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Case presentation, DRESS syndrome in a rheumatoid arthritis patient secondary to sulfasalazine & literature review with discussion of differential diagnosis, diagnostic criteria & management options Ahmed Yehia

Case presentation, DRESS syndrome in a rheumatoid arthritis patient secondary to sulfasalazine & literature review with discussion of differential diagnosis, diagnostic criteria & management options Ahmed Yehia, MD Internal Medicine Immunology (Allergy & Rheumatology) Beni-Suef

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Late? Ahmed Yehia, MD Internal Medicine Immunology (Allergy & Rheumatology) Beni-Suef
History
Personal History E.S.A. female patient 25 years old , housewife ,married with 1 offspring that is 3 years old ,was born & living in Beni-Suef . No special habits of medical importance .
Complaint Persistent fever 15 days before admission.
Present History The condition started 15 days before admission by acute onset & stationary course of high-grade fever , constant through the day not relieved by antipyretics & not associated with confusion, convulsions ,headache ,blu rring of vision nor projectile vomiting.
 The fever was associated with cough & expectorations of yellowish sputum about half cup /day with no positional nor diurnal variations .  No chest pain, PND nor orthopnea.
 Also, there was vomiting related to meals & preceeded by nausea about 6 times /day & watery diarrhea about 15 times / day not related to meals .  There was diffuse ,colicky abdominal pain not referred to any site relieved by analgesics .
 No hematemesis , melena .  No hair loss , photosensitivity , oral , genital ulcers nor arthritis .  The patient sought medical advice , antibiotics were prescribed without improvement .
 5 days before admission she complained of red & itchy rash all over the body associated with yellow eyes ,dark colored urine. No dysuria , oliguria ,urgency , frequency nor loin pain .
Past History The patient is known Rheumatoid arthritis 2 years ago (arthritis of small joints of hand & wrist joint , the patient is on steroids , hydroxychloroquine & sulfasalazine ) .
 The patient is not diabetic nor hypertensive .  No history of previous operations .  No history of blood transfusion .  No history of TB nor Bilharziasis .  No history of drug allergy.
Family History
No consanguinity . No common diseases . No Similar condition .
Examination
General  The patient is fully conscious, well oriented to time , place & persons.  The patient is cooperative ,of average mood , mentality & intelligence.
 Temperature : 40o C .  RR : 22/min .  BP : 120/80 .  Pulse : 132/min., equal on both sides , of average volume , no special character & intact peripheral pulsations .
Head & Neck Jaundice Red elevated maculopapular skin rash No pallor , hair loss ,subconjunctival hemorrhage , ulcers nor deformity . No lymph nodes nor enlarged thyroid ; central trachea & carotid is felt equally on both sides .
Head & Neck Jaundice Red elevated maculopapular skin rash No pallor , hair loss ,subconjunctival hemorrhage , ulcers nor deformity . No lymph nodes nor enlarged thyroid ; central trachea & carotid is felt equally on both sides .
UPPER LIMBS & Lower Limbs Red elevated skin rash No Pallor , cyanosis , clubbing , subcutaneous nodules nor palmer erythema .  No arthritis ,deformity , muscle weakness , joint pain nor effusion .
Lower Limbs  Intact peripheral pulsation, lax calf muscles , no lower limb edema ,cyanosis nor clubbing .
Chest & Heart  Bilateral equal air entry .  Harsh vesicular breathing with prolonged expiration , no wheezes nor crepitation .  Apex: in the fifth space ,left midclavicular line .  Normal S1 , S2 .  No audible murmur nor additional sounds .
ABDOMINAL EXAMINATION  Distended abdomen with full flanks , freely mobile with respiration , no tenderness nor rigidity ,no organomegaly nor ascites detected by clinical examination.
 Normal motor & power examination .  Intact sensation .  Normal reflexes .  No gait abnormality , abnormal movements nor neck rigidity.
Investigations
 Hb : 14.5 /10.4 . (11-17).  PCV : 42.9 . (35-52).  MCV : 79 . (76-100).  MCH : 27 . (27-34).  Plt : 248 . (150-400).  WBCS : 38 /9 . (3.5-10). Mainly neutrophils No blast cells.
 Na : 135 .  K : 3.7 .  Creatinine : 0.6.  Urea : 32 .  pH : 7.43 .  pCo2 : 54 .  HCO : 35 .
 Iron : 34 .  TIBC :235 .  Ferritin : 394 .  TSAT : 14%.  T.Bilirubin :4.9 .  D.Bilirubin : 3.8 /2.29 .
CRP : 14 mg/dl . ESR :130 mm (1st hour)
 PT : 11.8 .  PC : 100 .  INR : 1 .  Retics : 1.7/3.8 .  AST : 80/39/23 .  ALT : 285/158/85 .
 HAV IgM: -ve . HBsAg : -ve . HCV AB: –ve . Blood C & S: -ve.  Widal test : +ve 1/320  RF, ANA : -ve .
U/S  Mild Hepato-splenomegaly ( 17.8 -14 cm ) .  Colonic gaseous distention
Criteria Major Features Minor Features / Supportive Requirements Yamaguchi et al. (1992) • Fever ≥ 39 °C lasting ≥ 1 week •Arthralgia or arthritis lasting ≥ 2 weeks •Nonpruritic, salmon- colored macular /maculopapular rash (during fever spikes) •Leukocytosis ≥ 10,000/µL with ≥ 80% neutrophils •Sore throat •Lymphadenopathy •Hepatomegaly or splenomegaly •Abnormal liver function tests (e.g. elevated transaminases) •Negative RF & ANA Must have ≥5 criteria including at least 2 major Sensitivity ~96%, Specificity ~92%. Fautrel et al. (2002) Major: Spiking fever ≥39 °C; arthralgia; transient erythema; pharyngitis; neutrophils ≥80%; glycosylated ferritin ≤20% Minor: Maculopapular rash; leukocytosis ≥10,000/µL Requirements: i) (a) ≥ 4 major, or (b) 3 major + 2 minor. ii) exclusion of infection, malignancy, etc.
Criteria Major Features Minor Features / Supportive Requirements / Exclusions Yamaguchi et al. (1992) • Fever ≥ 39 °C lasting ≥ 1 week •Arthralgia or arthritis lasting ≥ 2 weeks •Nonpruritic, salmon- colored macular /maculopapular rash (during fever spikes) •Leukocytosis ≥ 10,000/µL with ≥ 80% neutrophils •Sore throat •Lymphadenopathy •Hepatomegaly or splenomegaly •Abnormal liver function tests (e.g. elevated transaminases) •Negative RF & ANA Must have ≥5 criteria including at least 2 major excluding infections, malignancies & other rheumatic diseases. Sensitivity ~96%, Specificity ~92%. Fautrel et al. (2002) Major: Spiking fever ≥39 °C; arthralgia; transient erythema; pharyngitis; neutrophils ≥80%; glycosylated ferritin ≤20% Minor: Maculopapular rash; leukocytosis ≥10,000/µL Requirements: i) (a) ≥ 4 major, or (b) 3 major + 2 minor. ii) exclusion of infection, malignancy, etc.
Is this adult-onset Still’s disease? With Arthritis Fever Rash Leukocytosis ++ALT, AST +Ferritin Against Fever pattern Rash pattern It is a diagnosis of exclusion.
Is this infection? With Fever Rash Against Blood culture: -ve
Is this DRESS?
By revising drug history, •Sulfasalazine was introduced about 1 month before onset of manifestations.
What is DRESS? It is SCAR. What is SCAR?
DRESS is classified as a SCAR (severe cutaneous adverse reaction) • Stevens–Johnson syndrome • Toxic epidermal necrolysis • Acute generalized exanthematous pustulosis • DRESS STAD
Severe cutaneous adverse reactions (SCAR) DRUG-INDUCED DELAYED DANGEROUS
Acute generalised exanthematous pustulosis (AGEP)
Toxic epidermal necrolysis & Stevens-Johnson syndrome
Mucosal involvement of SJS/TEN.
What is DRESS? Bocquet first introduced the acronym DRESS in 1996, at which time, it stood for Drug rash with Eosinophilia & Systemic symptoms.
Other names in the literature The term drug-induced hypersensitivity syndrome (DIHS) is sometimes used alternatively or in addition to DRESS. • It may be a better umbrella term, with DRESS best viewed as a subset of DIHS with cutaneous involvement. Hypersensitivity syndrome (HSS) Hypersensitivity syndrome named for the inciting drug (phenytoin hypersensitivity syndrome, allopurinol hypersensitivity syndrome, etc.) Drug-induced delayed multiorgan hypersensitivity syndrome (DIDMOHS) Pseudolymphoma
DRESS Cutaneous manifestations (the most frequent finding, 99– 100% of patients) Symmetrical maculopapular (morbilliform) eruption including the trunk & extremities, often covering > 50% of BSA, with varying morphology targetoid lesions Blisters pustules
• Erythroderma or exfoliative dermatitis (involving > 90% BSA) may follow in ~ 10% • Facial edema is striking, present in 75% of cases. • Mucosal involvement affects 25% (lips, mouth, throat, genitalia) • Less commonly, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme or a purpuric rash but milder & skin detachment is rarely seen.
Facial edema in ~ 75% patients.
Rashes in DRESS can be quite polymorphic. •Urticaria, pustules, blisters, exfoliative dermatitis, and target- lesions have been observed ,making differentiation from SCARs potentially difficult. •Moreover, mucosal involvement can occur in DRESS, though is more mild than that seen in Stevens-Johnson Syndrome/toxic epidermal necrolysis or erythema multiforme.
Symptomatically, patients may experience pruritus or burning pain. The rash can last many weeks.
•Anecdotally, facial & ear rash with edema may signal that a drug-induced morbilliform eruption is progressing to, or at risk for progression to DRESS.
In rare instances (<3 %), the rash maybe mild or absent.
“Rash” was replaced with “reaction” because of the diverse range in skin manifestations in DRESS, most notably, the absence of rash entirely, depending on which diagnostic criteria are used. Whether skin manifestations should be required to achieve a diagnosis of DRESS is a critical issue confounding research efforts & clinical care.
Can we diagnose drug reaction after this long time?
Type I IgE Mediated Classic Allergy (Immediate) Type II IgG/IgM Mediated RBC lysis Type III IgG Mediated Immune complex Disease Type IV T cell Delayed Type Hypersensitivity Gel and Coombs classification of hypersensitivities.
Delayed!!! For how long? •DRESS syndrome generally develops 2–8 weeks following exposure to the offending drug & symptoms resolve in most cases after drug withdrawal. •The prodromal phase of DRESS is often characterized by nonspecific symptoms, such as fever, malaise &
Can we diagnose DRESS without eosinophilia?
Hematologic derangement is typically observed. Eosinophilia occurs in 90% (it is not universally present despite the E in DRESS). Atypical lymphocytosis in ~ 65.80% of patients. Additional CBC abnormalities (observed in >50% of patients): • Leukocytosis • Neutrophilia • Lymphocytosis • monocytosis
Percentages of clinical features of DRESS syndrome reported in 2 large studies (Kardoun and Cacoub et al.)
DRESS diagnosis • Sometimes difficult since the clinical manifestations may be incomplete or nonspecific & it can also present as a purely systemic disease without any cutaneous involvement. • So, multiple diagnostic criteria have been developed & used to standardize the diagnosis and management of DRESS, albeit with limited success.
Bocquet et al. proposed criteria for diagnosis of DRESS/drug‑induced hypersensitivity (DRESS is confirmed by the presence of 1 & 2 & 3) • Cutaneous drug eruption • Adenopathy >2 cm in diameter or hepatitis (liver transaminases >2 times of normal or interstitial nephritis or interstitial pneumonia or carditis • Hematologic abnormalities eosinophilia >1.5×109/L or atypical lymphocytes
What’s RegiSCAR for DRESS? Registry of severe cutaneous adverse reaction diagnosis score for DRESS.
RegiSCAR scoring system • <2: Excluded • 2 to 3: Possible • 4 to 5: Probable • ≥6: Definite
As some of the variables included in the RegiSCAR DRESS score may not be available when the patient is first evaluated, the score is most useful as a retrospective validation of suspected cases. The cumulative score ranges from -4 to 9 & defines four levels of certainty regarding the diagnosis of DRESS: Excluded Possible Probable definite. A value between -1 and 2 is assigned to each feature.
A Japanese group suggested another set of diagnostic criteria. •Universal adaptation of this criteria may be limited since one of the criteria includes HHV-6 activation & some tests, such as measurement of IgG titer anti-HHV 6, are yet not routinely available.
Japanese group’s criteria for diagnosis of DRESS/ drug‑induced hypersensitivity 1. Maculopapular rash developing >3 weeks after starting with the suspected drug 2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug 3. Fever >38°C 4. Liver abnormalities (alanine aminotransferase >100U/L)* 5. Leucocyte abnormalities (at least one present) (a) Leucocytosis (>11×109/L) (b) Atypical lymphocytosis (>5%) (c) Eosinophilia (>1.5×109 /L) 6. Lymphadenopathy 7. Human Herpes 6 reactivation The diagnosis is confirmed by the presence of • 7 criteria (typical DIHS) • 5 (1-5) (atypical DIHS).
Drug-induced hypersensitivity reactions manifesting with many of the systemic signs & symptoms we associate with DRESS, without the rash, can & do occur. Drug-induced liver injury, or DILI, which encompasses both direct liver toxicity from drug and immune-mediated drug-induced liver injury. Immune-mediated DILI can occur with fever, rash, & eosinophilia (what we think of as DRESS). Drug induced acute interstitial nephritis classically manifests with rash, fever, & eosinophilia along with acute kidney injury starting days after initiation of drug, but can have a delayed development of weeks to months after drug initiation & present with signs/symptoms meeting diagnostic criteria of DRESS
.‫روماتولوجي‬ ‫دكتور‬ ‫أنا‬ ‫مالي؟‬ ‫أنا‬
.‫جدا‬ ‫مهم‬ ‫أقدم‬ ‫من‬ ‫واحد‬ ‫مع‬ ‫بيحصل‬ ‫ده‬ .‫باسمه‬ ‫بيتسمى‬ ‫كان‬ ‫لدرجة‬ ‫أصدقائنا‬ •DRESS has been classically associated with allopurinol under the name “allopurinol hypersensitivity syndrome”.
It may be fatal due to • Acute liver failure causing coagulation problems, jaundice, & impaired consciousness • Multiorgan failure • Fulminant myocarditis • Haemophagocytosis.
Drugs causing DRESS in rheumatology • Sulfasalazine, Minocycline, Dapsone Immunomodulatory antibiotics • Leflunomide, Hydroxychloroquine Non-antibiotic DMARDs • Allopurinol, Febuxostat Hypouricemic drugs • Strontium ranelate Anti-osteoporotic drugs • Celecoxib, Ibuprofen, Phenylbutazone Diclofenac NSAIDs • Bosentan ET-1 antagonists • Solcitinib JAK1 inhibitors
‫القائمة‬ ‫ومازالت‬ ‫الروماتولوجي‬ ‫في‬ ‫تزيد‬. •An increasing number of other medications prescribed by rheumatologists have been reported to cause DRRESS.
Is sulfasalazine highly accused of DRESS? •Allopurinol & sulfasalazine together accounted for almost two thirds of cases.
DIFFERENTIAL DIAGNOSIS Due to the heterogeneity of clinical presentation, DRESS is often misdiagnosed.
DRESS overlapping with more common criminals in rheumatology. •Rash •Liver affection •Lymphadenopathy •Fever
DRESS overlapping with more common criminals in rheumatology (Rash). SLE Vasculitis Still’s disease Other drug hypersensitivities
DRESS overlapping with more common criminals in rheumatology (Fever). SLE Still’s disease Other drug hypersensitivities Infections Hematological malignancies
DRESS overlapping with more common criminals in rheumatology (Liver affection). Autoimmune hepatitis Still’s disease Drug hepatotoxicity: MTX, leflunomide
DRESS overlapping with more common criminals in rheumatology (Lymphadenopathy). SLE, Kikuchi Fugimoto Sarcoid Still’s disease Other drug hypersensitivities Infections Hematological malignancies
Organ involvement • The extent & type of organ injury varies. • Involvement of at least 1 internal organ occurs in approximately 90% of patients. • Approximately 35% of patients may have 2 internal organs involved. • Up to 20% may have > 2 organ involvement. • Internal organ involvement may precede the development of rash. So, may mimic CAPS (catastrophic antiphospholipid syndrome)
Rapid-onset DRESS described by Soria et al. in 2019 It occurs 15 days after initial drug intake. It may reflect prior sensitization to culprit drug, though data on prior exposure was not available in this study.
Mini-DRESS •It refer to mild forms of DRESS. •A controversial topic regarding DRESS diagnosis is the view that DRESS exists on a spectrum in regard to severity. •Others are of the opinion that mild DRESS does not exist & is in fact an oxymoron. (Skirt syndrome)
Overlap Syndromes • A potential source of clinical complexity. • They refer to cases presenting with signs & symptoms of DRESS along with SJS/TEN or AGEP. • A retrospective study by Bouvresse et al. showed that application of RegiSCAR criteria enabled resolution of 20% of cases initially suggestive of overlap, to < 3% as true overlap cases. • Notably though, diagnostic resolution was achievable only retrospectively; in the acute phase of disease, such distinction STAD
Can skin biopsy be diagnostic? • Histologic findings are variable on skin biopsy in DRESS & none is pathognomonic. • So, it is not recommended performing skin biopsy to distinguish morbilliform drug eruption from DRESS. • Rather, the utility of skin biopsy in potential DRESS cases lies in ruling out alternative diagnoses.
Histologic findings in DRESS can mimic those of Erythema multiforme AGEP Angioimmunoblastic T- cell lymphoma
So, DRESS is a challenge & you won’t diagnose it if you don’t consider it. Why? Non-specific manifestations (fever, rash,…) Skin manifestations in DRESS are highly variable. Away from the culprit drug. Overlapping with other more encounters in rheumatology practice.
Management of DRESS
Identifying Culprit Drug •The most important intervention in DRESS syndrome is the immediate discontinuation of culprit drug. •This necessitates correct culprit drug identification which can be quite challenging as many patients take multiple medications.
What is the gold standard test to determine the culprit drug?
There is currently no test during active disease that can reliably determine culprit drug, so the gold standard is physician identification based on patient history, coupled with recognizing “high-risk” medications .
Prolonged latency • The reaction typically occurs 2 to 8 weeks after drug exposure. • Drugs taken for < 2 weeks or > 3 months before DRESS onset are unlikely to be the culprit. • In some cases, drugs that have been stopped prior to onset of disease can still be suspected, if the drug or drug metabolite is still present in the body due to a long drug half-life or impaired clearance.
‫ييجي‬ ‫اللي‬ ‫الباب‬ ‫ما‬ ‫طب‬ ‫و‬ ‫سده‬ ‫الريح‬ ‫منه‬ ‫لك‬ ‫استريح‬. • Though halting culprit drug is paramount in clinical care, discontinuing or labeling a patient allergic to a drug that in fact the patient could safely take is not without consequences. • The replacement medication could be less effective, more dangerous, and/or more expensive.
) ( ‫سرقة‬ ‫في‬ ‫فيهما‬ ‫مشتبه‬ ‫ودكتور‬ ‫سجون‬ ‫رد‬ ‫سوابق‬ . ‫أن‬ ‫تتوقع‬ ‫من‬ ( ‫وتتحرى‬ ‫الجاني‬ ‫يكون‬ investigate ) ‫وأوال؟‬ ‫أكثر‬ ‫عنه‬
•Approximately 75% are due to a few high-risk drugs.
Do we have tools for more accurate identification?
In vivo skin testing •Patch testing & /or •Intradermal testing. •Results are highly variable depending on the drug being tested & timing of testing relative to disease onset & resolution, though for some drugs, skin testing may be a useful testing option.
Intradermal testing Intradermal testing with a delayed reading has been utilized in anecdotal reports. Concentrations are usually 10- to 100-fold lower than those under takenfor immediate immunoglobulin E (IgE)-mediated reactions. Nonetheless, there is a risk of reaction recurrence. Thus, the test should only be performed in exceptional circumstances.
In vitro tests — In vitro tests are only performed in specialized centers and largely remain a research tool. • Lymphocyte transformation test (LTT) . It measures the proliferation of T cells after stimulation with a drug in vitro and is best performed during the recovery stage of th edisease. • Drug-induced cytokine assays (interferon [IFN]- gamma, tumor necrosis factor [TNF]- alpha,upregulation of cell activation markers such as CD69). • Analysis of cytotoxic potential of effector cells (eg, granzyme B, granulysin, CD107).
Drug challenges •Generally contraindicated in patients with DRESS as it could lead to lethal recurrence of disease.
Drug challenges If there is no effective alternative treatment available, a drug could potentially be re-introduced in a hospital setting that allows for prompt identification of recurrence & intervention in case of a reaction. e.g. DRESS occurring in the setting of multidrug treatment for HIV infection or TB.
Going forward, it may be possible to incorporate HLA testing during active disease to help rule in/out potential culprit drugs, though further research is required on this topic.
• There has been an explosion in the field of pharmacogenomics with the recognition that specific HLA alleles predispose to DRESS & other forms of delayed type DHRs from certain drugs. • The prime example is the association between HLA*B57:01 & the antiretroviral agent abacavir. • Given that HLA-B*57:01 screening fully prevents disease & is cost-effective, the FDA recommends HLA screening of all patients prior to initiating abacavir therapy.
HLA alleles associated with DRESS
A multidisciplinary team composed of the appropriate specialists depending on organs involved. •Allergists •Dermatologists •Hepatologists if liver affection •Nephrologists if kidney injury •……..
Management According to severity
For patients with mild disease without organ involvement or only modest elevation of ALT, AST (<3 times ULN) • We suggest symptomatic treatment of skin inflammation & pruritus with topical corticosteroids (Grade 2C). • High or ultra-potent topical corticosteroids applied 2 : 3 times/day until resolution of the skin eruption.
Patients with severe disease & involvement of the lungs or kidneys • Oral glucocorticoids as first-line therapy (Grade 2C). • A moderate to high dose (0.5 to 1mg/kg per day) of prednisone or prednisone equivalents until clinical improvement & normalization of lab. parameters are achieved. • Systemic glucocorticoids should be tapered slowly over 8 to 12 weeks.
Patients with severe disease & involvement of the lungs or kidneys •Oral cyclosporine is an alternative treatment for patients with severe organ involvement who do not respond to glucocorticoids or for patients in whom corticosteroids are contraindicated.
Numerous alternatives have been tried when systemic corticosteroids were contraindicated or failed. Cyclophosphamide Interferons Mycophenolate mofetil Rituximab plasmapheresis muromonab-CD3
Long‑term Sequelae of DRESS Syndrome. Are they common? A continuation of organ dysfunction that developed during the acute phase Appear after a symptom-free period (in some after many months, up to 2 years after acute disease) Depression, anxiety, fear toward taking medications might develop. > 11% of DRESS patients are affected by chronic complications (Chen et al.).
Do DRESS patients need follow up? •There are no agreed upon guidelines regarding frequency & duration of patient follow-up but routine follow-up for at least 2 years after acute disease is generally advisable. •Systematic screening for psychological symptoms during the first 12 months post disease is recommended.
•DRESS is a challenging drug adverse reaction which can cause life threatening ‑ organ dysfunction. •Clinicians must be alert to this possibility to reach the correct diagnosis & institute the appropriate management.
•Avoid dismissing DRESS (or a potential culprit drug) based on a •shorter latency period between drug exposure & disease onset. •Absence of eosinophilia. •Absence of rash. •Mild, systemic symptoms or organ involvement
•Given the clinical complexity, heterogeneity in presentation & overlapping features with other diseases, scoring systems may help DRESS diagnosis.
•DRESS is a dynamic process & characteristic features are not all present concurrently. In such cases, the diagnosis of DRESS requires a high degree of suspicion and clinical judgment.
Take aways • Laboratory tests should be obtained & repeated closely for trend even if initial labs are normal in any patient presenting with robust eruption, in particular if • prominent facial/ear involvement • patient is feeling systemically unwell • feverish • lymphadenopathy.
but DRESS is the nightmare of every physician. DRESS is the dream of every girl, DRESS
‫الله‬ ‫جزاكم‬ ‫خيرا‬. Thank You
• Current data and recommendations on viral testing (by PCR or serologies) and interpretation of results are variable. Given potential for viral infection/reactivation to cause or exacerbate DRESS, the authors currently advise testing HHV6, HHV7, CMV, and EBV viral loads via PCR from peripheral blood at the time of diagnosis/initial work-up, and if negative, perform repeat testing if the patient’s disease is recalcitrant to systemic immunosuppressive treatment (for consideration of antiviral therapy). Finally, additional laboratory tests may be considered to rule out alternative diagnoses (for example, but not limited to, antinuclear antibody; blood culture; hepatitis A, B, and C viral studies; chlamydia; and mycoplasma

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Case presentation, DRESS syndrome in a rheumatoid arthritis patient secondary to sulfasalazine & literature review with discussion of differential diagnosis, diagnostic criteria & management options Ahmed Yehia

  • 1.
    Late? Ahmed Yehia, MD InternalMedicine Immunology (Allergy & Rheumatology) Beni-Suef
  • 2.
  • 3.
    Personal History E.S.A. femalepatient 25 years old , housewife ,married with 1 offspring that is 3 years old ,was born & living in Beni-Suef . No special habits of medical importance .
  • 4.
    Complaint Persistent fever15 days before admission.
  • 5.
    Present History The conditionstarted 15 days before admission by acute onset & stationary course of high-grade fever , constant through the day not relieved by antipyretics & not associated with confusion, convulsions ,headache ,blu rring of vision nor projectile vomiting.
  • 6.
     The feverwas associated with cough & expectorations of yellowish sputum about half cup /day with no positional nor diurnal variations .  No chest pain, PND nor orthopnea.
  • 7.
     Also, therewas vomiting related to meals & preceeded by nausea about 6 times /day & watery diarrhea about 15 times / day not related to meals .  There was diffuse ,colicky abdominal pain not referred to any site relieved by analgesics .
  • 8.
     No hematemesis, melena .  No hair loss , photosensitivity , oral , genital ulcers nor arthritis .  The patient sought medical advice , antibiotics were prescribed without improvement .
  • 9.
     5 daysbefore admission she complained of red & itchy rash all over the body associated with yellow eyes ,dark colored urine. No dysuria , oliguria ,urgency , frequency nor loin pain .
  • 10.
    Past History The patientis known Rheumatoid arthritis 2 years ago (arthritis of small joints of hand & wrist joint , the patient is on steroids , hydroxychloroquine & sulfasalazine ) .
  • 11.
     The patientis not diabetic nor hypertensive .  No history of previous operations .  No history of blood transfusion .  No history of TB nor Bilharziasis .  No history of drug allergy.
  • 12.
  • 13.
    No consanguinity . Nocommon diseases . No Similar condition .
  • 14.
  • 15.
    General  The patientis fully conscious, well oriented to time , place & persons.  The patient is cooperative ,of average mood , mentality & intelligence.
  • 16.
     Temperature :40o C .  RR : 22/min .  BP : 120/80 .  Pulse : 132/min., equal on both sides , of average volume , no special character & intact peripheral pulsations .
  • 17.
    Head & Neck Jaundice Red elevatedmaculopapular skin rash No pallor , hair loss ,subconjunctival hemorrhage , ulcers nor deformity . No lymph nodes nor enlarged thyroid ; central trachea & carotid is felt equally on both sides .
  • 18.
    Head & Neck Jaundice Redelevated maculopapular skin rash No pallor , hair loss ,subconjunctival hemorrhage , ulcers nor deformity . No lymph nodes nor enlarged thyroid ; central trachea & carotid is felt equally on both sides .
  • 19.
    UPPER LIMBS & LowerLimbs Red elevated skin rash No Pallor , cyanosis , clubbing , subcutaneous nodules nor palmer erythema .  No arthritis ,deformity , muscle weakness , joint pain nor effusion .
  • 20.
    Lower Limbs  Intactperipheral pulsation, lax calf muscles , no lower limb edema ,cyanosis nor clubbing .
  • 21.
    Chest & Heart Bilateral equal air entry .  Harsh vesicular breathing with prolonged expiration , no wheezes nor crepitation .  Apex: in the fifth space ,left midclavicular line .  Normal S1 , S2 .  No audible murmur nor additional sounds .
  • 22.
    ABDOMINAL EXAMINATION  Distended abdomenwith full flanks , freely mobile with respiration , no tenderness nor rigidity ,no organomegaly nor ascites detected by clinical examination.
  • 23.
     Normal motor& power examination .  Intact sensation .  Normal reflexes .  No gait abnormality , abnormal movements nor neck rigidity.
  • 24.
  • 25.
     Hb :14.5 /10.4 . (11-17).  PCV : 42.9 . (35-52).  MCV : 79 . (76-100).  MCH : 27 . (27-34).  Plt : 248 . (150-400).  WBCS : 38 /9 . (3.5-10). Mainly neutrophils No blast cells.
  • 26.
     Na :135 .  K : 3.7 .  Creatinine : 0.6.  Urea : 32 .  pH : 7.43 .  pCo2 : 54 .  HCO : 35 .
  • 27.
     Iron :34 .  TIBC :235 .  Ferritin : 394 .  TSAT : 14%.  T.Bilirubin :4.9 .  D.Bilirubin : 3.8 /2.29 .
  • 28.
    CRP : 14mg/dl . ESR :130 mm (1st hour)
  • 29.
     PT :11.8 .  PC : 100 .  INR : 1 .  Retics : 1.7/3.8 .  AST : 80/39/23 .  ALT : 285/158/85 .
  • 30.
     HAV IgM:-ve . HBsAg : -ve . HCV AB: –ve . Blood C & S: -ve.  Widal test : +ve 1/320  RF, ANA : -ve .
  • 32.
    U/S  Mild Hepato-splenomegaly (17.8 -14 cm ) .  Colonic gaseous distention
  • 41.
    Criteria Major FeaturesMinor Features / Supportive Requirements Yamaguchi et al. (1992) • Fever ≥ 39 °C lasting ≥ 1 week •Arthralgia or arthritis lasting ≥ 2 weeks •Nonpruritic, salmon- colored macular /maculopapular rash (during fever spikes) •Leukocytosis ≥ 10,000/µL with ≥ 80% neutrophils •Sore throat •Lymphadenopathy •Hepatomegaly or splenomegaly •Abnormal liver function tests (e.g. elevated transaminases) •Negative RF & ANA Must have ≥5 criteria including at least 2 major Sensitivity ~96%, Specificity ~92%. Fautrel et al. (2002) Major: Spiking fever ≥39 °C; arthralgia; transient erythema; pharyngitis; neutrophils ≥80%; glycosylated ferritin ≤20% Minor: Maculopapular rash; leukocytosis ≥10,000/µL Requirements: i) (a) ≥ 4 major, or (b) 3 major + 2 minor. ii) exclusion of infection, malignancy, etc.
  • 42.
    Criteria Major FeaturesMinor Features / Supportive Requirements / Exclusions Yamaguchi et al. (1992) • Fever ≥ 39 °C lasting ≥ 1 week •Arthralgia or arthritis lasting ≥ 2 weeks •Nonpruritic, salmon- colored macular /maculopapular rash (during fever spikes) •Leukocytosis ≥ 10,000/µL with ≥ 80% neutrophils •Sore throat •Lymphadenopathy •Hepatomegaly or splenomegaly •Abnormal liver function tests (e.g. elevated transaminases) •Negative RF & ANA Must have ≥5 criteria including at least 2 major excluding infections, malignancies & other rheumatic diseases. Sensitivity ~96%, Specificity ~92%. Fautrel et al. (2002) Major: Spiking fever ≥39 °C; arthralgia; transient erythema; pharyngitis; neutrophils ≥80%; glycosylated ferritin ≤20% Minor: Maculopapular rash; leukocytosis ≥10,000/µL Requirements: i) (a) ≥ 4 major, or (b) 3 major + 2 minor. ii) exclusion of infection, malignancy, etc.
  • 43.
    Is this adult-onsetStill’s disease? With Arthritis Fever Rash Leukocytosis ++ALT, AST +Ferritin Against Fever pattern Rash pattern It is a diagnosis of exclusion.
  • 44.
  • 45.
  • 46.
    By revising drughistory, •Sulfasalazine was introduced about 1 month before onset of manifestations.
  • 47.
    What is DRESS? Itis SCAR. What is SCAR?
  • 48.
    DRESS is classifiedas a SCAR (severe cutaneous adverse reaction) • Stevens–Johnson syndrome • Toxic epidermal necrolysis • Acute generalized exanthematous pustulosis • DRESS STAD
  • 49.
    Severe cutaneous adversereactions (SCAR) DRUG-INDUCED DELAYED DANGEROUS
  • 50.
  • 51.
  • 53.
  • 54.
    What is DRESS? Bocquetfirst introduced the acronym DRESS in 1996, at which time, it stood for Drug rash with Eosinophilia & Systemic symptoms.
  • 55.
    Other names inthe literature The term drug-induced hypersensitivity syndrome (DIHS) is sometimes used alternatively or in addition to DRESS. • It may be a better umbrella term, with DRESS best viewed as a subset of DIHS with cutaneous involvement. Hypersensitivity syndrome (HSS) Hypersensitivity syndrome named for the inciting drug (phenytoin hypersensitivity syndrome, allopurinol hypersensitivity syndrome, etc.) Drug-induced delayed multiorgan hypersensitivity syndrome (DIDMOHS) Pseudolymphoma
  • 56.
    DRESS Cutaneous manifestations (themost frequent finding, 99– 100% of patients) Symmetrical maculopapular (morbilliform) eruption including the trunk & extremities, often covering > 50% of BSA, with varying morphology targetoid lesions Blisters pustules
  • 57.
    • Erythroderma orexfoliative dermatitis (involving > 90% BSA) may follow in ~ 10% • Facial edema is striking, present in 75% of cases. • Mucosal involvement affects 25% (lips, mouth, throat, genitalia) • Less commonly, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme or a purpuric rash but milder & skin detachment is rarely seen.
  • 58.
    Facial edema in~ 75% patients.
  • 59.
    Rashes in DRESS can bequite polymorphic. •Urticaria, pustules, blisters, exfoliative dermatitis, and target- lesions have been observed ,making differentiation from SCARs potentially difficult. •Moreover, mucosal involvement can occur in DRESS, though is more mild than that seen in Stevens-Johnson Syndrome/toxic epidermal necrolysis or erythema multiforme.
  • 61.
    Symptomatically, patients may experiencepruritus or burning pain. The rash can last many weeks.
  • 62.
    •Anecdotally, facial &ear rash with edema may signal that a drug-induced morbilliform eruption is progressing to, or at risk for progression to DRESS.
  • 63.
    In rare instances(<3 %), the rash maybe mild or absent.
  • 64.
    “Rash” was replaced with“reaction” because of the diverse range in skin manifestations in DRESS, most notably, the absence of rash entirely, depending on which diagnostic criteria are used. Whether skin manifestations should be required to achieve a diagnosis of DRESS is a critical issue confounding research efforts & clinical care.
  • 65.
    Can we diagnosedrug reaction after this long time?
  • 66.
    Type I IgE Mediated ClassicAllergy (Immediate) Type II IgG/IgM Mediated RBC lysis Type III IgG Mediated Immune complex Disease Type IV T cell Delayed Type Hypersensitivity Gel and Coombs classification of hypersensitivities.
  • 67.
    Delayed!!! For howlong? •DRESS syndrome generally develops 2–8 weeks following exposure to the offending drug & symptoms resolve in most cases after drug withdrawal. •The prodromal phase of DRESS is often characterized by nonspecific symptoms, such as fever, malaise &
  • 68.
    Can we diagnoseDRESS without eosinophilia?
  • 69.
    Hematologic derangement is typicallyobserved. Eosinophilia occurs in 90% (it is not universally present despite the E in DRESS). Atypical lymphocytosis in ~ 65.80% of patients. Additional CBC abnormalities (observed in >50% of patients): • Leukocytosis • Neutrophilia • Lymphocytosis • monocytosis
  • 70.
    Percentages of clinicalfeatures of DRESS syndrome reported in 2 large studies (Kardoun and Cacoub et al.)
  • 71.
    DRESS diagnosis • Sometimesdifficult since the clinical manifestations may be incomplete or nonspecific & it can also present as a purely systemic disease without any cutaneous involvement. • So, multiple diagnostic criteria have been developed & used to standardize the diagnosis and management of DRESS, albeit with limited success.
  • 72.
    Bocquet et al.proposed criteria for diagnosis of DRESS/drug‑induced hypersensitivity (DRESS is confirmed by the presence of 1 & 2 & 3) • Cutaneous drug eruption • Adenopathy >2 cm in diameter or hepatitis (liver transaminases >2 times of normal or interstitial nephritis or interstitial pneumonia or carditis • Hematologic abnormalities eosinophilia >1.5×109/L or atypical lymphocytes
  • 73.
    What’s RegiSCAR for DRESS? Registry ofsevere cutaneous adverse reaction diagnosis score for DRESS.
  • 74.
    RegiSCAR scoring system • <2:Excluded • 2 to 3: Possible • 4 to 5: Probable • ≥6: Definite
  • 75.
    As some ofthe variables included in the RegiSCAR DRESS score may not be available when the patient is first evaluated, the score is most useful as a retrospective validation of suspected cases. The cumulative score ranges from -4 to 9 & defines four levels of certainty regarding the diagnosis of DRESS: Excluded Possible Probable definite. A value between -1 and 2 is assigned to each feature.
  • 76.
    A Japanese groupsuggested another set of diagnostic criteria. •Universal adaptation of this criteria may be limited since one of the criteria includes HHV-6 activation & some tests, such as measurement of IgG titer anti-HHV 6, are yet not routinely available.
  • 77.
    Japanese group’s criteria for diagnosisof DRESS/ drug‑induced hypersensitivity 1. Maculopapular rash developing >3 weeks after starting with the suspected drug 2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug 3. Fever >38°C 4. Liver abnormalities (alanine aminotransferase >100U/L)* 5. Leucocyte abnormalities (at least one present) (a) Leucocytosis (>11×109/L) (b) Atypical lymphocytosis (>5%) (c) Eosinophilia (>1.5×109 /L) 6. Lymphadenopathy 7. Human Herpes 6 reactivation The diagnosis is confirmed by the presence of • 7 criteria (typical DIHS) • 5 (1-5) (atypical DIHS).
  • 78.
    Drug-induced hypersensitivity reactionsmanifesting with many of the systemic signs & symptoms we associate with DRESS, without the rash, can & do occur. Drug-induced liver injury, or DILI, which encompasses both direct liver toxicity from drug and immune-mediated drug-induced liver injury. Immune-mediated DILI can occur with fever, rash, & eosinophilia (what we think of as DRESS). Drug induced acute interstitial nephritis classically manifests with rash, fever, & eosinophilia along with acute kidney injury starting days after initiation of drug, but can have a delayed development of weeks to months after drug initiation & present with signs/symptoms meeting diagnostic criteria of DRESS
  • 79.
  • 81.
    .‫جدا‬ ‫مهم‬ ‫أقدم‬ ‫من‬‫واحد‬ ‫مع‬ ‫بيحصل‬ ‫ده‬ .‫باسمه‬ ‫بيتسمى‬ ‫كان‬ ‫لدرجة‬ ‫أصدقائنا‬ •DRESS has been classically associated with allopurinol under the name “allopurinol hypersensitivity syndrome”.
  • 82.
    It may befatal due to • Acute liver failure causing coagulation problems, jaundice, & impaired consciousness • Multiorgan failure • Fulminant myocarditis • Haemophagocytosis.
  • 83.
    Drugs causing DRESSin rheumatology • Sulfasalazine, Minocycline, Dapsone Immunomodulatory antibiotics • Leflunomide, Hydroxychloroquine Non-antibiotic DMARDs • Allopurinol, Febuxostat Hypouricemic drugs • Strontium ranelate Anti-osteoporotic drugs • Celecoxib, Ibuprofen, Phenylbutazone Diclofenac NSAIDs • Bosentan ET-1 antagonists • Solcitinib JAK1 inhibitors
  • 84.
    ‫القائمة‬ ‫ومازالت‬ ‫الروماتولوجي‬ ‫في‬ ‫تزيد‬. •Anincreasing number of other medications prescribed by rheumatologists have been reported to cause DRRESS.
  • 85.
    Is sulfasalazine highly accusedof DRESS? •Allopurinol & sulfasalazine together accounted for almost two thirds of cases.
  • 86.
    DIFFERENTIAL DIAGNOSIS Due to theheterogeneity of clinical presentation, DRESS is often misdiagnosed.
  • 87.
    DRESS overlapping withmore common criminals in rheumatology. •Rash •Liver affection •Lymphadenopathy •Fever
  • 88.
    DRESS overlapping with morecommon criminals in rheumatology (Rash). SLE Vasculitis Still’s disease Other drug hypersensitivities
  • 89.
    DRESS overlapping with morecommon criminals in rheumatology (Fever). SLE Still’s disease Other drug hypersensitivities Infections Hematological malignancies
  • 90.
    DRESS overlapping with morecommon criminals in rheumatology (Liver affection). Autoimmune hepatitis Still’s disease Drug hepatotoxicity: MTX, leflunomide
  • 91.
    DRESS overlapping with morecommon criminals in rheumatology (Lymphadenopathy). SLE, Kikuchi Fugimoto Sarcoid Still’s disease Other drug hypersensitivities Infections Hematological malignancies
  • 92.
    Organ involvement • Theextent & type of organ injury varies. • Involvement of at least 1 internal organ occurs in approximately 90% of patients. • Approximately 35% of patients may have 2 internal organs involved. • Up to 20% may have > 2 organ involvement. • Internal organ involvement may precede the development of rash. So, may mimic CAPS (catastrophic antiphospholipid syndrome)
  • 93.
    Rapid-onset DRESS describedby Soria et al. in 2019 It occurs 15 days after initial drug intake. It may reflect prior sensitization to culprit drug, though data on prior exposure was not available in this study.
  • 94.
    Mini-DRESS •It refer tomild forms of DRESS. •A controversial topic regarding DRESS diagnosis is the view that DRESS exists on a spectrum in regard to severity. •Others are of the opinion that mild DRESS does not exist & is in fact an oxymoron. (Skirt syndrome)
  • 95.
    Overlap Syndromes • A potentialsource of clinical complexity. • They refer to cases presenting with signs & symptoms of DRESS along with SJS/TEN or AGEP. • A retrospective study by Bouvresse et al. showed that application of RegiSCAR criteria enabled resolution of 20% of cases initially suggestive of overlap, to < 3% as true overlap cases. • Notably though, diagnostic resolution was achievable only retrospectively; in the acute phase of disease, such distinction STAD
  • 96.
    Can skin biopsybe diagnostic? • Histologic findings are variable on skin biopsy in DRESS & none is pathognomonic. • So, it is not recommended performing skin biopsy to distinguish morbilliform drug eruption from DRESS. • Rather, the utility of skin biopsy in potential DRESS cases lies in ruling out alternative diagnoses.
  • 97.
    Histologic findings in DRESS can mimicthose of Erythema multiforme AGEP Angioimmunoblastic T- cell lymphoma
  • 98.
    So, DRESS isa challenge & you won’t diagnose it if you don’t consider it. Why? Non-specific manifestations (fever, rash,…) Skin manifestations in DRESS are highly variable. Away from the culprit drug. Overlapping with other more encounters in rheumatology practice.
  • 99.
  • 100.
    Identifying Culprit Drug •The mostimportant intervention in DRESS syndrome is the immediate discontinuation of culprit drug. •This necessitates correct culprit drug identification which can be quite challenging as many patients take multiple medications.
  • 101.
    What is the goldstandard test to determine the culprit drug?
  • 102.
    There is currentlyno test during active disease that can reliably determine culprit drug, so the gold standard is physician identification based on patient history, coupled with recognizing “high-risk” medications .
  • 103.
    Prolonged latency • The reactiontypically occurs 2 to 8 weeks after drug exposure. • Drugs taken for < 2 weeks or > 3 months before DRESS onset are unlikely to be the culprit. • In some cases, drugs that have been stopped prior to onset of disease can still be suspected, if the drug or drug metabolite is still present in the body due to a long drug half-life or impaired clearance.
  • 104.
    ‫ييجي‬ ‫اللي‬ ‫الباب‬‫ما‬ ‫طب‬ ‫و‬ ‫سده‬ ‫الريح‬ ‫منه‬ ‫لك‬ ‫استريح‬. • Though halting culprit drug is paramount in clinical care, discontinuing or labeling a patient allergic to a drug that in fact the patient could safely take is not without consequences. • The replacement medication could be less effective, more dangerous, and/or more expensive.
  • 105.
    ) ( ‫سرقة‬ ‫في‬‫فيهما‬ ‫مشتبه‬ ‫ودكتور‬ ‫سجون‬ ‫رد‬ ‫سوابق‬ . ‫أن‬ ‫تتوقع‬ ‫من‬ ( ‫وتتحرى‬ ‫الجاني‬ ‫يكون‬ investigate ) ‫وأوال؟‬ ‫أكثر‬ ‫عنه‬
  • 106.
    •Approximately 75% are dueto a few high-risk drugs.
  • 107.
    Do we have toolsfor more accurate identification?
  • 108.
    In vivo skintesting •Patch testing & /or •Intradermal testing. •Results are highly variable depending on the drug being tested & timing of testing relative to disease onset & resolution, though for some drugs, skin testing may be a useful testing option.
  • 109.
    Intradermal testing Intradermal testing with adelayed reading has been utilized in anecdotal reports. Concentrations are usually 10- to 100-fold lower than those under takenfor immediate immunoglobulin E (IgE)-mediated reactions. Nonetheless, there is a risk of reaction recurrence. Thus, the test should only be performed in exceptional circumstances.
  • 110.
    In vitro tests— In vitro tests are only performed in specialized centers and largely remain a research tool. • Lymphocyte transformation test (LTT) . It measures the proliferation of T cells after stimulation with a drug in vitro and is best performed during the recovery stage of th edisease. • Drug-induced cytokine assays (interferon [IFN]- gamma, tumor necrosis factor [TNF]- alpha,upregulation of cell activation markers such as CD69). • Analysis of cytotoxic potential of effector cells (eg, granzyme B, granulysin, CD107).
  • 111.
    Drug challenges •Generally contraindicatedin patients with DRESS as it could lead to lethal recurrence of disease.
  • 112.
    Drug challenges If thereis no effective alternative treatment available, a drug could potentially be re-introduced in a hospital setting that allows for prompt identification of recurrence & intervention in case of a reaction. e.g. DRESS occurring in the setting of multidrug treatment for HIV infection or TB.
  • 113.
    Going forward, itmay be possible to incorporate HLA testing during active disease to help rule in/out potential culprit drugs, though further research is required on this topic.
  • 114.
    • There hasbeen an explosion in the field of pharmacogenomics with the recognition that specific HLA alleles predispose to DRESS & other forms of delayed type DHRs from certain drugs. • The prime example is the association between HLA*B57:01 & the antiretroviral agent abacavir. • Given that HLA-B*57:01 screening fully prevents disease & is cost-effective, the FDA recommends HLA screening of all patients prior to initiating abacavir therapy.
  • 115.
  • 116.
    A multidisciplinary teamcomposed of the appropriate specialists depending on organs involved. •Allergists •Dermatologists •Hepatologists if liver affection •Nephrologists if kidney injury •……..
  • 117.
  • 118.
    For patients withmild disease without organ involvement or only modest elevation of ALT, AST (<3 times ULN) • We suggest symptomatic treatment of skin inflammation & pruritus with topical corticosteroids (Grade 2C). • High or ultra-potent topical corticosteroids applied 2 : 3 times/day until resolution of the skin eruption.
  • 119.
    Patients with severedisease & involvement of the lungs or kidneys • Oral glucocorticoids as first-line therapy (Grade 2C). • A moderate to high dose (0.5 to 1mg/kg per day) of prednisone or prednisone equivalents until clinical improvement & normalization of lab. parameters are achieved. • Systemic glucocorticoids should be tapered slowly over 8 to 12 weeks.
  • 120.
    Patients with severedisease & involvement of the lungs or kidneys •Oral cyclosporine is an alternative treatment for patients with severe organ involvement who do not respond to glucocorticoids or for patients in whom corticosteroids are contraindicated.
  • 121.
    Numerous alternatives have been triedwhen systemic corticosteroids were contraindicated or failed. Cyclophosphamide Interferons Mycophenolate mofetil Rituximab plasmapheresis muromonab-CD3
  • 122.
    Long‑term Sequelae ofDRESS Syndrome. Are they common? A continuation of organ dysfunction that developed during the acute phase Appear after a symptom-free period (in some after many months, up to 2 years after acute disease) Depression, anxiety, fear toward taking medications might develop. > 11% of DRESS patients are affected by chronic complications (Chen et al.).
  • 123.
    Do DRESS patientsneed follow up? •There are no agreed upon guidelines regarding frequency & duration of patient follow-up but routine follow-up for at least 2 years after acute disease is generally advisable. •Systematic screening for psychological symptoms during the first 12 months post disease is recommended.
  • 124.
    •DRESS is achallenging drug adverse reaction which can cause life threatening ‑ organ dysfunction. •Clinicians must be alert to this possibility to reach the correct diagnosis & institute the appropriate management.
  • 125.
    •Avoid dismissing DRESS(or a potential culprit drug) based on a •shorter latency period between drug exposure & disease onset. •Absence of eosinophilia. •Absence of rash. •Mild, systemic symptoms or organ involvement
  • 126.
    •Given the clinical complexity,heterogeneity in presentation & overlapping features with other diseases, scoring systems may help DRESS diagnosis.
  • 127.
    •DRESS is adynamic process & characteristic features are not all present concurrently. In such cases, the diagnosis of DRESS requires a high degree of suspicion and clinical judgment.
  • 128.
    Take aways • Laboratorytests should be obtained & repeated closely for trend even if initial labs are normal in any patient presenting with robust eruption, in particular if • prominent facial/ear involvement • patient is feeling systemically unwell • feverish • lymphadenopathy.
  • 129.
    but DRESS isthe nightmare of every physician. DRESS is the dream of every girl, DRESS
  • 130.
  • 131.
    • Current dataand recommendations on viral testing (by PCR or serologies) and interpretation of results are variable. Given potential for viral infection/reactivation to cause or exacerbate DRESS, the authors currently advise testing HHV6, HHV7, CMV, and EBV viral loads via PCR from peripheral blood at the time of diagnosis/initial work-up, and if negative, perform repeat testing if the patient’s disease is recalcitrant to systemic immunosuppressive treatment (for consideration of antiviral therapy). Finally, additional laboratory tests may be considered to rule out alternative diagnoses (for example, but not limited to, antinuclear antibody; blood culture; hepatitis A, B, and C viral studies; chlamydia; and mycoplasma

Editor's Notes

  • #3 Esraa Saeed Abbas
  • #48 Pattern of manifestations Exclusion
  • #53 Let’s know its family. أعرفكم على عيلته الأول.
  • #58 Skin manifestations of SJS/TEN. (A,B) Widespread skin detachment in a TEN patient. (C) Atypical targets. Flat erythematous macules with a darker center. SJS: Stevens–Johnson syndrome; TEN: Toxic epidermal necrolysis.
  • #59 (A) Affected eye with conjunctivitis. (B) Lip involvement. Severe cheilitis with hemorrhagic crust. SJS: Stevens–Johnson syndrome; TEN: Toxic epidermal necrolysis.
  • #61 A lot of names
  • #63 Morbilliform is an adjective pertaining to the eruption of measles, measles-like rashes. Typically a morbilliform rash is generalised and erythematous, with macules or papules. Morbilliform drug eruption is the most common form of drug eruption. Many drugs can trigger this allergic reaction, but antibiotics are the most common group. The eruption may resemble exanthems caused by viral and bacterial infections. A morbilliform skin rash in an adult is usually due to a drug. In a child, it is more likely to be viral in origin. Morbilliform drug eruption is also called maculopapular drug eruption, exanthematous drug eruption and maculopapular exanthem.
  • #65 Classic cutaneous findings in a patient with DRESS. a Morbilliform exanthem most prominent on the trunk. b Significant facial edema and erythema
  • #66 SCAR في نفسه أوي SJ في نفسه أوي
  • #67 Generalised skin eruption 3 weeks after allopurinol therapy
  • #73  The Gell and Coombs classification is conceptually useful even if it is unable to cover all mechanisms involved in drug allergy Type II reactions involve antibodies directed against antigenic components of peripheral blood or tissue cells or foreign antigens, resulting in cell destruction. Examples of this type include autoimmune hemolytic anemia, pemphigus vulgaris, and Goodpasture syndrome. Type IV reactions involve T cell–mediated tissue inflammation and typically occur more than 48 hours after exposure. Examples of this type are tuberculin (purified protein derivative [PPD]) reactions and contact dermatitis
  • #74 The latency phase (from drug initiation to onset of reaction) typically rangesfrom two to eight weeks. However, the latency may be shorter in cases attributed to antibiotics,especially beta-lactam, and iodine contrast media [42,43]. The prodromal phase of DRESS isoften characterized by nonspecific symptoms, such as fever, malaise, and lymphadenopathy.
  • #82 In an effort to define more accurately the DRESS syndrome, a scoring system has also been developed the RegiSCAR scoring system.
  • #86 *This can be replaced by other organ involvement, such as renal involvement
  • #101 The rule is misdiagnosis.
  • #107 & the clinical course of the cutaneous manifestations may not parallel that of visceral organs.
  • #109 زد الطين بلة.
  • #110 زد الطين بلة. The controversy in part stems from the heterogeneity in clinical manifestations between patients and variable timing of onset of manifestations even within one patient.
  • #111 زد الطين بلة. The controversy in part stems from the heterogeneity in clinical manifestations between patients and variable timing of onset of manifestations even within one patient.
  • #114 طالما الدنيا كلها ملخبطة كده يبقى العينة هي الحل.
  • #115 زيادة الطين بلة
  • #116 تخيل لو وجدت طفل تايه في القاهرة عمرك ما هتتوقع إنه من إسكندرية أو على الأقل هيبقى احتمال بعيد حتى المريض لما تسأله عن أدوية جديدة هيقول لا. أو لو لقيت حاجة مكسورة هتبحث عن الجاني حواليك مش بعيد.
  • #118 Suspect DRESS, then suspect the culprit drug. Like any allergy, stop the offending.
  • #122 False negative متهم يهرب من العدالة False positive بريء يحبس ظلما : though halting culprit drug is paramount in clinical care, discontinuing or labeling a patient allergic to a drug that in fact the patient could safely take is not without consequences. The replacement medication could be less effective, more dangerous, and/ or more expensive.
  • #124 Why know high risk?
  • #131 DRESS is a T cell-mediated delayed-type drug hypersensitivity reaction (DHR).
  • #135 The PREDICT-1 study demonstrated HLA-B*57:01 carriage rates of ~ 6% in Caucasians and 2–3% in African-Americans and admixed American populations, and that screening had a 47.9% positive predictive value, 100% negative predictive value, and completely eliminated abacavir-induced hypersensitivity [13•]. Other known drug:HLA allele associations in DRESS are listed in Table 1. This list will continue to grow, as the search for at risk HLA alleles has become a major area of investigation. This is incredibly important clinically because for the first time, there is potential to prevent cases of DRESS by laboratory testing [14–16]. Moreover, the identification of specific drug:HLA allele associations has significant implications for identifying culprit drug. Instituting widespread HLA testing is not without complexity [17]. The major caveats for the clinician to recognize are that HLA allele associations are currently known for a limited number of drugs, there is a wide range in quality of data supporting HLA allele associations, prevalence of at risk HLA alleles can vary greatly amongst different populations so may not be applicable to the provider’s patient/ population, and the positive and negative predictive values (PPV and NPV) of having predisposing HLA alleles are highly variable. To this last point, abacavir:HLA-B*57:01 has the highest known PPV to our knowledge yet is only ~ 50% [13•]. The low positive predictive value of HLA allele associations suggests that additional factors contribute to onset of disease. One potential contributing factor is elevated drug level. In support, research has demonstrated increased risk of allopurinol-induced DRESS in HLA-B*58:01-positive patients with reduced kidney function [18, 19]. Similarly, polymorphisms in genes encoding drug metabolizing enzymes or drug-drug interactions affecting liver metabolism resulting in elevated drug levels may contribute to disease [20–23]. These observations support considering liver and kidney function prior to/at the time of DRESS onset and potential drug-drug interactions when evaluating DRESS patients and attempting to identify culprit drug.
  • #143 Psychological scar
  • #149 Atypical cutaneous presentation of DRESS. Target and target-like macules and papules on the a chest and abdomen and b back. c Mild mucosal involvement yet with d prominent ear involvement classically seen in DRESS