Sandbox:M.Romo

Introduction

Eculizumab (Soliris) is a fully humanized IgG2/IgG4 monoclonal antibody that inhibits the terminal complement protein C5, preventing its cleavage into C5a (proinflammatory) and C5b (membrane attack complex coordinator). Eculizumab is known to be effective in reducing the frequency of relapse in highly clinically active, AQP4-IgG–positive disease. It provided the first FDA-approved treatment for neuromyelitis optica spectrum disorder (NMOSD), which has drastically changed the natural history of patients with NMOSD.

While the survival benefit of Solaris in the setting of NMOSD is undeniable, as occurs with all proteins, there is a potential for immunogenicity. Surprisingly, very few cases of lupus reactivation have been reported, and by literature review using PubMed and MEDLINE using discoid lupus erythematosus and/or eculizumab, cero case-reports were retrieved. Among the most common adverse effects of Soliris reported are high blood pressure and headache. Only 1-10% report anaphylactic reaction and 10-15% experiment rash.

The pathophisiology of this mechanism remains to be established. The reactivation of DLE may be due to a than a immune mediated pathway by itslef. As per Soliris drug add evaluating immunogenicity using an electro-chemiluminescence (ECL) bridging assay, only two of the 96 Soliris-treated patients with NMOSD developed antibodies against Soliris.

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.

Case Presentation

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 developed rash in all four extremities, sparing the torso. Cutaneous examination, it was possible to observes erythematous papules and scaly patches on 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.

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

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).

Cutaneous side effects following topical use of 5FU may include contact dermatitis (such as allergic or irritant), dermatitis or seborrheic dermatitis (localized or distant from the site of application), erosions, eye-related symptoms (such as conjunctivitis and corneal irritation), a flare of rosacea or seborrheic dermatitis, herpes simplex virus reactivation, nail changes (such as melanonychia and onycholysis), photosensitivity, secondary bacterial infections, telangiectasia formation, and, albeit rarely, neutropenia and other systemic reactions [5-7]. Adverse skin events to systemic 5FU include acral erythema (also referred to as hand-foot syndrome or palmar-plantar erythrodysesthesia), actinic keratosis inflammation, alopecia, hyperpigmentation (of the nails and serpentine supravenous overlying superficial veins), photo-recall reactions (on sun-exposed areas), photosensitivity, and seborrheic dermatitis exacerbation .

Patients with DLE induced by systemic 5FU or its prodrugs have previously been reported as having DLE-like eruptions or DLE-like lesions

To the best of my knowledge, DLE induced by systemic 5FU and its prodrugs has been described in 19 oncology patients (including the patient discussed in this report). There have been nine men and 10 women. The mean onset age of the individuals was 59 years (Table ​(Table1)1) [12,13].

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.

Abnormal Immune Responses Though the etiology and pathogenesis of LE are not fully understood till now, it has been accepted that the abnormal activated immune cells and abundant production of pathogenic autoantibodies to a broad range of autoantigens are necessary in the development of LE, which eventually causing the formation of complexes and tissue damage

Also, researchers have found that the immune response targeting to dsDNA frequently starts from the reaction with ribonucleoproteins like nucleosomes and snRNP [102]. As we know, under the stimulation of UV irradiation or other factors, cell necrosis and apoptosis happen, thereby nucleosomes are released from the nucleus and induce the tissue damage by the formation of complexes. It has been demonstrated that nucleosomes appear to be one of the primary antigens in the initiation of SLE

researchers have the following findings: (1) the IgG autoantibody profile in DLE + SLE− subjects is similar to that in healthy people; (2) the titers of autoantibodies to the nuclear antigens related to disease activity of SLE, such as dsDNA, dsRNA, and SS-A, show increasing trend from healthy to DLE − SLE+ subjects; and (3) the IgG: IgM ratios of nuclear-specific autoantibodies progressively elevate from healthy to DLE − SLE+ subjects [98]. According to these findings, it can be hypothesized that high titers of IgM autoantibodies may be nonpathogenic and increased IgG: IgM ratios of nuclear-specific autoantibodies indicate a disease risk for SLE. It has been found in SLE that increased expression of IFN signature genes is significantly correlated with elevated levels of serum IgG autoantibodies, implying the pathogenic role of IFN in promoting IgM to IgG class-switching in SLE [109]

]. Interestingly, unlike the high titer of anti-Ro antibodies in SCLE and SLE, negative or low titer results for anti-Ro antibodies are most common in the DLE, which may be one character that can be used for differentiating DLE from SCLE and SLE [114].

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. It has been demonstrated that cytotoxic lymphocytes can destroy stem cells of hair follicle and cause the scarring in the skin lesions DLE. Among the three types of UV, UVB and UVA have been implicated in the formation of skin lesions, but not for UVC. Notably, of all LE subtypes, the degree of inflammatory infiltrate is greatest in the skin lesions of DLE, implying some relation.

Till now, more than 180 autoantibodies have been found in the serum of SLE patients. Interestingly, more than 90% of SLE patients are serum ANA positive and frequently show a high titer, while serum ANA positive only can be seen in few DLE patients and the titers are usually at low range (< 1:160) [107].

Though the etiology and pathogenesis of LE by itself is not fully understood till now, it has been accepted that the abnormal activated immune cells and abundant production of pathogenic autoantibodies to a broad range of autoantigens are necessary in the development of LE, which eventually causing the formation of complexes and tissue damage.

Also, researchers have found that the immune response targeting to dsDNA frequently starts from the reaction with ribonucleoproteins like nucleosomes and snRNP [102]. As we know, under the stimulation of UV irradiation or other factors, cell necrosis and apoptosis happen, thereby nucleosomes are released from the nucleus and induce the tissue damage by the formation of complexes

Abnormal expression of inflammatory cells and the disorder of immune system play an important role in the development of LE.

^bThe onset duration is the number of weeks from the patient starting the drug to the appearance of the DLE lesions

^cThe resolution duration is the number of weeks from the patient stopping the drug to the complete clearing of the DLE lesions

Drug-induced lupus erythematosus is a rare adverse event of biological treatment, mainly observed with tumor necrosis factorea antagonists and also known as lupus-like syndrome

Here, we report the case of a 39-year-old man with onset of cutaneous discoid lupus erythematosus during subcutaneous administration of the IL-17A inhibitor secukinumab, which was initiated for the treatment of chronic plaque psoriasis.

The exact pathomechanism of this type of lupus erythematosus is unknown. T-helperetype 17 cells can promote inflammation through IL-17A, IL-17F, tumor necrosis factorea, IL-6, IL-21, and IL-22 secretion.4 These cytokines may lead to manifestation of lupus erythematosus because they serve as local inflammatory and tissue-damaging factors with stimulatory effects on B cells.4

Drug-induced lupus erythematosus (DILE) is a lupus-like autoimmune disorder, which usually occurs with chronic exposure to certain drugs and resolves after cessation of the culprit medication. Among cutaneous DILE, subacute DILE has been mostly reported. Overall, discoid DILE (drug-induced LE) is a very rare subtype of DILE with less than 30 published cases almost exclusively associated with 5-fluorouracil agents.

Given the clinical findings, serological and histological results, along with the timeline of eruption consistent with the introduction of a new drug, the patient was diagnosed with palbociclib-induced discoid lupus and began treatment with highpotency topical steroids

Drugs most commonly associated with druginduced lupus erythematosus include hydralazine, procainamide, quinidine, isoniazid, minocycline, and targeted immunotherapy.2

Suffice to say, the knowledge of the pathogenesis of skin lupus is incomplete, and further research on the difference among three types of LE is needed to better understand the skin lupus.