Difficult Cases: Itching without Rash

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Difficult CasesItching without Rash

• Gerald Lee, MD
• Cem Akin, MD, PhD, FAAAAI

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Case 1

• A 82 year old male presents for evaluation of
  pruritus for one year.
• Episodes are generalized and occur daily. He
  reports a decreased quality of life from this
  pruritus.
• Although there was initially no rash, he later
  developed raised nodules and plaques, where each
  lesion lasts around one week.
• The itching is worse with heat but improves with
  showering.
• He has been previously evaluated by dermatology,
  and has tried topical triamcinolone, clobetasol,
  and oral hydroxyzine 50mg BID without relief.

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Case 1

• PMH Hypertension, erectile dysfunction,
  osteoarthritis with history of bilateral hip
  replacement, history of abdominal surgery for
  bullet wound (veteran)
• Meds Clobetasol propionate 0.05 cream, HCTZ,
  hydroxyzine, lisinopril, terazosin, vitamin B
  complex
• Allergies NKDA
• FH No history of atopy
• SH Works security, Korean and Vietnam war
  veteran
• ROS Negative for fever, night sweats, weight
  loss, lymphadenopathy, jaundice, joint pain,
  heat/cold intolerance. Positive for BPH symptoms
  and hip pain.

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Physical Exam

• Gen pleasant, well appearing
• HEENT normal
• CV normal
• Lung normal
• Abd ventral hernia, no organomegaly
• MS spine kyphosis, thickened elbow, knee, and
  hand joints
• Lymph no LAD
• Skin raised nodular excoriated lesions over the
  arms, legs, chest and trunk, sparing the back.

Photo source Gerald Lee, used with permission
5
Question

• What is this rash most consistent with?
• Urticaria
• Scabies
• Prurigo Nodularis
• Vasculitis

ANSWER on next slide
Photo Gerald Lee, used with permission
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Prurigo Nodularis

• Nodular skin rash of unknown etiology associated
  with chronic pruritus
• Nodules themselves are pruritic, and substance P
  () nerves have been demonstrated in lesions.
• Distribution is symmetric but typically spares
  the hard to reach upper back (butterfly sign)
• Hypothesized to be a secondary lesion

Bolognia, J. et al. (2012) Dermatology. 111-125.
Photo Katotomichelakis M. et al. CC 2.0
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Question

• What is your next management step?
• A. Reassure this is non-allergic and tell him to
  follow up with his dermatologist
• B. Skin testing to indoor inhalants and foods
• C. CBC with differential, comprehensive metabolic
  panel, TSH, Chest X-ray
• D. No testing, start 2nd generation
  antihistamines and continue topical steroids

ANSWER on next slide
8
Question

• What is your next management step?
• A. Reassure this is non-allergic and tell him to
  follow up with his dermatologist
• B. Skin testing to indoor inhalants and foods
• C. CBC with differential, comprehensive metabolic
  panel, TSH, Chest X-ray
• D. No testing, start 2nd generation
  antihistamines and continue topical steroids

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Causes of Chronic Pruritus
Dermatologic Non-dermatologic Non-dermatologic Non-dermatologic
Dry skin (xerosis) Urticaria Atopic Dermatitis Seborrheic Dermatitis Psoriasis Contact Dermatitis Pemphigoid Dermatitis herpetiformis Arthropod Bites Bedbugs Scabies Lice Systemic Neurologic Psychogenic
Dry skin (xerosis) Urticaria Atopic Dermatitis Seborrheic Dermatitis Psoriasis Contact Dermatitis Pemphigoid Dermatitis herpetiformis Arthropod Bites Bedbugs Scabies Lice Uremia Cholestasis Malignancy Lymphoma Myeloma Myelodysplasia Polycythemia vera Thyroid disease HIV infection Medications (next slide) Brachioradial pruritus Notalgia paresthetica Postherpetic itch Diabetic neuropathy Anxiety/Depression Obsessive-Compulsive disorder Delusions of parasitosis / formication Substance abuse
Adapted from Yosipovitch, G. and Bernhard, JD.
(2013) NEJM 3681624-34.
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Drugs associated with pruritus without rash

• Cholestasis OCPs, sulfonamides, chlorpromazine,
  tricyclic antidepressants
• Hepatotoxicity acetaminophen, anabolic steroids,
  minocycline, INH, phenytoin, sulfonamides
• Xerosis beta blockers, calcium channel blockers,
  statins, retinoids, tamoxifen, clofibrates
• Neurologic tramadol, codeine, morphine,
  fentanyl, methamphetamines
• Idiopathic chloroquine, clonidine, gold salts,
  lithium

Yosipovitch, G. and Bernhard, JD. (2013) NEJM
3681624-34. Garibyan L., Chiou AS., Elmariah SB.
(2013) Dermatologic Therapy. 2692-103.
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Unique Features of Pruritic Syndromes
Feature Suggested Diagnosis
Sparing of the upper back Suggests itching without rash (upper back difficult to scratch)
Pruritus after bathing Hematologic malignancy (lymphoma, polycythemia vera, mastocytosis) Hemochromatosis Idiopathic aquagenic pruritus
Pruritus worse at night with associated constitutional symptoms Hodgkin lymphoma (may precede onset by 5 years)
Pruritus does not interfere with sleep Psychogenic
Burning sensation, relief with ice application Neuropathic
Bolognia, J. et al. (2012) Dermatology. 111-125.
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Case 1

• CBC Normal WBC and differential. Borderline
  anemia at 13.1 gm/dL and thrombocytopenia with
  platelets of 133.
• CMP normal
• ESR, CRP normal
• TSH normal
• LDH 207
• SPEP normal

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Question

• For pruritus of undetermined origin, which
  therapy would be the least helpful?
• A. Antihistamines (e.g. hydroxyzine)
• B. Antidepressants (e.g. mirtazapine)
• C. GABA Analogues (e.g. gabapentin)
• D. mu-opioid antagonists (e.g. naltrexone)

ANSWER on next slide
14
Question

• For pruritus of undetermined origin, which
  therapy would be the least helpful?
• A. Antihistamines (e.g. hydroxyzine)
• B. Antidepressants (e.g. mirtazapine)
• C. GABA Analogues (e.g. gabapentin)
• D. mu-opioid antagonists (e.g. naltrexone)

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Antihistamines and Pruritus

• Histamine receptor blockers have strong efficacy
  in histamine-mediated conditions such as
  urticaria.
• However, randomized control trials have not
  demonstrated the efficacy of antihistamines in
  other pruritic disorders, including eczema.
• An evidence based review of 16 studies showed 2
  negative RCTs, 1 positive RCT, and 13 poor
  quality trials Klein PA and Clark RA. (1999) Arch
  Dermatol. 135(12)1522-1525.
• Chlorpheniramine had no effect on pruritus in
  atopic dermatitis in a multicenter RCT Munday J
  et al. (2002) Dermatology. 20540-5.

Yosipovitch, G. and Bernhard, JD. (2013) NEJM
3681624-34.
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Initial therapies

• Regular application of moisturizers, especially
  after bathing
• Keeping fingernails short
• Wearing light and loose clothing
• Maintaining a comfortable temperature in the home
• Using a humidifier during the winter
• Restricting time in the shower or bathtub
• Using cool or lukewarm water while bathing
• Avoiding cleansers with high pH or contain alcohol

Patel, T. , Yosipovitch G. (2010) Skin Therapy
Lett. 15(5)5-9.
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Topical Therapies

• Topical glucocorticoids
• Helpful only for inflammatory skin lesions rather
  than for pruritus
• Capsaicin
• Best for neuropathic disorders
• May have transient burning
• Anesthetics (pramoxine, lidocaine/prilocaine)
• Evidence for short term benefit for pruritus, but
  no safety data available for long term or
  extensive use
• Coolants (menthol 1-3)
• Provides a cooling sensation that may reduce itch
• Patients who state cool temperatures help may
  benefit

Patel, T. , Yosipovitch G. (2010) Skin Therapy
Lett. 15(5)5-9.
18
Systemic Therapies

• Antidepressants
• Thought to centrally reduce perception of
  pruritus in the CNS
• Mirtazapine - start at 7.5mg at night and titrate
  up to 15mg daily
• Paroxetine 10 to 40mg daily
• GABA Analogues
• Particularly helpful in neuropathic pruritus,
  also affects CNS
• Note can worsen pruritus of cholestasis
• Gabapentin 100 to 1200mg TID
• Pregabalin 25 to 200 mg BID
• Combination therapy with both mirtazapine and a
  GABA analogue may be required
• Mu-opioid antagonists
• Addresses a possible imbalance of mu and kappa
  opioid systems
• Naltrexone 12.5 to 50mg daily
• Higher side effect profile nausea, anorexia,
  abdominal pain and diarrhea, particularly in the
  elderly

Yosipovitch, G. and Bernhard, JD. (2013) NEJM
3681624-34.
Patel, T. , Yosipovitch G. (2010) Skin Therapy
Lett. 15(5)5-9.
19
Case 1

• Referral to hematology for evaluation of mild
  cytopenias, who recommends close monitoring for
  now
• CXR and previous CT scans were negative for
  malignancy
• Initially tried mirtazapine 7.5mg at night, but
  still was itching
• Could not tolerate mirtazapine 15mg at night, but
  responded well to low dose gabapentin 600mg/day.
• I continue to reassess this patient for control
  and also an underlying cause of pruritus

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Case 2

• A 61 year old woman presents with chronic
  dermatitis of the arms for 7 years.
• Her itching initially occurred without a rash
• She described a burning pain (dysesthesia) of the
  arms
• Months later, she developed a chronic papular
  rash with significant excoriations
• Her symptoms were worsened by sun exposure but
  relieved with cold compresses.

Convers, K.D., Sturm, J.M. and Slavin, R.G.
(2013) Allergy Asthma Proc 34(6) 558-561.
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Case 2

• She has been evaluated by multiple dermatologists
  in the past
• Skin biopsies previously revealed epidermal
  necrosis, suggestive of excoriation, and
  superficial perivascular lymphocytic infiltrate
  with eosinophils.
• She was diagnosed with a hypersensitivity
  reaction, but her pruritus failed to improve
  despite topical corticosteroids, systemic
  antihistamines and a trial of empiric
  valacyclovir.

Convers, K.D., Sturm, J.M. and Slavin, R.G.
(2013) Allergy Asthma Proc 34(6) 558-561.
22
Case 2

• PMH none
• Meds clobetasol 0.05 ointment topically BID,
  duloxetine 60mg daily, cetirizine 10mg daily, and
  hydroxyzine 25mg PRN
• ROS mild neck pain, subjective weakness and
  muscle aches of her bilateral upper extremities.

Convers, K.D., Sturm, J.M. and Slavin, R.G.
(2013) Allergy Asthma Proc 34(6) 558-561.
23
Question

• Skin exam reveals excoriated papules and plaques
  in various stages of healing, involving the
  extensor surfaces of the arms, posterior base of
  the neck, and bilateral shoulders.
• What would be the most important other organ
  system to assess on physical exam on this
  patient?
• A) Neurologic, to assess for neuropathy
• B) Neck, to assess for goiter
• C) Lymphatic, to assess for lymphadenopathy
• D) Abdominal, to assess for liver disease

ANSWER on next slide
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Question

• Skin exam reveals excoriated papules and plaques
  in various stages of healing, involving the
  extensor surfaces of the arms, posterior base of
  the neck, and bilateral shoulders.
• What would be the most important other organ
  system to assess on physical exam on this
  patient?
• A) Neurologic, to assess for neuropathy
• B) Neck, to assess for goiter
• C) Lymphatic, to assess for lymphadenopathy
• D) Abdominal, to assess for liver disease

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Case 2

• Neurologic exam was significant for decreased
  muscle strength of the brachioradialis muscles
  bilaterally
• Sensory exam was normal
• Musculoskeletal exam was significant for
  tenderness to palpation along C4-C7
• The upper extremity rash appeared to follow the
  distribution of C5-C6 dermatomes
• Rest of the exam was normal.

Convers, K.D., Sturm, J.M. and Slavin, R.G.
(2013) Allergy Asthma Proc 34(6) 558-561.
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Dermatomal Distribution of the Arm
Work found at http//en.wikipedia.org/wiki/Lateral
_cutaneous_nerve_of_forearm / CC BY-SA 3.0
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Workup

• Laboratory
• CBC with differential, CMP, TSH, CPK, CRP normal
• Radiology
• Chest X-ray normal
• Cervical spine X-ray anterolisthesis of C6 on C7
  and spondylosis of C5-C7 with osteophytes
• Cervical spine MRI herniated disk at C5-C6
  centrally with severe stenosis of the foramen

Convers, K.D., Sturm, J.M. and Slavin, R.G.
(2013) Allergy Asthma Proc 34(6) 558-561.
28
Diagnosis

• Brachioradial pruritus syndrome
• Localized pruritus and burning of the
  dorsolateral aspect of the upper extremities
• Ice pack sign relief with cold compresses is
  thought to be pathognomonic
• Considered a variant of cervical spine
  radiculopathy, but presents with pruritus, rather
  than pain.
• Other associated cervical spine pathologies
  include nerve root compression, tumor, and a
  cervical rib.

Convers, K.D., Sturm, J.M. and Slavin, R.G.
(2013) Allergy Asthma Proc 34(6) 558-561.
29
Question

• What first line therapy should be attempted to
  control pruritus in this patient?
• A. Hydroxyzine
• B. Gabapentin
• C. Prednisone
• D. Mirtazapine

ANSWER on next slide
30
Question

• What first line therapy should be attempted to
  control pruritus in this patient?
• A. Hydroxyzine
• B. Gabapentin
• C. Prednisone
• D. Mirtazapine

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Case 2

• Patient was started on gabapentin, and was
  titrated up to 300mg, 4 times a day
• Her symptoms improved, but did not resolve
  despite high doses of gabapentin
• She was referred to an orthopedist, and received
  epidural steroids with complete resolution of her
  pruritus and rash.

Convers, K.D., Sturm, J.M. and Slavin, R.G.
(2013) Allergy Asthma Proc 34(6) 558-561.
32
Conclusions

• Chronic pruritus without preceding rash has a
  broad differential diagnosis
• Systemic causes
• Neuropathic causes
• Psychogenic causes
• Antihistamines are rarely effective for
  non-histamine causes of chronic pruritus.