BSD Workshop: Case 25 RAC5556

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•  F49 •  Migraine •  Single

miscarriage •  1 year history

gradually progressive skin discolouration

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BSD Workshop: Case 25 RAC5556

Initial investigations (2008)

  IgG anticardiolipin antibodies (IgG aCL): 190.8 GPL kU/L → 75mg aspirin od commenced

2010  •  Odd sensory disorder right arm •  Nerve conduction studies:

– Non-specific sensori-motor neuropathy •  Ongoing sensory disorder in hands and

leg cramps

Investigations: June 2011

  Atypical p-ANCA detected and Myeloperoxidase (MPO) < 1 kU/L → identical results in September 2011   IgG aCL: 2.7 GPL kU/L

In July 2011, she developed crops of necrotic papules within areas of livedo racemosa on her ankles

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Differen+al  Diagnosis  for  BSD  Workshop  

•  Polyarteri+s  nodosa  •  Livedoid  vasculopathy  •  Microscopic  polyarteri+s  •  Chrug  Strauss  syndrome  •  Cholesterol  emoblism  

Histology Report: Lymphocytic true vasculitis including muscular vessels in the subcutis with widespread thrombosis of superficial vessels. Appearances in keeping with a systemic vasculitis, such as polyarteritis nodosa. In view of the widespread thrombotic element, suggest ruling out additional coagulopathy including cryoglobulins.

Necrotic plaques resolved with a course of high dose prednisolone

Investigations: February 2012

  ANCA negative   MPO: < 0.2 kIU/L   IgG aCL: 0.8 GPL kU/L

Other Normal investigations: 2008 - 12

  FBC   U&E   LFT   ESR   CRP

  Vasculitis screen including: - Proteinase 3 antigen - Lupus anticoagulant antibody - ß-2-glycoprotein-1 antibody - Clotting - Cryoglobulin & cryofibrinogen - Hepatitis B serology

Favoured Clinicopathological Diagnosis

Cutaneous polyarteritis

nodosa (c-PAN)

Current daily treatment

  5mg prednisolone (on reducing dose since Aug

‘11): No further ulcers or chilblains

  300mg aspirin (dose increased from 75mg in

Aug ‘11) – but livedo racemosa progressing

  50mg losartan (started in April ‘12)

  45mg amitriptyline & 10mg rizatriptan

  Omeprazole & Calcichew

Livedo racemosa •  First introduced by

Ehrmann in 19071

•  Originates from the Latin word racemus (bunch / cluster of grapes)

•  No effective treatment for livedo racemosa & may extend despite antiplatelets or anticoagulants  

Ehrmann S. Ein Gefaessprozess Bei Lues. Wien Med Wochenschr 1907;57:777-82

Biopsy of livedo racemosa2,3

•  Biopsy uninvolved skin at the centre of a livedo racemosa area and affected area

•  Obtain deep, adequate size biopsies (1-2cm) •  More than 1 biopsy:

–  Sensitivity of biopsy increases from 27% (1 biopsy) to

80% (3 biopsies)

•  Obtain serial sections of the biopsies

2. Zelger B et al. Life history of cutaneous vascular lesions in Sneddon’s syndrome. Hum Pathol 1992;23:668-75 3. Wohlrab J et al. Diagnostic impact and sensitivity of skin biopsies in Sneddon’s syndrome. A report of 15 cases. Br J Dermatol 2001;145:285-8

Livedo racemosa vs livedo reticularis Livedo racemosa Livedo reticularis

Clinical features4,5

-  Location: More generalised -  Shape: Irregular, broken circular segments

-  Location: Limbs -  Shape: Regular, enclosed circular segments

Physiology4,5 Reduced blood flow and oxygen tension at the peripheries of the skin segments

Aetiology4,5 Always pathological -  Physiologic livedo

reticularis (cutis marmorata) -  Primary livedo reticularis -  Idiopathic livedo reticularis -  Amantadine-induced livedo reticularis6

4. Uthman IW et al. Livedo racemosa: a striking dermatological sign for the antiphospholipid syndrome. J Rheumatol 2006 Dec;33(12):2379-82

5. Kraemer M et al. The spectrum of differential diagnosis in neurological patients with livedo reticularis and livedo racemosa. A literature review. J Neurol 2005;252:1155-66

6. Shealy CN et al. Livedo reticularis in patients with parkinsonism receiving amantidine. JAMA1970;212:1522-3

Diseases associated with livedo racemosa5

  Sneddon’s syndrome

  Antiphospholipid

syndrome

  Systemic lupus +/- APS

  Polyarteritis nodosa

  Livedoid vasculopathy

  Cholesterol embolisation

Rare  Associa+ons  – Polycythaemia  ruba  vera  – Essen+al  thrombocytaemia  

– DIC  – Thromboangii+s  obliterans  

– Cryofibrogenemia  – Grave’s  hyperthyroidism  – Calciphylaxis  – Hyperoxaluria  

5. Kraemer M et al. The spectrum of differential diagnosis in neurological patients with livedo reticularis and livedo racemosa. A literature review. J Neurol 2005;252:1155-66

Sneddon’s syndrome

  Diagnostic hallmark: Generalised livedo racemosa and ischaemic

stroke   1st described by Champion and Rook in 19607

  1st characterised as a separate and distinct disease process by Sneddon in 19658

7. Champion RH, Rook A. Livedo reticularis. Proc R Soc Med 1960;53:961-2 8. Sneddon IB. Cerebrovascular lesions and livedo reticularis. Br J Derm 1965;77:180-5

Cutaneous polyarteritis nodosa (c-PAN)9,10

  Rare form of vasculitis involving medium sized arteries

  Aetiology unknown   Chronic condition with relapses and remission   Good prognosis 9. Morgan AJ et al. Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol 2010 Jul;49(7):750-6 10. Ishiguro N et al. Cutaneous polyarteritis nodosa: a report of 16 cases with clinical and histopathological analysis and a

review of the published work. J Dermatol 2010 Jan;37(1):85-93

 

Associations with c-PAN9   Common associations: - Group A ß haemolytic streptococcal infection - Hepatitis B infection - Inflammatory bowel disease - Extended course of minocycline

  Rarer associations: - Hepatitis C infection - Parvovirus B-19 infection - Mycobacterium tuberculosis infection 9. Morgan AJ et al. Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol 2010;49:750-6

Clinical features of c-PAN9,10   Cutaneous manifestations: - Tender subcutaneous nodules - Livedo racemosa - Tender indurated plaques - Necrosis - Punched-out ulcers - Purpura   Extra-cutaneous manifestations: - Fever - Myalgia - Arthralgia - Neuropathy - Paraesthesia 9. Morgan AJ et al. Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol 2010 Jul;49(7):750-6 10. Ishiguro N et al. Cutaneous polyarteritis nodosa: a report of 16 cases with clinical and histopathological analysis and a

review of the published work. J Dermatol 2010 Jan;37(1):85-93    

Laboratory abnormalities in c-PAN9   Frequently: - Mild anaemia - Moderate leukocytosis - Raised ESR - Anti-phosphatidylserine-prothrombin complex antibody (IgM >> IgG)11   Rare reported cases: - p-ANCA12

- Lupus anticoagulant antibody11

- Anticardiolipin antibody (IgG11,12 > IgM) 9. Morgan AJ et al. Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol 2010;49:750-6 11. Kawakami T et al. High titer of anti-phosphatidylserine-prothrombn complex antibodies in patients with cutaneous

polyarteritis nodosa. Arthritis Rheum 2007;57:1507-13 12. Pereira BAF et al. Cutaneous polyarteritis nodosa in a child with positive antiphospolipid and p-PANCA. Scand J Rheumatol

1995;24:386-8

Treatment of c-PAN9,10   NSAIDS   Colchicine   Aspirin   Steroids   Steroid sparing agents   Dapsone   IV Ig   Perilesional injections of granulocyte-macrophage colony-stimulating factor13 9.  Morgan AJ et al. Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol 2010 Jul;49(7):750-6 10.  Ishiguro N et al. Cutaneous polyarteritis nodosa: a report of 16 cases with clinical and histopathological analysis and a review of the published work. J Dermatol 2010 Jan;37(1):85-93 13. Tursen U et al. Rapid healing of chronic leg ulcers during perilesional injections of granulocyte-macrophage colony-

stimulating factor therapy in a patient with cutaneous polyarteritis nodosa. JEADV 2006;20:1341-3

 

RSM: Summary   Case of generalised livedo acemosa   Features entirely in keeping with c-PAN BUT.... Dr R disagreed

s/b Bernhard Zelger Dear X and other colleagues involved in this lady`s case

This is a case of antiphospholipid-syndrome and as such no vasculitis, but a coagulopathy. Clinically, livedo (in this case racemosa) is characteristic of a coagulopathy and on the lower legs there is in addition also livedo vasculopathy (by others in my experience wrongly called livedo vasculitis).

As I showed in my presentation in Oxford this disease shows in stage II beside presence of fibrin thrombi (which would be stage I when present alone) plentiful lymphocytes accentuated around a superficial defect (as shown here in your series of histologies), but also involving deeper and larger vessels. This is yet an expected finding of reorganisation of stage I and will end as restitutio ad integrum or scar formation, atrophy blanche clinically and fibrosis, stage III livedo vasculopathy histologically.

s/b Bernhard Zelger (Cont)

Laboratory work up (it is typical that some coagulopathic parameters may become positive and negative in due course of disease showing undulation/roller-coaster of coagulation cascade) and previous history (abortion, misscarriage) excellently fit APS. The question is if patient will develop lupus erythemathodes or another collagenosis/systemic disease in due course which is well established in the literature. Previously, such cases would have been considered in the field of Sneddon syndrome, but this was before the respective laboratory parameters were worked out. And these laboratory parameters nicely parallel the ulcers, i.e. in livedo racemosa with livedo vasculopathy one has a much greater chance to find a causative coagulation factor than without ulcers.

Many thanks for sharing this case with me

Best greetings, from Innsbruck, Bernhard (zelger)

Just as an attachment / addition to my previous email. Classic PN (panarteriitis nodosa) characteristically affects arteries (or arterioles) at the border dermis-subcutis only, very rarely there is superimposed livedo vasculopathy which might then be difficult to differentiate histologically.

Clinically, in classic PN nodules are present beside livedo racemosa which is then also more starry sky-like (i.e. inflammatory) and shows in addition severe arthropathy of ankle region the latter of which by the way is mostly the earliest clinical finding.

Microscopic PN is (completely) different. It accentuates postcapillary venules and may also involve larger vessels. In your case accentuation is on capillaries.

Best greetings

Bernhard

Learning  Points  

•  Always  be  prepared  to  re-­‐assess  a  diagnosis  •  Don’t  be  afraid  to  get  it  wrong  •  Don’t  be  afraid  to  ask  for  help!  

Thank  You