non-healing ulcer work up powerpoint presentation

working up non-healing ulcer

1. Work up for non-healing ulcer (NHU) Dr Ritasman Baisya DM Rheumatology Assistant Professor , AIIMS Kalyani

2. Points of discussion What is an ulcer Non-healing ulcer (NHU) Ulcers in Rheumatology Case based discussion Vasculitic ulcer – a special concern Take home points

3. What is an ulcer   A break in the continuity of the covering epithelium, either skin or mucous membrane, due to molecular death. Erosion & ulcers are secondary skin lesions that develop over primary lesions. Parts of an Ulcer- a. Margin: It may be regular or irregular. It may be rounded or oval . b. Edge: which connects floor of the ulcer to the margin . c. Floor : it is the one which is seen d . Base : on which ulcer rests. It may be bone or soft tissue .

4. Clinical classification of ulcer 1 Spreading ulcer: Edge is inflamed, irregular and edematous. A cute painful ulcer F loor does not contain healthy granulation tissue P rofuse purulent discharge and slough; surrounding area is red and edematous.

5. 2. Healing ulcer Edge is sloping with healthy pink/red granulation tissue Scanty/minimal serous discharge in the floor; Slough is absent ; Surrounding area does not show any signs of inflammation or induration B ase is not indurated. Innermost red zone of healthy granulation tissue Middle bluish zone of growing epithelium O uter whitish zone of fibrosis and scar formation.

6. Stages of Wound healing Haematoma formation – first 24 hours Inflammation/ debridement – 24 hours -4 days Proliferation – up to 30 days Remodelling/ maturationn – maximum 300 days

7. Non-healing ulcer (NHU) C hronic ulcer Not healed by six weeks Healing arrested in the inflammatory phase Unable to transition to the proliferation phase with concurrent up regulation of angiogenesis and matrix deposition Prolonged pro-inflammatory phase Persistent elevation of pro inflammatory cytokines - inhibits action of fibroblasts & epithelial cells High MMPs, reduced TIMPs Reduced VEGF

8. Causes for non-healing ulcers   1 . Local causes -Repeated trauma , Presence of foreign body / slough , ongoing infection / osteomyelitis 2 . Regional causes - Venous, Arterial insufficiency, Neuropathic 3 . Systemic causes – A. Diseases - Diabetes mellitus, renal failure, autoimmune diseases etc . B. Drugs - Immunosuppressive, cytotoxic C. Nutritional deficiencies.

9. Causes of ulcer in rheumatic diseases Vasculitis :  RA, SLE , Myositis , PAN , ANCA vasculitis Venous insufficiency – APS, Behcet disease , Prothrombotic state Arterial disease :  PAD in Takayasu , SLE , RA Pressure /Trophic – Scleroderma, myositis Neuropathy :  Nerve damage can contribute to ulcers Others – Pyoderma gangrenoseum (PG) , calciphylaxis Infective Trauma Drug induced

10. Prevalence of autoimmune & vasculitic ulcer Data from 31,619 patients were reported - Venous - 47.6 % Arterial - 14.5% Combined - 17.6%. Vasculitis & other inflammatory ( PG , calciphylaxi s , drugs ) – 20 % Körber A, Klode J, Al- Benna S, Wax C, Schadendorf D, Steinstraesser L, et al. Etiology of chronic leg ulcers in 31,619 patients in Germany analyzed by an expert survey. J Dtsch Dermatol Ges 2011;9:116-21.

11. Case 1 A 52-year-old female Diagnosed with RA, 7 years ago Current treatment: Methotrexate, hydroxychloroquine, and prednisone Presenting Symptoms : Increased joint pain and swelling New onset of painful leg ulcer on the lower left leg

12. Case 1 Physical Examination : Tender & swollen wrist joint with deformity Ulceration with necrotic tissue on the lower left leg, with surrounding erythema (redness). Diagnosis – RA with leg ulcer ( probable vasculitic )

13. RA associated ulcer More common leg ulcers Risk factor- Older age , high RF , rheumatoid nodules , venous thrombosis , erosive arthritis Prolonged steroid use , atherosclerosis , pressure points can exacerbate risk

14. Ten of the 20 patients had ulcers with multifactorial etiology. Fifteen had signs of venous insufficiency, 11 had histopathological evidence of vasculitis . F our had reduced arterial circulation and T wo patients had diabetes.

15. Diagnostic Tests : Blood Tests : Elevated ESR, CRP, rheumatoid factor (RF), positive anti-CCP antibodies. Ulcer Biopsy : Showing signs of vasculitis and ischemia. X-rays : Joint erosion typical of RA

16. Work up Skin Biopsy – challenging to diagnose (vasculitis is present histologically in approximately 50% to 55% of patients with RA ) – rule out infection/malignancy Arterial and venous imaging – Doppler or angiography ( rule out thrombus /atherosclerosis ) Nerve conduction study if suspicion of neuropathy

17. Management of the case A , Before rituximab therapy. B, Complete healing after rituximab therapy. RA Management : Optimal steroid dosage Adjust methotrexate dosage and consider adding biologics (e.g., Rituximab , TNF inhibitors) for better disease control . Ulcer Treatment : Topical Care: Wound debridement, dressing changes, and moisture balance . Antibiotics : If infection is suspected . Vascular Support: Compression therapy or surgical options if needed.

18. Points to remember Critical limb ischemia-related ulcer – Surgical revascularisation (endovascular treatment ) Medical management– Aggressive therapy for the underlying RA, using disease-modifying anti-rheumatic drugs and biologic agents such as tumor necrosis factor-a inhibitors and rituximab, is beneficial Steroid is needed for severe disease

19. Case 2 50 year old female Diagnosed with systemic sclerosis 10 years ago. Recurrent painful skin ulcers on the distal fingers and hands with gangrenous changes No history of trauma History of RP , digital pits , skin thickening , GERD , ILD Treated with Nifedipine , PDE5 inhibitor and MMF No improvement of ulcer with topical antibiotics

20. Old investigation ANA- 3+ topoisomerase pattern ANA immunoblot – Scl70 strong positive HRCT chest – fibrotic NSIP , dilated esophagus 2DEcho- mild PAH with PASP- 30 mm Hg Nail fold capillary –advanced pattern changes What to do ?

21. Scleroderma – skin ulcers (SU) Scleroderma skin ulcers ( SSc -SU) - up-to 50% of patients  Loss of substance involving epidermis, basement membrane, and dermis, and frequently deeper skin structures Lesions may be multiple, recurrent, and/or relapsing They are localized at one or more skin areas, often acral zones of the hands and feet SU refers to all ulcerative cutaneous lesions, including DU.

22. Schematic representation of skin lesions in SSc patients Giuggioli D, Manfredi A, Lumetti F, Colaci M, Ferri C. Scleroderma skin ulcers definition, classification and treatment strategies our experience and review of the literature. Autoimmun Rev. 2018 Feb;17(2):155-164.

23. Classification of SSc -SU 5 subtypes according to prominent pathogenetic mechanism(s) and localization 1 .  digital ulcer  (DU) of the hands or feet , 2. SU on bony prominence, 3 . SU on  calcinosis 4 . SU of lower limbs 5 . DU presenting with gangrene. This latter is a very harmful evolution of both DU of the hands and feet needing a differential diagnosis with  critical limb ischemia Giuggioli D, Manfredi A, Lumetti F, Colaci M, Ferri C. Scleroderma skin ulcers definition, classification and treatment strategies our experience and review of the literature. Autoimmun Rev. 2018 Feb;17(2):155-164.

24. Systemic treatment Systemic therapy – based on the severity/activity of the whole SSc M ild-moderate (sporadic ulcerative manifestation) - a combination of vasodilators, i.e. calcium-channel blockers, prostanoids , phosphodiesterase type 5 (PDE-5) inhibitors, and/or endothelin receptor antagonists (ERA), and low-dose aspirin. R ecurrent, severe SU - grow factors such as granulocyte colony stimulating factor (GCSF) and/or erythropoietin (EPO) was carried out. Associated ILD / progressive skin changes - cycles of immunosuppressant/ immunomodulators (cyclophosphamide, mycophenolate , or rituximab)

25. Local treatment W ound bed preparation (WBP) procedures TIME approach : necrotic tissue, infection/inflammation, moisture balance, and epithelization Debridement of necrotic tissue Confirmation of infection, including osteomyelitis M oisture retentive dressing ( occlusive , absorptive , hydrating dressing) Advanced dressings- alginate , hydro-colloid , hydro-fiber Regenerative approach for severe cases - autologous adipose tissue-derived cell fractions

26. Others Pain management – opioid , TCA , nerve block Management of pruritus Regular follow up

27. Advanced therapy Negative Pressure Therapy (NPWT) : Growth factor therapy Skin grafts Platelet-rich plasma (PRP) therapy Hyperbaric oxygen therapy Cellular grafts

28. Case 3 40 year old female Diagnosed as SLE for 10 years History of lupus nephritis , multiple Cutaneous rash , arthritis Presented with large ulcer on elbow for 3 months She was on low dose steroid and HCQ Her serology reports- ANA positive , ANA profile- Sm-RNP , dsDNA positive , low complement , ACL negative

29. Case 4 40 years female Diagnosed as SLE with secondary APS for last 10 years History of serositis , discoid rash , malar rash , arthritis History of pregnancy morbidity She had history of toe gangrene and spontaneous amputation Now presented with left 4 th toe ulcer Serology – ANA positive , low complements with APL positive

30. SLE and ulcer Ulcers in SLE can be – oral , nasal or skin ulcer S econdary to immune complex-mediated vasculitis. ( Vasculitic ulcer ) However, coexistent prothrombotic states such as antiphospholipid syndrome may also play a role in some patients Venous insufficiency may also play a role in delayed healing in lupus patients

31. Treatment Immunosuppressive therapy – high dose CYC or B cell depleteing agent ( Rituximab or Belimumab ) Treatment with anti-coagulant or anti-platelet if associated secondary APS TIME approach same for Scleroderma ulcers

32. Case 5 50 year old female Presented with breathlessness and dry cough for 4 weeks she also had muscle weekness in lower limb for same duration She had new onset ulcers over both the fingers for last 6 months Examination – diffuse crepitation all over lung , finger ulcers and gangrenous changes Investigation – HRCT chest – NSIP pattern ILD with pneumonitis , Anti MDA5 strong positive , CK – normal Diagnosis – MDA5 dermatomyositis with RP-ILD with cutaneous ulcers

33. Ulcers in Dermatomyositis 3–19 % of DM patients (1,5–7). S ignificant pain and disability at risk for secondary infection. poor prognosis for disease control, as they have been associated with increased resistance of both skin and muscle disease to immunosuppressive therapies (8,9). vary with regards to location and severity. a correlation between cutaneous ulcerations and internal malignancy Narang NS, Casciola -Rosen L, Li S, Chung L, Fiorentino DF. Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease. Arthritis Care Res (Hoboken). 2015 May;67(5):667-72.

34. Location Extensor surfaces overlying joints (particularly over the fingers, elbows, and knees ) Lateral nailfolds or digital pulp, and sun-exposed areas such as the anterior chest and ear helix. M ultiple potential factors – Vasculopathy V asculitis E xcessive inflammation at the interface between the dermis and epidermis E xcoriation in response to pruritus. Associated antibody MDA5 NXP2 MDA5 associated ulcer more prone to RP-ILD and refractory to therapy

35. Work up of ulcers in Dermatomyositis – often a covert sign Laboratory tests: Muscle enzymes , Autoantibodies :   MDA5 , NXP2 Imaging studies - Muscle MRI, chest x ray , CT chest Punch biopsy of an ulcer site:  Endoscopy (esophageal manometry ):  To assess for swallowing difficulties.  Pulmonary function tests Cancer screening tests:  Based on patient risk factors, tests like colonoscopy, mammogram, or prostate-specific antigen (PSA) may be ordered. 

36. T reatment Often refractory to treatment with immunosuppressives agents. Role of Systemic steroids, rituximab, sildenafil, bosentan and botulinum toxin local injection with variable success. limited data on use of MMF and IVIG. PDE5 inhibitors are newly used for vasculopathic ulcer management Jakinibs can be tried in refractory cases

37. Case 5 30 year old male History of recurrent aphthous ulcer in mouth History of uveitis Presented with large painful ulcer over anterior leg for one months On examination – this ulcer was large 10,10 cm with violaceous margin and undermined edge with seroanguinous discharge Investigation – Pathergy positive ESR , CRP raised Diagnosis ? BD with Pyoderma gangrenosum

38. Pyoderma gangrenosum It is a neutrophilic dermatosis resulting in cutaneous ulceration. The lesions have rapid onset and progression with necrotic borders and surrounding inflammation and erythema. inflammatory bowel disease, psoriasis, ankylosing spondylitis , behcet disease

39. Criteria of PG George C, Deroide F, Rustin M. Pyoderma gangrenosum - a guide to diagnosis and management . Clin Med ( Lond ). 2019 May;19(3):224-228

40. Treatment protocol of PG George, C., Deroide , F., & Rustin, M. (2019). Pyoderma gangrenosum – a guide to diagnosis and management. Clinical Medicine, 19(3), 224-228.

41. Case 6 30 year old male Presented with epistaxis , ear discharge He also has new onset ulcers over the dorsum of the hand CT PNS – pan-sinusitis PR3 Antibody positive Diagnosis ? GPA with vasculitic ulcer on hand

42. Case 7 35 year old male History of asthma in past Complaints of purpuric rash on both legs with secondary ulceration Recurrent episodes Complaining paresthesia and weakness of distal leg Investigation – Hyperesoinophilia , Raised ESR and CRP, MPO(ELISA ) – positive Diagnosis ? EGPA with LCV rash with secondary ulceration

43. Case 8 A 67-year-old female History of fatigue, weight loss Generalized livedo racemosa and nodules of the lower leg with secondary ulceration The leg ulcers have been recurring for the last 3 years. Investigation – HBsAg antigen positive , ANCA negative Diagnosis ? PAN with cutaneous ulcer

44. Case 9 A 55 year old female Presented with arthralgia , myalgia Red rash over both legs with secondary ulceration Investigation – Raised ESR , CRP , HCV positive , cryoglobuline positive , low complement Diagnosis ? HCV associated cryoglobulinemic vasculitis

45. Vasculitic Ulcer Pathogenetically, 2 main groups: inflammatory microangiopathy and occlusive microangiopathy . Vasculitic ulcers are mainly found distal to the malleolus in the dorsal region of the foot . They are shallow but can be deep and punched out and normally have intense surrounding erythematous areas.  N ecrotic with marked vascularity with a mixture of red granulation and necrotic tissue on the wound bed

46. Work up Timing of biopsy : from a relatively fresh lesion (within 24-48 hours of appearance ) Biopsy depth: a deep punch biopsy may be needed to adequately sample the affected blood vessels in the deeper layers of the skin.  Extent of the biopsy - at the active edge of the lesion where the tissue has not been destroyed by the necrotic process or in the peri - ulcerative area when new lesions tend to develop Direct immunofluorescence (DIF ): a DIF study may be performed on the biopsy sample to identify deposits of immune complexes within the blood vessel wall

47. Histopathology findings Neutrophil infiltration: Fibrinoid necrosis: Endothelial cell damage: Perivascular inflammation:

48. DIFFERENTIAL DIAGNOSIS OF VASCULITIC WOUNDS/ mimickers Infections associated with vasculitic and chronic wounds ( Hepatitis C , Hepatitis B , NTM ) Sickle cell-associated leg ulcers Infective endocarditis Atrophie blanche or livedoid vasculopathy ( occlusive causes ) Cholesterol emboli Calciphylaxis ( CKD , Hyperparathyroidism ) Cryoglobulinemia APS Prothrombotic state

49. Hydroxyurea indced ulcer Hepatitis C associated ulcer Sickle cell disease ulcer Calciphylaxis ulcer Livedoid vasculopathic ulcer

50. Laboratory testing to investigate autoimmune or prothrombotic states in patients with chronic non-healing wounds ( vasculitis ulcer and mimicker ) Tests Associated conditions ANA , ANA profile , complement (C3,C4) SLE Anti centromere , anti ScL70 Scleroderma SSA, SSB antibody Sjogren disease Anti U1RNP MCTD Myositis specific and associated antibodies , muscle enzymes Inflammatory Myositis RF, ACPA RA ANCA (MPO & PR3 – ELISA ) GPA, EGPA , MPA ACL , Anti B2GP1 , Lupus Anticoagulant APS Prothrombin gene mutaton , Factor V Leiden ,MTHFR mutation , PAI Genetic prothrombotic state Calcium , P, creatinine , urea Calciphylaxis Vascular imaging ( Duplex study , CT or MR angiogram ) Large vessel vasculitis HIV , HEPB ,HEP C , IGRA assay Infective

51. Important points on non-healing vasculitic ulcer All the vasculitis can potentially cause skin ulcers. The patient’s basic circulatory disturbances (atherosclerosis ) are important The associated presence of hyper- coagulable disorders is a predisposing factor to skin ulcers. Cryoprotein -related vasculitis and PAN - higher risk of ulcer formation . Histological confirmation of vasculitis is mandatory. Treatment is similar to other types of ulcers. Surgical debridement must be performed with great attention due to the risk of “ pathergy phenomenon.”

52. Take home points A utoimmune and vasculitic causes should be considered in patients with chronic NHU. NHU can be multi-factorial – arterial , venous , vasculitis or vasculopathic A multidisciplinary approach allows investigation for underlying systemic disease. Meticulous history and physical examination, along with laboratory workup For biopsy of vasculitic ulcer , the team should carefully include reticular dermis and subcutaneous tissue. T.I.M.E approach of local treatment is mandatory Pain control is essential .