting agents to deeply intercept with AID as autoreactive B-cells and plasma cells are effectively depleted.

These data are the first demonstrating that T-cell engager treatment and the subsequent killing of plasma cells have profound benefits on several different manifestation of autoimmune skin disease. These effects concern inflammatory lesions such as heliotropic erythema and Gottron's papules, vascular lesions like digital ulcers and damage-associated lesions such as hypopigmentation and calcifications. This broad effect of teclistamab on a variety of disease-associated skin lesions suggests that a deep reset of autoimmunity by targeting B-cells and plasma cells could allow a substantial repair and reorganization of the affected skin leading to more robust healing of lesions [11].

B-cell activation, plasma cell differentiation and autoantibody production are central features of AID. B-cell depletion by monoclonal antibodies like rituximab and inhibition of B-cell activation by monoclonal antibodies like belimumab have become established strategies in the treatment of AID, including autoimmune skin diseases like pemphigus vulgaris. However, not all patients with autoimmune disease respond to conventional B-cell depletion with rituximab, indicating that better therapeutic strategies are needed. The inability to fully revert AID by drugs like rituximab may be based on insufficient B-cell depletion in tissues as well as the failure to target plasmablasts or long-lived plasma cells, which lack CD20 expression, the target antigen of rituximab [12].

Emerging data suggest that T-cell engagers may represent a promising novel therapeutic strategy for controlling refractory AID with improvements observed in several different non-cutaneous organs affected by AID, such as lungs, joints and muscles [4–7]. A potential advantage of the use of T-cell engagers is their powerful cell depletion efficacy, which potentially allows to induce a state of immune reset where not further continuous immunosuppression is needed. Notably, two of the three patients presented herein, achieved seroconversion of their disease-associated autoantibodies and did not require further immunosuppression. Treatment with T-cell engagers seems to be well-tolerated in patients with AID, though monitoring for cytokine release syndrome is warranted. Cytokine release syndrome can be observed with T-cell engager treatment of AID, but is mostly mild in nature.

While this case series shows that T-cell engager therapy can substantially improve cutaneous manifestations of AID, the findings should be interpreted with caution considering that the data are based on few patients. Further data on the safety and efficacy of these drugs in autoimmune skin diseases and systemic AID with cutaneous disease manifestations is warranted. However, the magnitude and consistency of clinical effects presented herein provide a compelling rationale for further investigations.

Taken together, this case series shows that depletion of B-cells and plasma cells by BCMA-directed T-cell engager therapy induced robust and sustained improvement of a variety of severe cutaneous manifestations of AID. These findings support further studies on the role of T-cell engager treatment in dermatology.