Antithyroid drug and ANCA positive vasculitis

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Anti-thyroid drug and ANCA positive vasculitis

• JCEM, vol84, No1, p13, 1999

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ANCA

• Anti-neutrophil cytoplasmic antibody

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Clinical manifestation

• 27 year-old female
• Thyroid goiter for 3 years.
• Follow up at OPD regularly.
• 91-8-12,
• C.C.Thyroid goiter, palpitation(120/min),
  hand tremor for several weeks.
• PEgoiter, tachycardia, no exophthalmos

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Thyroid function test
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Thyroid sonogram

• 87-9-16 Multiple nodular goiter, bilateral ,
  R/O autoimmune thyroiditis
• 88-8-5 Ditto
• 89-7-11in favor of MNG rather than
  autoimmune thyroid disease.
• 90-1-1MNG
• 90-12-27 atypical MNG
• 91-7-23 more favor autoimmune thyroid
  disease, D/D include MNG.

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Diagnosis ?
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• Thyroid I-131 uptake and scan
• Uptake at 24 hour is 45
• Thyroid scan the gland is enlarged with even
  distribution of radioactivity
• Impression The scintigraphic findings are
  compatible with thyrotoxicosis.

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• 91-8-12,
• Inderal and Tapazol were prescribed.

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Clinical manifestation

• 91-8-21, acute nuchalgia for 2 days with fever
  off and on.
• PE
• HA negative, photophobia negative
• Neck not rigid, no meningeal sign,
• BT 38.5 c, Multiple small petechiae over ??,
• Dx R/O dengue fever.
• Admission

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• Figure 3. Purpura on the Lower Leg of a Patient
  Found to Have Leukocytoclastic Angiitis in a
  Skin-Biopsy Specimen. There are also several
  darker areas of necrosis. (Photograph kindly
  provided by Robert A. Briggaman.)

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• Persistent fever with chillness during hospital
  days
• Refer to NCKU on 91-8-26, W1

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Figure 4. Leukocytoclastic Angiitis in a
Skin-Biopsy Specimen from a Patient with Purpura.
There is extensive karyorrhexis of the vascular
and perivascular leukocytes (leukocytoclasia).
(Hematoxylin and eosin, x500.)
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ANCA positive vasculitides

• Wegener's granulomatosis (WG),
• Churg-Strauss syndrome (CSC)
• Microscopic polyangiitis, (MP)
• some drug-induced vasculitides.

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ANCA

• cytoplasmic (cANCA)
• strongly associated with for antiproteinase3
  (PR3-ANCA)
• 90 WG are PR3-ANCA and cANCA positive
• cANCA is 80-97 specific for WG
• Drug-induced ANCA positive vasculitis
• may be associated with pANCA, MPO-ANCA, cANCA or
  PR3-ANCA

• pericytoplasmic (pANCA)
• directed against a number of antigens
• the most important -- myeloperoxidase (MPO-ANCA)
• Most patients with CSS or MP are pANCA and
  MPO-ANCA positive

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Analysis of cases

• There are 26 previously reported cases of ANCA
  positive vasculitis in association with
  antithyroid drugs ( Table 1).
• Seventy-four percent were female.
• Forty-eight percent were Japanese patients.
• The average age of affected patients was 46.6
  years (range 8 to 82 years of age).
• PTU therapy was implicated in 88.
• Underlying disease
• 63was not clear from the case report,
• in all but one of the remainder was Graves'.
• JCEM, 1999,

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Organ involvement

• Renal involvement-- 66.7,
• arthralgia in 48,
• fever in 37,
• skin involvement in 29.6,
• respiratory tract involvement in 25.9,
• myalgia in 22.2,
• scleritis in 14.8
• other manifestations in 18.5.

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Renal biopsy

• 17 patients was done
• Crescentic or necrotizing GN in 94.1.
• Mesangial proliferation in 11.8.
• Immunofluorescence test
• pauci-immune
• or non-specific in all biopsies.

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Analysis of cases

• pANCA pattern--81.5,
• an undifferentiated positive ANCA was reported in
  a further 14.8.
• cANCA was positive in 11.1 and was seen in
  isolation in one patient.
• MPO-ANCA was positive in 78.3 of cases
• PR3-ANCA was positive in 72.7 of the 11 cases

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Therapy

• Cessation of the initiating drug.
• Renal involvement
• steroids and /or
• cyclophosphamide was given to 88.2 patients
• Plasmapheresis-One patient

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Result

• Improvement in 85.2.
• In 7.4, renal function declined
• In 3.7, no significant change
• Death occurred in a patient in whom renal
  function was stable and was due to LVF and COAD.

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Discussion

• Vasculitis is a rare complication during
  treatment of thyrotoxicosis
• Positive ANCA in association with the vasculitis
  has been recently described
• Antithyroid drugs related ANCA vasculitis
• more frequently in women, reflect female
  preponderagce of thyrotoxicosis
• In fact men be more common

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ANCA associated vasculitis

• a variety of constitutional symptoms
• fever,
• myalgia,
• arthralgia,
• "flu-like" syndrome

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ANCA associated vasculitis

• Vessels in skin, kidneys, respiratory tract,
  skeletal muscle, peripheral nerves and other
  areas may be involved.

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ANCA associated vasculitis

• The commonest cutaneous lesion is
  leukocytoclastic vasculitis
• preferentially affects the lower limbs
• typically causes purpuric lesions.
• Other cutaneous manifestations are protean.

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ANCA associated vasculitis

• pathogenesis not clearly understood.
• PTU accumulate in neutrophils
• bind to myeloperoxidase,
• changing its structure
• autoantibody formation

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Pathogenesis

• The pauci-immune or non-specific pattern of
  immunofluorescence in renal biopsies implies that
  drug-induced lupus erythematosis is unlikely to
  be the mechanism.

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Drug-induced pANCA vasculitis

• hydralazine,
• sulphasalazine therapy (n2)
• minocycline (n1)
• Diagnosis requires a positive ANCA.
• MPO-ANCA is the commonest pattern.
• Biopsies from clinically involved area.
• If renal involvement? renal biopsy ?determining
  appropriate therapy and long term prognosis.

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Drug-induced pANCA vasculitis

• Diagnosis
• positive ANCA.
• MPO-ANCA is the commonest pattern.
• Biopsies from clinically involved area.
• If renal involvement? renal biopsy ?determining
  appropriate therapy and long term prognosis.

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Drug-induced pANCA vasculitis

• Treatment
• depends upon severity of the illness.
• Fever, arthralgia, myalgia, malaise, "flu-like"
  syndrome and cutaneous vasculitis respond well to
  cessation of the drug.

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Treatment

• Steroids and/or cyclophosphamide is warranted
  --If renal manifestation are severe, rapidly
  progressive, or biopsy shows, crescentic GN,.
• In most cases, renal function will improve, but
  creatinine clearance sometimes does not return to
  baseline

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Drug-induced pANCA vasculitis

• Crescentic or necrotizing GN-- high risk for CRI
• Pulmonary manifestations
• from minor nasal involvement to life-threatening
  pulmonary haemorrhage.
• If severe or life-threatening,
• plasmapheresis should be considered, in addition
  to steroids and/or cyclophosphamide.
• Scleritis --either topical or systemic steroids.

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Drug-induced pANCA vasculitis

• Prognosis is good.
• ANCA titers may fall with time, but remain
  positive in many patients.
• We found several ANCA positive patients treated
  with either PTU or carbimazole without clinical
  manifestations of vasculitis (unpublished data).

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Conclusion

• ANCA positivity may lead to
• earlier consideration of definitive therapy.
• Possibly long-term antithyroid therapy should
  not be given to patients with positive ANCA,
• carbimazole should be better than PTU.