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Daniela Flores Soto - 5006975

Paola M. Rivera Rivera - 5006865

Luis E. Vega Escribano - 5006250

Jose M. Agosto Valentin - 5006212
Adolfo Eduardo Villanueva - 5005660

Diego Mariani Grillasca - 5005309

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The heliotrope rash is a lilac or violaceous eruption on the upper eyelids. The "V sign" is a large, and irregular shaped area of erythema in the anterior chest. 

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Skin manifestation occur only in dermatomyositis. The skin findings in dermatomyositis are heliotrope rash, Gottron papules, and "V sign". The heliotrope rash are lilac or violaceous eruption on the upper eyelids. In the other hand, Gottron papules are erythematous or violaceous papule that often have overlying scale and appear symmetrically over extensor/dorsal aspects of metacarpophalangeal and interphalangeal joints. The "V sign" is a large, and irregular shaped area of erythema in the anterior chest. Also, the disease present the symptoms characteristic of an idiopathic inflammatory myopathies like muscle weakness, typically proximally in the neck, shoulders, thigh, and pelvic area.

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The pathophysiology of Dermatomyositis (DM) starts with the complement system activating and forming the MAC complex, leading to capillary destruction and ischemia. Followed by subsequent immune cell recruitment and migration of these immune cells into the muscle; along with cytokine secretion; amplify inflammation and tissue damage, ultimately resulting in the characteristic muscle and skin manifestations of the disease. In Dermatomyositis, immune complexes formed by autoantibodies binding to antigens may trigger this activation. Autoantibodies form immune complexes with their target antigens, which deposit in tissues like the skin and muscles, causing inflammation and tissue damage. There are five autoantibodies used as diagnostic markers, since they are highly specific for dermatomyositis. In Kamperman et al., these autoantibodies are Anti-Mi-2 (skin rash and muscle weakness), Anti-MDA5 (clinically amyopathic DM w. increased risk for interstitial lung disease), Anti-TIF1-γ (cancer-associated DM), Anti-NXP-2 (juvenile DM w. calcinosis), and Anti-SAE (severe skin disease). The complement system is a part of the innate immune response and can be activated by antibodies (classical pathway), pathogen surfaces (alternative pathway), or lectins (lectin pathway). The classical pathway is the pathway of choice for autoantibodies.

The central component of the complement system, C3, gets cleaved into C3a and C3b. C3a acts as an inflammatory mediator, while C3b plays a key role in opsonization and further complement activation. C3b binds to the surface of pathogens or damaged cells, marking them for destruction and enhancing phagocytosis. The complement cascade progresses with the formation of the neoantigen C3bNEO and C5 convertase, which cleaves C5 into C5a and C5b. C5b initiates the assembly of the membranolytic attack complex (MAC, which extends from C5b-9), which inserts into cell membranes. The MAC complex is deposited in and around the endothelial cell walls of the endomysial capillaries (which are small blood vessels within muscle tissue), causing direct damage to these cells. The insertion of MAC into endothelial cell membranes is what causes lysis and death of these cells. As endothelial cells are destroyed, the number of functional capillaries in the muscle decreases, leading to ischemia (reduced blood flow). The surviving capillaries may become dilated in response to the loss of surrounding capillaries and increased demand for blood flow as compensation. Reduced blood supply particularly affects the muscle fibers around the edges (perifascicular regions) of muscle fascicles. This leads to atrophy (shrinking and weakening) of these muscle fibers, which is a prime characteristic of Dermatomyositis. The damaged tissue releases chemokines and cytokines as signals that attract immune cells from the bloodstream. Following Hornung, T., & Wenzel, J. (2014), these immune cells express adhesion molecules that allow them to adhere to the endothelial cells of the remaining capillaries, facilitating their migration into the muscle tissue. Immune cells move through the endothelial cell layer and into the muscle tissue.  Once inside the muscle, these immune cells contribute to the local inflammatory response. Activated immune cells, including B cells, CD4+ T cells, and macrophages, secrete pro-inflammatory cytokines such as TNF-α, IL-1, and IFN-γ. And these cytokines further promote inflammation, attracting more immune cells and enhancing the immune response .This ultimately creates a feedback loop that provokes/perpetuates repeated tissue damage. The inflammatory environment and immune cell activity result in further muscle fiber damage and atrophy, which are the main factors to the clinical symptoms of muscle weakness and skin rashes seen in Dermatomyositis.

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Different guidelines are set in place to determine and confirm Dermatomyositis. The Bohan and Peter criteria proposed in 1975 is the most well-known to confirm the diagnosis that is used to categorize patients in either polymyositis or dermatomyositis. What this criteria entails is a combination of different protocols to define Dermatomyositis. The criteria are broken up into 5 different criteria. (1)symmetric weakness of limb-girdle muscles and anterior neck flexors; (2) muscle biopsy evidence of myositis (3) elevation in serum skeletal-muscle enzymes; (4) a triad of needle EMG findings; and (5) presence of dermatologic features including heliotrope rash, Gottron’s sign, and erythematous dermatitis involving the face, neck, and upper torso. According to this a ≥3 and a rash present is used if a DM diagnosis is present. Additionally, in 2017 there was another guideline proposed called (EULAR/ACR) that included criteria with and without a biopsy. This is still being used in research and clinical trials (Cassard, 2024).

More generally, the first step is to take a thorough clinical history that encompasses any symptoms the patient is dealing with such as symmetrical and proximal muscle weakness, skin symptoms (Gotronn’s papules, heliotrope rash), fatigue, etc. Next would be to perform a physical examination for proximal muscle weakness and skin lesions.

Laboratory Tests are used to test for elevated muscle enzymes that include creatine kinase, AST/ALT, and aldolase which is also seen in muscular diseases. Autoantibodies are importantly tested such as anti-M2 which is specific for this disease/ seen in photosensitive rashes and anti-MDA5, anti-TIF𝛾/⍶, and anti-MJ/NXP2 that are also associated with the disease. Anti-Jo1 has also been seen associated with the disease. Imaging Studies can also be an added benefit in attaining the proper diagnosis. Most commonly MRI is used and least likely is CT to help identify where muscle damage has occurred and to help locate where it is best to take a biopsy sample.

Electromyography is another method to achieve the proper diagnosis due to the measurement of muscle activity and differentiate between a myopathic disease and a neurogenic pathology. Skin Biopsy is considered to be the “gold standard” for the diagnosis of dermatomyositis. What the biopsy shows is Perivascular, perimysial, and peri-fascicular inflammatory infiltrates of CD8 and CD4 T cells. Also, muscle fiber necrosis can be noted to further confirm a diagnosis.

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Dermatomyositis - Diagnosis | Johns Hopkins

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​​Each patient with DM requires an individualized therapeutic plan that takes into account the cutaneous disease severity, presence of concomitant muscle disease systemic involvement, other comorbidities, including underlying malignancy, and the overall impact of disease on patient’s quality of life. The treatment goal is to obtain control of cutaneous disease with the safest combination of therapeutics.

First-line therapy includes aggressive photoprotection (on a year-round basis, not only during summer months), antipruritic agents (e.g., amitriptyline or gabapentin), and topical anti-inflammatory medications (corticosteroids and calcineurin inhibitors).

-   Antimalarials (hydroxychloroquine, chloroquine, and quinacrine) → Overall tolerability and anti-inflammatory effect and photoprotection

-   Anti-inflammatory (Methotrexate, Systemic corticosteroids [Prednisone])

-   Immunosuppressants (Mycophenolate mofetil, IVIg, Ritixumab) → Neutralize autoantibodies, downregulate proinflammatory cytokines, binds complement, decrease formation of membrane attack complex

Other therapies for DM include immunosuppressive agents such as cyclophosphamide, tacrolimus, sirolimus, cyclosporine, azathioprine, and chlorambucil have been used in treatment of refractory myositis and DM-associated lung disease.

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Introduction:

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by skin lesions and muscle weakness, often involving other organs. Conventional treatments frequently fail to achieve complete remission, particularly in severe cases with multi-organ involvement.

Case Presentation:

- Patient Profile: A 55-year-old man with a history of myocardial infarction and statin use, presenting with low-grade fever, muscle weakness, erythematous rash, and violaceous papules on joints. Symptoms progressed to severe dysphagia, dyspnea, and extensive cutaneous ulcers.

- Clinical Findings: Elevated creatine kinase and C-reactive protein, negative myositis-specific antibodies, and muscle biopsy showing myofiber necrosis. Skin biopsy revealed interface dermatitis with IgG and complement deposits, confirming DM diagnosis.

Treatment and Course:

1. Initial Treatments:

- Discontinued statins and started methylprednisolone and IVIG, with temporary improvement.

2. Complications and Escalated Treatments:

- Developed jejunal perforation requiring emergency surgery, followed by additional surgeries for complications.

- Administered high-dose glucocorticoids, IVIG, prednisone, MMF, and RTX with limited success.

3. Introduction of Begelomab:

- Identified DPP-4/CD26 expression in the patient's tissues. Initiated Begelomab (4 mg/m² daily for 5 days), resulting in significant improvement in skin and gastrointestinal symptoms.

- Administered additional cycles of Begelomab due to relapses, alongside maintenance therapy, achieving marked clinical response.

4. Adverse Events and Final Outcome:

- Despite initial success, the patient developed acute hepatitis C infection, leading to respiratory failure and death from aspiration pneumonia.

Discussion:

- Refractory DM: Managing refractory DM is challenging due to variability in disease presentation and limited treatment guidelines.

- Begelomab Efficacy: This case illustrates the potential of Begelomab, a monoclonal antibody against DPP-4/CD26, in achieving clinical remission in severe, refractory DM, suggesting its promise as a novel treatment option.

Conclusion:

Begelomab demonstrated significant efficacy in a severe case of DM, highlighting its potential as a new therapeutic strategy for refractory DM, despite the patient's eventual death due to unrelated complications.

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Affiliations

¹ Università Vita-Salute San Raffaele.

² Division of Immunology, Transplantation and Infectious diseases, IRCCS Ospedale San Raffaele.

³ Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.

Affiliations

¹ Università Vita-Salute San Raffaele.

² Division of Immunology, Transplantation and Infectious diseases, IRCCS Ospedale San Raffaele.

³ Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.

Abstract

Rationale: Severe refractory idiopathic inflammatory myopathy (IIM) represents a challenge for the clinician. The lack of efficacy of available tools reflects our incomplete insight into the molecular events sustaining the inflammatory tissue damage in these patients. We present the first case of refractory IIM treated with anti-dipeptidyl peptidase-4 (DPP-4)/cluster of differentiation 26 (CD26) monoclonal antibody.

Patient concerns: A 55-year old man presented with proximal muscle weakness, diffuse erythematous skin lesions which rapidly evolved into ulcerations, dysphagia and dysphonia.

Diagnosis: Increased serum creatine kinase levels and histological findings at muscle and skin biopsies were compatible with the diagnosis of dermatomyositis (DM). Several lines of treatment failed to control the disease including steroids, mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Despite therapy, the patient also had recurrent intestinal vasculitis causing bowel perforation. Concurrently, DPP-4/CD26 expression in the patient's skin and skeletal muscle was observed.

Interventions: The patient was treated with begelomab, a murine immunoglobulin G2b monoclonal antibody against DPP-4/CD26.

Outcomes: Dysphagia, skin lesions and intestinal vasculitis resolved and the patient experienced a significant improvement of his quality of life.

Conclusion: Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.

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Conflict of interest statement

The authors have no conflicts of interests to disclose.

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dipeptidyl-peptidase iv inhibitors / immunology*

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national center for biotechnology information

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Begelomab for severe refractory dermatomyositis: A case report - PubMed

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Blockade of DPP-4/CD26, which is expressed on T cells and mediates T cell activation and function, is safe and might be effective in patients with refractory DM.

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Hint: search for physiopatology section.

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Which autoantibody corresponds to the classical symptoms of skin rash and muscle weakness of Dermatomyositis?

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I leave you a podcast about polymyositis/dermatomyositis so you can listen to it, understand the topic better, and have a high yield review for USMLE Step 1.

References:

2021. MSK | Polymyositis/Dermatomyositis – The Medbullets Ste 1 Podcast. [Audio podcast episode] https://open.spotify.com/episode/422NPxzv3kzIlNDSNprkeq?si=7134461247b84741

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Listen to this episode from The Medbullets Step 1 Podcast on Spotify. In this episode, we review the high-yield topic of Polymyositis / Dermatomyositis from the MSK section. Follow Medbullets on social media: Facebook: www.facebook.com/medbullets Instagram: www.instagram.com/medbulletsofficial Twitter: www.twitter.com/medbullets --- Send in a voice message: https://podcasters.spotify.com/pod/show/medbulletsstep1/message

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Gottron papules are erythematous or violaceous papules that often have an overlying scale and appear symmetrically over extensor/dorsal aspects of metacarpophalangeal and interphalangeal joint.

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Dermatomyositis (DM): Skin manifestation image

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Dermatomyositis (DM): Skin manifestation image

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The muscle fibers begin to atrophy as the putative antibodies, directed against the endothelial cells of the endomysial capillaries, activate the classical complement cascade. The MAC is deposited on the capillaries surrounding the muscle fibers which leads to endothelial cell death and ischemic muscle fiber damage. The complement activation leads to the release of proinflammatory cytokines and chemokines that upregulate the expression of adhesion molecules (VCAM-1, ICAM-1) on the endothelial cell (Chandra & Aggarwal, 2023).

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Here you can find a Review Article on the topic to deepen your understanding of the pathology.

Reference:

Kamperman, R. G., van der Kooi, A. J., de Visser, M., Aronica, E., & Raaphorst, J. (2022). Pathophysiological Mechanisms and Treatment of Dermatomyositis and Immune Mediated Necrotizing Myopathies: A Focused Review. International journal of molecular sciences, 23(8), 4301. https://doi.org/10.3390/ijms23084301

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Pathophysiological Mechanisms and Treatment of Dermatomyositis and Immune Mediated Necrotizing Myopathies: A Focused Review

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Idiopathic inflammatory myopathies (IIM), collectively known as myositis, are a composite group of rare autoimmune diseases affecting mostly skeletal muscle, although other organs or tissues may also be involved. The main clinical feature of myositis is subacute, progressive, symmetrical muscle weakness in the proximal arms and legs, whereas subtypes of myositis may also present with extramuscular features, such as skin involvement, arthritis or interstitial lung disease (ILD). Established subgroups of IIM include dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), anti-synthetase syndrome (ASyS), overlap myositis (OM) and inclusion body myositis (IBM). Although these subgroups have overlapping clinical features, the widespread variation in the clinical manifestations of IIM suggests different pathophysiological mechanisms. Various components of the immune system are known to be important immunopathogenic pathways in IIM, although the exact pathophysiological mechanisms causing the muscle damage remain unknown. Current treatment, which consists of glucocorticoids and other immunosuppressive or immunomodulating agents, often fails to achieve a sustained beneficial response and is associated with various adverse effects. New therapeutic targets have been identified that may improve outcomes in patients with IIM. A better understanding of the overlapping and diverging pathophysiological mechanisms of the major subgroups of myositis is needed to optimize treatment. The aim of this review is to report on recent advancements regarding DM and IMNM.