Paola M. Rivera Rivera - 5006865

Luis E. Vega Escribano - 5006250

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

Diego Mariani Grillasca - 5005309

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.

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. 

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.

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.

References:

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

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