Ectopic pregnancy cost-effectiveness of therapy

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#### Introduction

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Eculizumab (Soliris) is a fully humanized long-acting IgG2/IgG4 monoclonal antibody that inhibits the terminal complement protein C5, preventing its cleavage into C5a which increases the permeability of blood vessels and attracts inflammatory cells by chemotaxis and C5b which coordinates the membrane attack.[1][2][3] Eculizumab is known to be effective in reducing the frequency of relapse in highly clinically active AQP4-IgG–positive neuromyelitis optica (NMO).[4][5] It provided the first FDA-approved treatment for neuromyelitis optica spectrum disorder (NMOSD) with positive AQP4-IgG and has drastically changed the natural history of patients with NMOSD._FDA-6|[6]

While the survival benefit of Solaris in the setting of NMOSD is undeniable, as occurs with all proteins, there is a potential for immunogenicity.[7] Surprisingly, very few cases of lupus reactivation by Eculizumab have been reported. Literature review using PubMed and MEDLINE using discoid lupus erythematosus and/or eculizumab, retrieved cero case-reports. According to a trial performed by Pittock et. al. using Eculizumab in patients with NMO, the most common adverse effects were found to be upper respiratory infections (28%) and headache (22%).[8] Overall, the percentage of patients treated with Eculizumab for any reason that develope rash range between 10-15%.[9]

Here, we report the case of a 75-year-old female with onset of cutaneous discoid lupus erythematosus after intravenous administration of the IgG2/IgG4 monoclonal antibody Eculizumab, which was initiated for the treatment of IgG–positive neuromyelitis optica.

The pathophisiology of drug-induced lupus erythematosus itself remains to be unknown.[10] Most cases are associated to chronic exposure of certain drugs such as hydralazine, procainamide, quinidine, isoniazid, minocycline, and targeted immunotherapy.[11][12][13][14] 95% of the cases resolve within 2 months after cessation of the culprit medication.[15] Among cutaneous DILE, subacute DILE has been mostly reported.[16] Drug induced DLE is also to be established; very few cases have been reported (less than 30), almost exclusively associated with 5-fluorouracil agents.[17] It has been accepted that the abnormal activation of immune cells and abundant production of pathogenic autoantibodies to a broad range of autoantigens are necessary in the development of LE, which ultimately cause the deposition of immune complexes in the tissues with stimulatory effects on B cells.[18][19][20][21] According to a study evaluating the immunogenicity of Soliris using an electro-chemiluminescence (ECL) bridging assay, only 2% of the 96 Soliris-treated patients with NMOSD developed antibodies against Soliris,[22][23] this does not explain the antigenic immune response by itself. Interestingly, lupus cutaneous lesions are mostly found in sun exposed areas. Research has found that the immune response targeting to dsDNA frequently starts from the reaction of ribonucleoproteins which are released from the nucleus by UV irradiation, inducing tissue damage by the formation of complexes who detect these as antigens.[24][25][26] Among the three types of UV radiation (A,B, and C), only UVB and UVA have been implicated in the formation of skin lesions.[27]

The evidence base documenting autoimmune reactions with the use of IgG2/IgG4 monoclonal antibody therapy is exceedingly small. To our knowledge, this is the first case reported of reactivation of quiescent discoid lupus erythematosus (DLE) due to Eculizumab in the setting of NMOSD.

It is fair to say that the knowledge of the pathogenesis of drug-induced discoid lupus erythematosus and LES in general, is incomplete, and further research is needed to better understand the pathophysiology behind this phenomenon.

The DLE lesions resolved within two months (mean: 36 days) after stopping the drug in 95% of the patients. Laboratory studies showed that antibodies to Ro/SSA and La/SSB were negative in 100% (three of three) of the patients. The elevated ANA titer was found to be decreased in all of the patients who were evaluated after the discontinuation of the drug. The definitive etiology for fluorouracil agent drug-induced DLE remains to be established.

Till now, more than 180 autoantibodies have been found in the serum of SLE patients. Interestingly, high titers of serum ANA and anti-Ro antibodies are found in SLE, unlike in DLE; this may be a key characteristic to distinguish SLE from DLE.[28][29][30]

Approximately 80% of DLE patients appear as localized lesions showing well-defined, varying sized, and coin-shaped erythematous, while less than 20% DLE patients have generalized skin lesions.[28]

#### Case Presentation

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A 75-year-old (race?) female presented for evaluation of an asymptomatic rash in her extremeties. Her past medical history was significant for discoid lupus erythematosus diagnosed (when?) achieving drug-induced remission with (treatment?) and (any other commorbidity?). Other chronic medications included (medications?). She was diagnosed with neuromyelitis optica (subtype) one year earlier and was initially managed with Rituximab by another provider. When she arrived to the clinic at physical examination she had residual bilateral numbness from the chest down to the extremities, strength was (description?), in addition to residual vision loss (what type of vision loss?) from a previous optic neuritis attack. No dermatologic lesions were observed. Her last labs exhibited (CBC, antibodies, etc?).

(Time?) after the initial evaluation, the patient had an NMO exacerbation and was admitted to the hospital for (IV/PO?) steroid treatment. The patient recovered, nevertheless, had another exacerbation (number) months after. A decision was made to switch her maintanance treatment from Rituximab to Soliris due to inadequate response. She was started with an increasing dose of at 900 mg four times every other week. After the fourth dose, she complained of developing rash in all four extremities, sparing the torso, with a onset duration of (number of weeks from the patient starting the drug to the appearance of the DLE lesions). Cutaneous examination, it was possible to observe well-defined, varying sized, and coin-shaped erythematous papules and scaly patches on all four extremities(Figure 1A-D). Hair, nails, and skin neighboring mucous membranes were unaffected. Soliris was discontinued and topical steroids were given. After one week evaluation via telemedicine, clinical worsening was observed; lesions continued to increase in number and location during the following week.

She was seen by dermatology service, which after correlating the history, clinical presentation, and laboratory studies concluded it was an exacerbation of discoid lupus erythematosus. No skin biopsy was performed. Laboratory evaluation revealed (positive/negative?) antinuclear antibody, (positive/negative?) anti-double-stranded deoxyribonucleic acid antibody, and (positive/negative?) anti-histone antibodies. Additional studies revealed (normal/high/low) parameters within complete blood cell count, serum chemistries, C-reactive protein, erythrocyte sedimentation rate, anti-Ro/Sjogren’s syndrome A (anti-Ro/SSA) antibody, anti-La/Sjogren’s syndrome B (anti-La/SSB) antibody, anti-ribonuclear protein (RNP) antibody, serum complements (C3 and C4), and urinalysis. She was started with prednisone 50 mg four times per day for four days. After (number) weeks, a clinical improvement in her lesions was observed, with a resolution duration of (number of weeks from the patient stopping the drug to the complete clearing of the DLE lesions).

It may be usefull a longer followup, including new labs and the final treatment. I found the prior administration of IV dexamethasone before other drug induced DLE, such as with 5FU, had good results clinically and laboratorily. Most case-reports confirm it with a biopsy showing a vacuolar interface dermatitis characterized by atrophic epidermis with follicular plugging, and a perivascular and periadnexal chronic inflammatory infiltrate.

#### Discusion

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It cannot be said with absolute certainty that eculizumab caused this patient’s severe cutaneous complication, as we felt it was unsafe to perform a rechallenge, and the patient refused to consider such a trial. However, it seems very likely that the eculizumab was an important contributing factor. The rash developed within 24 hours of the first eculizumab dose and skin symptoms started during the infusion, skin biopsy findings were consistent with a drug-induced eruption, the patient had no history of rashes, and there was no other obvious inciting event. Could a drug–drug interaction including eculizumab have triggered the rash? The patient was also taking twice weekly trimethoprim-sulfamethoxazole (TMP-SMX) as Pneumocystis carinii prophylaxis, an agent that can cause severe dermatological complications including Stevens-Johnson syndrome. However, he had been receiving a stable dose of TMP-SMX for more than a month and had previously taken this agent multiple times without any problems. Other chronic medications included pantoprazole, levothyroxine, darbepoetin alfa, folate, vitamin B12, vitamin D plus calcium, and epsilon amino-caproic acid (because of a distant history of recurrent gastrointestinal bleeding related to mucosal arteriovenous malformations).

## References

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1. ↑ Dubois, Eline A.; Cohen, Adam F. (2009). "Eculizumab". British Journal of Clinical Pharmacology. 68 (3): 318–319. doi:10.1111/j.1365-2125.2009.03491.x. ISSN 0306-5251.
2. ↑ Pittock, Sean J.; Berthele, Achim; Fujihara, Kazuo; Kim, Ho Jin; Levy, Michael; Palace, Jacqueline; Nakashima, Ichiro; Terzi, Murat; Totolyan, Natalia; Viswanathan, Shanthi; Wang, Kai-Chen; Pace, Amy; Fujita, Kenji P.; Armstrong, Róisín; Wingerchuk, Dean M. (2019). "Eculizumab in Aquaporin-4–Positive Neuromyelitis Optica Spectrum Disorder". New England Journal of Medicine. 381 (7): 614–625. doi:10.1056/NEJMoa1900866. ISSN 0028-4793.
3. ↑ Thomas, Thomas C.; Rollins, Scott A.; Rother, Russell P.; Giannoni, Michelle A.; Hartman, Sandra L.; Elliott, Eileen A.; Nye, Steven H.; Matis, Louis A.; Squinto, Stephen P.; Evans, Mark J. (1996). "Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv". Molecular Immunology. 33 (17–18): 1389–1401. doi:10.1016/S0161-5890(96)00078-8. ISSN 0161-5890.
4. ↑ Pittock, Sean J.; Berthele, Achim; Fujihara, Kazuo; Kim, Ho Jin; Levy, Michael; Palace, Jacqueline; Nakashima, Ichiro; Terzi, Murat; Totolyan, Natalia; Viswanathan, Shanthi; Wang, Kai-Chen; Pace, Amy; Fujita, Kenji P.; Armstrong, Róisín; Wingerchuk, Dean M. (2019). "Eculizumab in Aquaporin-4–Positive Neuromyelitis Optica Spectrum Disorder". New England Journal of Medicine. 381 (7): 614–625. doi:10.1056/NEJMoa1900866. ISSN 0028-4793.
5. ↑ Pittock, Sean J; Lennon, Vanda A; McKeon, Andrew; Mandrekar, Jay; Weinshenker, Brian G; Lucchinetti, Claudia F; O'Toole, Orna; Wingerchuk, Dean M (2013). "Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study". The Lancet Neurology. 12 (6): 554–562. doi:10.1016/S1474-4422(13)70076-0. ISSN 1474-4422.
6. _FDA_6-0|↑ "FDA approves first treatment for neuromyelitis optica spectrum disorder, a rare autoimmune disease of the central nervous system | FDA".
7. ↑ Jawa, Vibha; Cousens, Leslie P.; Awwad, Michel; Wakshull, Eric; Kropshofer, Harald; De Groot, Anne S. (2013). "T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation". Clinical Immunology. 149 (3): 534–555. doi:10.1016/j.clim.2013.09.006. ISSN 1521-6616.
8. ↑ Pittock, Sean J.; Berthele, Achim; Fujihara, Kazuo; Kim, Ho Jin; Levy, Michael; Palace, Jacqueline; Nakashima, Ichiro; Terzi, Murat; Totolyan, Natalia; Viswanathan, Shanthi; Wang, Kai-Chen; Pace, Amy; Fujita, Kenji P.; Armstrong, Róisín; Wingerchuk, Dean M. (2019). "Eculizumab in Aquaporin-4–Positive Neuromyelitis Optica Spectrum Disorder". New England Journal of Medicine. 381 (7): 614–625. doi:10.1056/NEJMoa1900866. ISSN 0028-4793.
9. ↑ "Side Effects of Soliris (Eculizumab), Warnings, Uses".
10. ↑ He, Ye; Sawalha, Amr H. (2018). "Drug-induced lupus erythematosus: an update on drugs and mechanisms". Current Opinion in Rheumatology. 30 (5): 490–497. doi:10.1097/BOR.0000000000000522. ISSN 1040-8711.
11. ↑ Pretel, M.; Marquès, L.; España, A. (2014). "Drug-Induced Lupus Erythematosus". Actas Dermo-Sifiliográficas (English Edition). 105 (1): 18–30. doi:10.1016/j.adengl.2012.09.025. ISSN 1578-2190.
12. ↑ Vasoo, S (2016). "Drug-induced lupus: an update". Lupus. 15 (11): 757–761. doi:10.1177/0961203306070000. ISSN 0961-2033.
13. ↑ Borchers, A. T.; Keen, C. L.; Gershwin, M. E. (2007). "Drug-Induced Lupus". Annals of the New York Academy of Sciences. 1108 (1): 166–182. doi:10.1196/annals.1422.019. ISSN 0077-8923.
14. ↑ Aguirre Zamorano, Ma Angeles; López Pedrera, Rosario; Cuadrado Lozano, Ma Jose (2010). "Lupus inducido por fármacos". Medicina Clínica. 135 (3): 124–129. doi:10.1016/j.medcli.2009.04.035. ISSN 0025-7753.
15. ↑ Cohen, Philip R (2020). "Discoid Lupus Erythematosus Lesions Associated with Systemic Fluorouracil Agents: A Case Report and Review". Cureus. doi:10.7759/cureus.7828. ISSN 2168-8184.
16. ↑ He, Ye; Sawalha, Amr H. (2018). "Drug-induced lupus erythematosus: an update on drugs and mechanisms". Current Opinion in Rheumatology. 30 (5): 490–497. doi:10.1097/BOR.0000000000000522. ISSN 1040-8711.
17. ↑ He, Ye; Sawalha, Amr H. (2018). "Drug-induced lupus erythematosus: an update on drugs and mechanisms". Current Opinion in Rheumatology. 30 (5): 490–497. doi:10.1097/BOR.0000000000000522. ISSN 1040-8711.
18. ↑ Li, Qianwen; Wu, Haijing; Zhou, Suqing; Zhao, Ming; Lu, Qianjin (2020). "An Update on the Pathogenesis of Skin Damage in Lupus". Current Rheumatology Reports. 22 (5). doi:10.1007/s11926-020-00893-9. ISSN 1523-3774.
19. ↑ Moulton, Vaishali R.; Suarez-Fueyo, Abel; Meidan, Esra; Li, Hao; Mizui, Masayuki; Tsokos, George C. (2017). "Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective". Trends in Molecular Medicine. 23 (7): 615–635. doi:10.1016/j.molmed.2017.05.006. ISSN 1471-4914.
20. ↑ Nalbandian, A.; Crispín, J. C.; Tsokos, G. C. (2009). "Interleukin-17 and systemic lupus erythematosus: current concepts". Clinical & Experimental Immunology. 157 (2): 209–215. doi:10.1111/j.1365-2249.2009.03944.x. ISSN 0009-9104.
21. ↑ Nalbandian, A.; Crispín, J. C.; Tsokos, G. C. (2009). "Interleukin-17 and systemic lupus erythematosus: current concepts". Clinical & Experimental Immunology. 157 (2): 209–215. doi:10.1111/j.1365-2249.2009.03944.x. ISSN 0009-9104.
22. ↑ "Soliris (Eculizumab): Uses, Dosage, Side Effects, Interactions, Warning".
23. ↑ "www.ema.europa.eu" (PDF).
24. ↑ Deocharan, B; Qing, X; Beger, E; Putterman, C (2016). "Antigenic triggers and molecular targets for anti-double-stranded DNA antibodies". Lupus. 11 (12): 865–871. doi:10.1191/0961203302lu308rr. ISSN 0961-2033.
25. ↑ Heimovski, Flavia Emilie; Simioni, Juliana A.; Skare, Thelma Larocca (2015). "Systemic lupus erythematosus and Raynaud's phenomenon". Anais Brasileiros de Dermatologia. 90 (6): 837–840. doi:10.1590/abd1806-4841.20153881. ISSN 0365-0596.
26. ↑ Riemekasten, G.; Hahn, B. H. (2005). "Key autoantigens in SLE". Rheumatology. 44 (8): 975–982. doi:10.1093/rheumatology/keh688. ISSN 1462-0332.
27. ↑ Holick MF (March 2016). "Biological Effects of Sunlight, Ultraviolet Radiation, Visible Light, Infrared Radiation and Vitamin D for Health". Anticancer Res. 36 (3): 1345–56. PMID 26977036.
28. ↑ 28.0 28.1 Li, Qianwen; Wu, Haijing; Zhou, Suqing; Zhao, Ming; Lu, Qianjin (2020). "An Update on the Pathogenesis of Skin Damage in Lupus". Current Rheumatology Reports. 22 (5). doi:10.1007/s11926-020-00893-9. ISSN 1523-3774.
29. ↑ Haber, Jessica S.; Merola, Joseph F.; Werth, Victoria P. (2017). "Classifying discoid lupus erythematosus: background, gaps, and difficulties". International Journal of Women's Dermatology. 3 (1): S62–S66. doi:10.1016/j.ijwd.2017.02.013. ISSN 2352-6475.
30. ↑ Deng, Jau-Shyong; Sontheimer, Richard D.; Gilliam, James N. (1984). "Relationships between antinuclear and anti-Ro/SS-A antibodies in subacute cutaneous lupus erythematosus". Journal of the American Academy of Dermatology. 11 (3): 494–499. doi:10.1016/S0190-9622(84)70198-8. ISSN 0190-9622.

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