Rheumatology / Hematology

40-year-old man referred from General Internal Medicine (GIM) for new painful itchy burning red bumpy rash primarily on arms and legs. It heals with pigmentation and is worse in the cold. There is leg numbness and tingling for a few months. He is feeling tired with joint pain in his hands and feet. He is constitutionally unwell.

Take a History.

• Onset of symptoms and progression (better, worse, stable)

• Description of the rash (raised, flat, pruritic, painful, red, brown, purple)

• Distribution of the rash

• Other trigger than the cold?

• Treatment and response

• Joint pain, swelling, morning stiffness, does activities makes pain better or worse?

• Distribution of the joint involvement (migratory?)

• Other neurologic symptoms: wrist or foot drop

• Systemic symptoms (fever, fatigue, weight loss), Raynaud symptoms,  photosensitivity, sicca symptoms (dry eyes, mouth). 

• ROS: lumps or bumps, respiratory, GI, GU (hematuria, foamy urines)

• PMX (known HBV, HCV, HIV, hem malignancy, past blood transfusion)

• RX

• Immunization

• FMX

• SHX, occupation, hobbies, travel, T/A/D (IV drugs), risks factors for HIV.

40-year-old man referred from General Internal Medicine (GIM) for new painful itchy burning red bumpy rash primarily on arms and legs. It heals with pigmentation and is worse in the cold. There is leg numbness and tingling for a few months. He is feeling tired with joint pain in his hands and feet. He is constitutionally unwell.

What do you look for on exam? 

• Weight. TA. General appearance. 

• Respiratory.

• Abdo: HSM

• Inguinal areas.

• Edema on lower extremities.

• Joint exam looking for arthritis. 

• Skin: palpable purpura. Ulcers. Necrosis. Livedo reticularis. Needle tracks.

• Nails (abnormal nail fold capillaroscopy - scleroderma, dermatomyositis etc.).

• Neuro: sensorial and motor (EGPA etc.).

40-year-old man referred from General Internal Medicine (GIM) for new painful itchy burning red bumpy rash primarily on arms and legs. It heals with pigmentation and is worse in the cold. There is leg numbness and tingling for a few months. He is feeling tired with joint pain in his hands and feet. He is constitutionally unwell.

Told has palpable purpura, no neurologic deficits, has tattoos. What is the differential? DDX:

• Cryoglubulinemia - with purpura, numbness/tingling, lesions to buttocks/lower extremities, triggered by cold

  • Infection - in the context of chronic HCV with tattoos

  • B cell lymphoproliferative disease

  • Autoimmune diseases

  • Essential cryoglobulinemia

• Autoinflammatory / Schnitzler syndrome with fever, urticaria, monoclonal gammopathy

• Urticarial Vasculitis if bruising, systemic Sx, rheumatologic fx on exam

• Drug induced vasculitis, or SSS

• Dermatomyositis

40-year-old man referred from General Internal Medicine (GIM) for new painful itchy burning red bumpy rash primarily on arms and legs. It heals with pigmentation and is worse in the cold. There is leg numbness and tingling for a few months. He is feeling tired with joint pain in his hands and feet. He is constitutionally unwell.

Told has palpable purpura, no neurologic deficits, has tattoos.

Shown a picture of multiple purpuric plaques and asked “is this contact dermatitis”? Why or why not?

No, purpuric plaques is suggestive of vasculitis and not typical findings or history for contact dermatitis. Would not explain the exacerbation with cold, numbness/tingling, joint pain or fatigue.

40-year-old man referred from General Internal Medicine (GIM) for new painful itchy burning red bumpy rash primarily on arms and legs. It heals with pigmentation and is worse in the cold. There is leg numbness and tingling for a few months. He is feeling tired with joint pain in his hands and feet. He is constitutionally unwell.

Told has palpable purpura, no neurologic deficits, has tattoos.

Shown a picture of multiple purpuric plaques. What investigations do you order?

• CBCd 

  • anemia, leukocytosis, thrombocytopenia that might suggest systemic inflammation, infection or hematologic ddx for purpura

• Renal and liver function.

  • organ involvement in vasculitis, including cryoglobulinemia or viral hepatitis

• Urine analysis (hematuria, proteinuria).

  • glomerulonephritis in small-vessel vasculitis with kidney involvement

• Rheumatoid factor.

  • can be positive in mixed cryoglobulinemia and some other vasculitidies

• C3, C4.

  • low complement supports an immune complex-mediated vasculitis (e.g. cryoglobulinemia, urticarial vasculitis)

• HBV & HCV serology.

  • Viral hepatitis can drive cryoglobulinemic vasculitis and other secondary vasculitidies.

• HIV.

  • infectious trigger for vasculitis or immunologic skin disease

• Cryoglobulins.

  • to diagnose cryoglobulinemia causing palpable purpura, neuropathy, arthralgias.

  • Cryoglobulinemia worsens with cold exposure.

• ANA

  • screen for underlying systemic autoimmune disease including lupus-associated vasculitis.

• ANCA

  • screen for ANCA-associated small vessel vasculitis (GPA, EGPA, etc.)

• Protein electrophoresis

  • look for monoclonal gammopathy (type 1 cryoglobulinemia, Schnitzlers syndrome) or paraprotein-related vasculitis

• Consideration for skin biopsy in collaboration with dermatology

  • confirm leukocytoclastic vasculitis and evaluate for immune complex deposition (e.g. IgA complement) to define type)

40-year-old man referred from General Internal Medicine (GIM) for new painful itchy burning red bumpy rash primarily on arms and legs. It heals with pigmentation and is worse in the cold. There is leg numbness and tingling for a few months. He is feeling tired with joint pain in his hands and feet. He is constitutionally unwell.

Told has palpable purpura, no neurologic deficits, has tattoos.

Shown a picture of multiple purpuric plaques.

Investigations given, showing RF+, anti-HCV+, ANA-, ANCAs-, cryoglobulins negative. (no comment on cryofibrinogens). 

What is the diagnosis?

Mixed cryoglobulinemic vasculitis due to chronic HCV infection. Or type 2 cryoglobulinemia. 

• systemic symptoms 

• palpable purpura worsened by cold 

• RF (+) 

• peripheral neuropathy 

• anti-HCV positivity 

• Cryoglobulin negative is likely negative from poor handling, needs special handling (warm collection, cold processing), often wiht false negatives**  

Hepatitis C is the leading cause of mixed cryoglobulinemia. 

Cryoglobuulins are often immunoglobulins with RF activity. ANA/ANCA negative excludes other vasculitides. 

You diagnose type 2 (mixed - infectious, vs type 1 - monoclonal) cryoglobulinemia, what do you recommend in terms of treatment? (patient had peripheral necrosis).

If MILD disease (arthralgias, myalgias, non-necrotic purpura, or purely sensory neuropathy)

• Avoid cold exposure

• Direct antiviral agents often sufficient

• ± short-term, low-dose glucocorticoids (≤0.5 mg/kg/day)

If MODERATE disease

• Avoid cold exposure

• Direct antiviral agents

• ± Rituximab (IgGAM, vaccine titres first!)

• pulse short-term, low-dose glucocorticoids (≤0.5 mg/kg/day)

• ± Colchicine, Methotrexate

If SEVERE disease - glomerulonephritis with impaired renal function, motor deficits, multiple mononeuropathy, extensive skin necrosis, or involvement of digestive, cardiac, or pulmonary systems

• Avoid cold exposure

• Antiviral agents, supress B-cell proliferation driving cryoglobulinemic vascuclitis

• Rituximab (IgGAM, vaccine titres first!)

• Cyclophosphomide

• life-threatening cases - high-dose glucocorticoids (0.5–1.0 g methylprednisolone for 3 days, then tapering oral steroids)

• life-threatening cases - Apheresis/Plasma exchange

• Pain management

• Immunization pre rituximab.

Vs type 1 assoc with monoclonal protein, more suggestive of underlying hemolytic malignancy

Patient with likely type 2 (mixed) cryoglobulinemia with chronic HCV infection. Cryoglobulins were negative.

What do you make of the negative cryoglobulins in diagnosis of cryoglobulinemia?

• Very delicate technique of blood collection where tubes have been rewarmed without anticoagulants.

• False negative results if protocol is not followed closely.

Patient with likely type 2 (mixed) cryoglobulinemia with chronic HCV infection. Disclose new positive hep C status to patient.

• Ensure proper setting (private environment, enough time ahead).

• Ask if anyone else they would like to have present for conversation.

• First verify patient understanding of his clinical situation.

• Disclose honestly and clearly the diagnosis.

• Allow time to digest the informations.

• Ask what he wants to know and answer questions.

• Consider having ID also involved in discussion as a multidisciplinary approach to ensure patients questions can be answered.

• Offer to help disclose the diagnosis to the family (if he wishes too).

• Ensure close follow up to answer questions that might have arise after the initial conversation.

GPA suspected. What investigations do you consider?

• CBCD

• Electrolytes, BUN, Creat, LFTs

• ESR, CRP.

• ANCA - PR3 - MPO

• Other:

  • liver function tests

  • C3, C4

  • ANA

  • anti-GBM antibodies

  • cryoglobulins

  • HBC, HCV, HIV

  • TB

  • blood cultures

• Urine analysis with urine sediment.

• CXR

• CAT-Scan chest +/- sinus.

• PFTs.

• Tissue biopsy depending on involved organs.

Patient with GPA, has active urinary sediment (RBC casts) and nodular changes on CXR. What is approach to treatment? 

• Hospital admission for induction, rapid progression without treatment and high mortality within months.

• Induction: Steroids 1 mg/kg/day x1 month, with slow taper over 6+ months + Rituximab (or cyclophosphamide but more a/e)

• MultiD - Rheum, Nephro, Resp

• Maintenance Tx: rituximab or azathioprine, MMF, methotrexate.

Patient with HIV, HCV and hemophilia. On x5 antiviral medications. Presents with arthralgias, rash and mononeuropathy. You suspect cryoglobulinemia with HCV/HIV. 

How do you treat cryoglobulinemia? 

Treat underlying disease - optimize HCV treatment with ID 

Then treat Cryoglobulinemia

• Avoid cold trigger

• Mild disease - antivirals

• Mod-Severe: short course steroids (low-high dose depending on severity), + rituximab +/- plasmapheresis 

• Pain control

Patient with recurrent infections. Turns out to be MGUS causing low immunoglobulins.

What is the diagnostic criteria for MGUS, smouldering and MM?

MGUS = Monoclonal gammopathy of undetermined significance

• M-protein level (serum monoclonal protein) = < 30 g/L

• Bone marrow clonal plasma cells = <10% 

• NO CRAB Biomarkers for myeloma 

Smouldering Multiple Myeloma (SMM)

• M-protein (serum monoclonal protein) = ≥ 30 g/L and/or..

• Bone marrow clonal plasma cells = 10-60% 

• NO CRAB Biomarkers for myeloma 

Multiple Myeloma 

• M-protein level (serum monoclonal protein) = any

• Bone marrow clonal plasma cells = ≥10% clonal plasma cells, or biopsy proven plasmocytoma

• PRESENT CRAB Biomarkers for myeloma, or Myeloma defining biomarkers

CRAB Features for symptomatic MM

• C – Hypercalcemia: Ca > 2.75 mmol/L (> 11 mg/dL)

• R – Renal impairment: CrCl < 40 mL/min or Cr > 177 µmol/L (> 2 mg/dL)

• A – Anemia: Hgb < 100 g/L or > 20 g/L drop from baseline

• B – Bone lesions: lytic lesions, osteoporosis with fractures (CT/MRI/PET helpful)

Myeloma-Defining Biomarkers (any one = active MM)

• Bone marrow clonal plasma cells ≥ 60%

• Serum involved:uninvolved free light chain ratio ≥ 100
  and involved FLC ≥ 100 mg/L

• >1 focal bone lesion ≥ 5 mm on MRI

Hypogammaglobulinemia is possible in MGUS due to:

• Immuneparesis from monoclonal clone suppressing normal Ig production

• Even without large marrow infiltration

What is the recommended treatment for MGUS?

• Monitoring only 

• Referral to hematology for further advice

Quick Pearls…

• MGUS → premalignant, low risk progression (~1% per year, but 30-40% in lifetime)

• SMM → intermediate; higher risk of progression (~10% per year early on)

• MM → requires therapy due to organ damage or biomarkers

IgG4 disease.

List x3 clinical features.

Summarize the diagnostic criteria.

Clinical Features:

• Often painless

• Middle aged, M>F

• Organ manifestations with mass-like enlargement

• Dense lymphoplasmocytic infiltrates on histology

• Tissue rich in IgG4+ plasma cells (can have FP and FN IgG4 screening, not diagnostic alone)

• Multiorgan involvement potential:

  • Pancreas

  • sclerosing cholangitis of the biliary tract

  • painless swelling of lacrimal glands

  • retroperitoneal fibrosis, tubulointerstitial nephritis

  • lymphadenopathy

  • inflammatory aortic aneurysms.

• Diagnosis can be considered by steroid trial once malignancy is ruled out. Mimics malignancy, but STEROID RESPONSE IS COMMON. 

28yo F with nephritis and a recent nosebleed. What x2 tests can help diagnose?

1 - Biopsy of the affected site, e.g. kidney with pauci-immune vasculitis (kidney, sinus, lung, skin). 

2- Bloodwork

• CBCd with eosinophilia

• ± cANCA with PR3 (order DIF and ELISA) = GPA 

• ± pANCA w MPO = EGPA (<60%), also can be + in GPA

Clinical characteristics of Granolomatosis with Polyangiitis (GPA) versus Eosinophilic Granolomatosis with Polyangiitis (EGPA). 

GPA = Sinus Disease (95%) + Lung Disease (85%) + Kidney Disease (80%)

• Affects adults, M=F

• Small-medium vessel vasculitis

• Systems involved

  • Sinuses - ulceration, cobbelstoning, septal perforation, saddle nose deformity

  • Pulmonary - Pulmonary nodules, lower lobe cavitary lesions, pulmonary hemorrhage

  • Kidneys - moreoften Asx but can lead to progressive renal failure

• ± cANCA associated with PR3 (proteinase 3), some have ± pANCA also

EGPA = Lower lung disease most common fx / Asthma + + Sinus disease = Neuropathy (mononeuritis multiplex) + Peripheral eosinophilia >1500/uL

• Most with preceeding Asthma/AR

• affects all ages, M=F

• Systemic vasculitis later in disease affecting the nerves, lung, heart, GI tract, kidneys 

• ± p-ANCA (+), ± MPO-ANCA (+) (<40-60%)

Both can have systemic Sx, fever, fatigue, weight loss, etc.

Diagnosis of GPA versus EGPA

GPA = Clinical Sx x3 for G.P.A x 3 letters (sinus ulceration/saddle nose, lung and kidney disease + more likely to bleed)

• ± cANCA associated with PR3

  • can also have pANCA or be seronegative!  

• Histology with neutrophilic microabscesses rimmed by granulomas and multinucleated giant cells with small-medium vessel vasculitis.

EGPA = Clinical Symptoms x4 for E.G.P.A x4 letters (sinus dz ± preceeding AR, asthma/lower airway predominant dz ± preceeding asthma, neuropathy mainly mononeuritis multiplex, and eosinophils >1500/uL) 

• ± MPO-ANCA, ± p-ANCA (<60%) 

• Eosinophilic granulomatous small vessel necrotizing vasculitis

• Histology with eosinophilic infiltrates, extravascular granulomas and small vessel necrotizing vasculitis 

List diseases associated with

1. c-ANCA 

2. p-ANCA

ANCA in general is (+) in virtually all systemic rheumatologic disease, <80% of ulcerative colitis and sclerosing cholangitis, and in drug-induced ANCA-associated vasculitis (moreoften pANCA+MPO). 

1. c-ANCA + PRS-ANCA (+) 

   1. GPA - <90% 

   2. Infection, subacute bacterial endocarditis

2. p-ANCA + MPO-ANCA (+) is less specific**

   1. EGPA - <60-80%

   2. GPA - <10%

   3. Microscopic polyangiitis (MPA) - <80%

   4. Autoimmune hepatitis 

   5. Ulcerative colitis

Clinical features of sarcoidosis

• who gets it 

• common sx 

• syndromes associated with more distinct phenotypes

1/3-2/3 may be asymptomatic

identified on routine CXR

More common in women, African-American

• 90% with lung manifestations - chronic non-productive cough, dyspnea with exertion, obstruction, hyperreactivity, chest pain, bronchiectasis

  • decreased DLCO over time with fibrosis in late stage disease

• uveitis

• neurologic involvement

• erythema nodosum 

• hypercalcemia

• bilateral hilar adenopathy

• extrathoracic lymph node involvement 

• BSx: fever, weight loss, fatigue 

• LOFGREN SYNDROME 

  • bilateral ankle arthritis

  • erythema nodosum 

  • bilateral hilar lymphadenopathy 

  • fever

• HEERFORDT SYNDROME (less common) 

  • parotid enlargement 

  • bilateral uveitis 

  • facial palsy 

  • fever 

Diagnosis of sarcoidosis

Diagnosis of exclusion - rule out… 

• infection - TB/mycobacteria/etc.

• immune mediated dx 

• berylliosis (environmental/occupational exposure, if unsure, berylliosis lymphoproliferation test to r/o)

• hypersensitivity pneumonitis 

• Blau syndrome (NOD2) - presents more in childhood, with uveitis, skin rash, arthritis

• neoplasm

ELEVATED CD4/CD8 ratio >4 has a 100% positive predictive value, separating sarcoidosis from other forms of ILD

ACE level elevated in 2/3 (affected by ACEi and steroids)

44yo female - Investigations to send in case of patient with recurrent fever, ankle arthritis, dry cough and dyspnea with exertion.

CBCd

CRP

LFTs, RFTs

Serum calcium hypercalcemia in sarcoid

Flow for ^^CD4:CD8 ratio (>4)

BAL for flow even better, for ^CD4:CD8 ratio (>4)

ACE ^ in 2/3

ANCA-MPO/PR3

Chest X-Ray

PFT with Plethsomnography (DLCO decreased)

ECG

Optho exam ?uveitis in Sarcoid/GPA/EGPA/etc

IGRA ?TB vs mycobacterial infection 

± Chest CT

prognosis of sarcoidosis 

Up to 2/3 have remission of disease

Lofgren’s generally with good prognosis (erythema nodosum, bilateral hilar adenopathy, ankle arthritis and fever) - Manage supportively 

treatment for sarcoidosis 

Respiratory disease somewhat improved with oral steroid 

Prednisone 20-40mg daily x1-3 months, sometimes over 3-24 months ± higher doses for more severe disease

• SLOW taper over 12 months

Antimetabolites - methotrexate / azathiprine if severe or unable to tolerate steroid

third line, no compelling evidence, but for refractory cases = Biologics - Infliximab / antiTNFa