Case Series on DRESS: An Unpredictable Adverse Drug Reaction

Drug rash with eosinophilia and systemic symptoms syndrome (DRESS) is a potentially life-threatening, drug-induced, multi-organ system reaction. The most frequently involved organ is the liver, followed by the kidneys and lungs. Early detection and diagnosis followed by withdrawal of the offending agent is vital to minimise the associated morbidity and mortality, and a detailed drug history is vital to identify the causative drugs. Although Spanish guidelines were developed by a panel of allergy specialists from the Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC) and are available in literature from 2020, many clinicians are still unaware about the management of this syndrome. Framing National guidelines for the early diagnosis and pharmaco-therapeutic management of DRESS will help healthcare professionals to save the patients from unintended vulnerability. We hereby present a case series on DRESS.


INTRODUCTION
DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) is a severe drug-induced hypersensitivity syndrome characterised by diffuse maculopapular rash, lymphadenopathy, multivisceral involvement, eosinophilia, and atypical lymphocytes with a mortality rate of 10-40%.DRESS is an uncommon severe adverse drug reaction. 1Although it is important to recognise the syndrome as early as possible to save the patients from unintended vulnerability, many clinicians fail to identify DRESS due to delayed onset of symptoms, 2 involvement of one or multiple organs, and the clinical features overlapping with other severe cutaneous adverse reactions (SCARs). 3Early diagnosis and prompt treatment following identification and withdrawal of offending drugs is necessary to provide better pharmaceutical care decreasing the risk of morbidity and mortality. 4A detailed medical and medication history is required to minimise complications from the syndrome.For the diagnosis of DRESS two major criteria has been developed by international standard group, ie, RegiSCAR and J-SCAR. 5n our study we have considered RegiSCAR criteria to identify DRESS.The mainstay of treatment is the use of systemic corticosteroids, but other options such as intravenous immunoglobulin, cyclosporine, mycophenolate mofetil, rituximab, and cyclophosphamide have been described. 6Spanish guidelines have been developed for DRESS, which may prove to be useful for the clinicians to identify DRESS and manage the condition appropriately. 7EDITERRANEAN JOURNAL OF RHEUMATOLOGY 34 2 2023 of cases. 8Recently, we found reports on Lamotrigine, Carbamazepine, Vancomycin, Minocycline, Ranitidine, Hydroxychloroquine, Raltegravir, Teicoplanin, Piperacillintazobactam, Ciprofloxacin, Meropenem, Co-trimoxazole, Amoxicillin-clavulanate.Most commonly, medicines associated with DRESS are anticonvulsants, Beta lactam, and Allopurinol.Other medicines that are known to be associated with DRESS are NSAIDS, Captopril, anti RVTs. 9The incidence of DRESS with anticonvulsants has been reported in 1 in 5000 to 1 in 10000 exposures. 10

CASE REPORT 1
A 32-year-old lady presented with complaints of a rash with itching for 20 days, fever for 17 days, vomiting, and loose stools for 1 day.The rash had started from the forearm, legs, and spread to the entire body.It was a maculopapular rash, mucosal involvement at the angles of the mouth.On examination, she was lethargic, febrile, and icterus was present, facial oedema was present with crustings at the angle of mouth and right side of hip.Systemic examination was otherwise normal.The detailed laboratory investigations are given in Table 1.Upon taking past medication history, the patient revealed that she had taken ayurvedic medicines for jaundice, but it did not subside.Hence, she consulted a local hospital where she was treated with Doxycycline, Ceftriaxone, Udiliv, Hepkart.She had joint pains for which Aceclofenac, Paracetamol, Rabeprazole, Domperidone, Deflazacort, and Leflunomide was advised for 1 month in suspicion of arthritis.After few weeks of medication intake she developed rashes, recurrent fever spikes with itching, With this detailed drug literature and results of laboratory investigations, Leflunomide-induced DRESS was considered as a final diagnosis as seen in Figures 1 and 2. Our patient had a RegiSCAR score of 7, which makes her a case of definite DRESS Syndrome.For the management, intravenous steroid therapy (Inj hydrocort 50 mg IV Q12H for 5 days followed by Tablet Wysolone  Cholestyramine was started for the washout of drugs.Patient`s LFT and ferritin were improved, other symptoms also subsided including fever, the maculopapular lesions, and itching.Biopsy was advised on follow-up if any of the symptoms reappears.She was discharged on oral steroids and cholestyramine.She did not take cholestyramine and came for follow-up with worsening skin lesions but did not get readmitted, lost to follow-up.On a follow up call, the patient's attendant informed us about death at home.

CASE REPORT 2
A 39 -year-old male presented to our hospital with chief complaints of pain in abdomen, fever spikes, rashes on skin, yellowish discoloration of skin, cough.No history of DM, HTN or Hypothyroidism.Provisional diagnosis was made to be tropical infection.Scrub typhus was negative.H/O back ache, multiple joint pains for 4 years.The patient was on admax 10 mg, NSAIDS on and off (Naproxen, Sulphasalazine).On examination: Erythematous maculopapular confluent rash over the skin involving 70% BSA as shown in Figures 4 and  5. Eosinophilia, deranged LFT was found.Patient was treated with Inj hydrocortisone 100mg IV Q12H.Clinical and laboratory symptoms normalised after 25 days after onset of DRESS.

CASE REPORT 3
A 36-year-old female presented to our hospital with fever associated with chills for 1 week, associated with joint pain, nausea, productive cough for 3 days, burning micturition for 1 month, B/L Flank pain.The provisional diagnosis was made to be acute febrile illness, UTI.On examination, the patient had rashes near the neck, pruritus (as shown in   (Biopsy proven: necrosis and granulomatous lymphadenopathy, Rif sensitive) started on ATT in Jan 2022.She has a history of malar erythema, rashes all over the body (on and off) for 3-4 months (as shown in Figures 6 and 7), diagnosed to have ANA positive in Sep,2021 and started on steroids since then.The rash had started from the forearm and then spread to the entire body.It was an erythematous maculopapular rash, mucosal involvement at the angles of the mouth.Lesions are associated with pain and burning sensation, lasts more than 24 hours and does not have any post inflammatory hyperpigmentation.The provisional diagnosis was made to be Neutrophilic urticaria (connective tissue disorder).The patient underwent pleurocentesis, paracentesis on day 2. Upon further investigation, the final diagnosis was made to be ATT induced DRESS with involvement of liver (Hepatitis), the patient started on IV NAC.Unfortunately, the offending drug could not be identified, as the ATT drugs were administered concurrently.Symptomatic and supportive treatment with IV and oral steroids was provided.CBP on the detailed laboratory investigations are given in Table 1.Clinical and laboratory symptoms normalised after 10 days of steroid therapy.The patient was discharged in a haemodynamically stable condition.

DISCUSSION
DRESS is initiated by pyrexia with body temperature >38°C, early in the course of the disease followed by development of rashes usually maculopapular morbilliform exanthem (usually starting on the face and then generalized), with multiple follicular papules over the body mimicking pityriasis rubra pilaris. 3The development of rashes may vary from mild exanthem to extensive blistering and skin loss but more often a pruritic macular erythema which may contain papules, pustules, and vesicles.If the drug is not withheld, the rash may progress to erythroderma or exfoliative dermatitis.Presence of facial oedema is a characteristic presentation of DRESS; it can be the predictor of a more serious reaction.DRESS is induced by Th2-lymphocytes and CD8+ cells.Th2 cells probably induce type IVb hypersensitivity responses affecting the skin, while CD8 + T cells cause damage to internal organs. 11Genetic polymorphisms of these elimination mechanisms have been implicated in several skin drug reactions, like DRESS. 12he Japanese Research Committee on Severe Cutaneous Adverse Reaction (J-SCAR) and the European registry on severe cutaneous adverse drug reactions (RegiSCAR) are the most commonly used clinical diagnostic criteria. 13egiSCAR seems to be more accurate and comprehensive, but the J-SCAR considered viral reactivation as a diagnostic criterion in contrast to RegiSCAR.There are some other diagnostic tests for its confirmation like the lymphocyte transformation test (LTT), the intradermal test (IDT), and skin biopsy.14 DRESS is a severe multiorgan hypersensitivity reaction often caused by a limited number of elicited drugs in patients with genetic predisposition, genetic factors are also crucial.The risk of DRESS may be as high as 25% for individuals who have a first degree relative experiencing this syndrome.One risk factor is polymorphism in genes encoding metabolic enzymes for drugs such as CYP450 enzymes and N-Acetyltransferase. Reduction activities of metabolic enzymes causes accumulation of drugs or active metabolites which can interact with cellular proteins, evoking immune responses.Polymorphisms in HLA genes explain the genetic disposition of patients with DRESS 15 .HLA-genes are also linked to other SCAR's other than DRESS, for example HLA-B*58:01  Viral infections could be a potential consideration at onset.In SCARs reactivation of several herpes viruses is common. Itould be EBV or HHV-6 followed by HHV-7 later CMV.Reports have shown that reactivation of herpes viruses could also develop in patients with other SCARs including SJS, TEN and MPC, however reactivation of HHV-6 is found exclusively in DRESS with frequency of 43-100% (the role of HHV-6 is unique in DRESS).15 DRESS commonly develops two to eight weeks after starting the offending drug with a mean onset of 3 weeks.Upon rechallenge with the associated drug, symptoms may recur within one day, however symptoms may flare up 3 to 4 weeks after stopping the medicine even after initial improvement.The delayed onset of clinical symptoms of DiHS/DRESS, usually 2-6 weeks after starting therapy, often causes the potential diagnostic delay or can lead to misdiagnosis by the physician.Early withdrawal of offending drugs is needed once the diagnosis is established.The recovery from this condition has been reported to be slow, lasting for several weeks to months.The EUROPEAN RegiSCAR decided on a scoring system based on clinical features, the extent of skin involve-ment and the clinical course to help clinicians confirm or exclude the diagnosis of DRESS syndrome.7 RegiSCAR criteria is frequently used for the diagnosis of DRESS.We have categorised our cases as per RegiSCAR critera as shown in Table 2. DRESS is usually accompanied with internal organ impairment.In terms of haematological changes, eosinophilia is a characteristic feature of the disease, evident in 66-95% of patients.Haematological abnormalities, especially eosinophilia and mononucleosis-like atypical lymphocytosis 27-67%, are also common.Eosinophilia can lead to infiltration of eosinophils into the tissues, which could be related to the tissue damage related to these organs.In addition, lymphadenopathy can be found in 54% of patients by physical examination.Liver injury being the most common type of organ damage found in 75-94%.Compared to other SCARs like SJS/TEN, liver injury associated with DRESS tends to be more severe and longer.15 Renal involvement Renal involvement is prevalent in 12-40% of patients with DRESS.Renal involvement in patients with DRESS is usually mild and will be recovered in time.Among the causative agents associated with renal involvement, allo-  Two or more 2

CASE SERIES ON DRESS: AN UNPREDICTABLE ADVERSE DRUG REACTION
At least three biological investigations done and negative to exclude alternative diagnoses purinol is found to be most common.Allopurinol induced SCAR is significantly associated with HLA-B* 58:01 allele in Han Chinese patients with gene dosage effect.Renal involvement in patients with DRESS is usually mild and will be recovered in less time.However, rarely severe interstitial nephritis, acute tubular necrosis/ vasculitis may develop and lead to renal mortality. 15ng involvement Lung involvement is the third most common type of organ involvement.It may present with impaired pulmonary function and interstitial pneumonitis, pleuritis and ARDs.
Studies have shown minocycline to be associated with lung involvement; however, abacavir is associated with severe pulmonary involvement. 15rdiac involvement Cardiac involvement is reported in 4-27% of patients with DRESS. it can be highly fatal where it occurs.They are usually present with LV dysfunction, ECG changes.medicines linked are minocycline, ampicillin, sulphonamides exhibit chest pain, dyspnoea, tachycardia, hypotension.two forms of myocarditis (self-limiting) and eosinophilic myocarditis (severe).However, neurological involvement is very rare.15

Gastrointestinal and other internal organ involvements
The most frequent gastrointestinal manifestation is gastroenteritis; mucosal erosions can develop and contribute to acute bleeding.Gastrointestinal complications include chronic protein-losing enteropathy, colitis, and pancreatitis. 7Additional manifestations such as myositis, peripheral nerve disorders, encephalitis, meningitis, uveitis, and salivary gland inflammation may be present.Rare cases of shock and multiple organ failure have also been reported. 7he management involves early detection and diagnosis followed by prompt withdrawal of the offending agent.Topical corticosteroids are recommended in DRESS with no visceral organ involvement.Oral and Systemic corticosteroids are recommended in DRESS with moderate to severe visceral organ involvement. 16It can reduce symptoms of delayed hypersensitivity reactions. 8They are also known to inhibit the effect of IL-5 on eosinophil accumulation in-vivo, 7 which may at least partly explain their benefit in the treatment of the idiopathic hypereosinophilic syndrome. 17Eosinophil accumulation is thought to be responsible for the internal organ involvement seen in DRESS syndrome.Immunosuppressive therapy with agents such as cyclophosphamide or cyclosporine may be even essential in cases where steroids are contraindicated or resistant.In severe DRESS, plasma exchange or intravenous immunoglobulin (IVIG) has also been used, although data on this is limited. 14he mainstay of treatment is the use of topical and systemic corticosteroids, but other options such as intravenous immunoglobulin, cyclosporine, mycophenolate mofetil, rituximab, and cyclophosphamide have been described. 7s per the Naranjo scale, the scores of each case were identified in the range of 6 to 8 and were categorised as probable adverse drug reactions (ADRs). 18

PREVENTION
Patch tests for antibiotics might prove effective against DRESS.An epicutaneous patch test is a useful tool for identifying the inducing agent for the DRESS syndrome. 19f a patch test yields a negative result and a suitable injectable form is available, then prick testing should be performed.Immediate readings should be taken at 20 minutes and delayed readings at 6 and 24 hours according to the European guidelines.If this is negative, subsequent intradermal testing is recommended. 7According to the Spanish guidelines for intradermal testing, the drug should be initially administered at the highest dilution (usually 1/100 of the skin prick test concentration), the interval between tests should be extended [145], different concentrations should not be tested on the same day, and special precautions should be adopted with HIV-infected patients. 7r primary prevention: 1. Pre-prescription Pharmacogenetic testing is recommended (HLA Screening) in identified risk populations with specific drugs to prevent DRESS.For example: • Carbamazepine: HLA*31:01 screening in Caucasian European patients and patients of Japanese origin.If positive for this allele, the use of carbamazepine may be considered if the benefits are thought to exceed the risks.
• Phenytoin and lamotrigine: HLA-A*24:02 has been associated with DRESS syndrome induced by phenytoin or lamotrigine in the Spanish population.• Allopurinol: HLA B* 58:01 screening in Han Chinese, Thai, and Korean populations and descendants, especially if chronic kidney disease is present.• Dapsone: HLA-B*13:01 screening in patients of Asian descent.• Abacavir: HLA-B*57:01 screening to prevent abacavir hypersensitivity syndrome (a DRESS-like syndrome) already in routine HIV clinical practice in developed countries 7 .2. Identification of the culprit drug is vital to prevent further cases of DRESS and the culprit drug must be notified in the allergy status of the patient and it should be brought to the patient and patient attenders' details.Further drug allergy alerts must be recorded in

Figure 1 .
Figure 1.Mucosal involvement of the lesions at the angles of the mouth.

Figure 3 )Figure 3 .
Figure 3. Development of rashes on the neck during the hospital stay.

Figure 2 .
Figure 2. Development of rashes on the arm due to Leflunomide.

Figures 4 and 5 .
Figures 4 and 5. Development of rashes on lower limbs during the hospital stay.

Figure 6 .
Figure 6.Development of rashes on back.

Figure 7 .
Figure 7. Development of rashes on back.