Clinical case 1

A 53-year-old male was referred to your clinic because of six months history of bilateral pain of wrists and
metacarpo-phalangeal (MCP) joints and of the left ankle, associated with morning stiffness of 20 minutes. The physical
examination revealed mild swelling of left ankle; both erythro-sedimentation rate (ESR) and C-reactive protein (CRP)
were increased (58 mmh and 23.4 mg/L, respectively), while high levels of rheumatoid factor were detected in the serum
(638 U.I). Finally, hepatic and renal functions were normal.

1. Which one of the following therapeutic and diagnostic approaches is the most appropriate?
a. The patient almost certainly has early rheumatoid arthritis and its useful to prescribe a DMARD as soon as
possible
False. although the patient has rheumatoid factor, the asymmetric swollen of joints and the involvement of the ankles
suggest also other possible conditions.
b. Wait and see
False. it is better to perform other diagnostic procedures because it is possible that this patient may present an early but
progressive polyarthritis
c. A symptomatic therapy (NSAID and/or low-dose steroids) can be prescribed and more diagnostic procedures should
be performed
True.

2. Which other four diagnostic procedures would you like to perform (four correct)?
a. Anti-cyclic citrullinated peptides
True. because anti-CCP positivity could orient towards an early rheumatoid arthritis
b. Complement C3/C4
False. The dosage of complement factor can be useful when a HCV related arthritis is suspected. Otherwise, in absence
of signs of vasculitis it is a second line investigation.
c. Hand X-rays
True. After 6 months X-ray should show bone erosions. However, it is useful as baseline for next re-evaluations.
d. HCV antibodies
True. Despite some studies showed a low cost-effectiveness for HCV and HBV screening in recent onset arthritis,
hepatitis C virus can be responsible for oligo- or rheumatoid like arthritis
e. Genotyping (assessment of HLA-DR alleles)
False. HLA typing doesnt add any useful information
f. Involved joints and metacarpophalangeal joints ultrasonography
True. Ultrasonography is useful to confirm the capsular swelling, to observe rheumatoid pannus and power Doppler
signal. In rheumatoid arthritis a synovitis can be frequently observed in subclinical involved metacarpophalangeal joints.
Anti-CCP and antinuclear antibodies were negative, ANA positive 1/160 with homogeneous pattern; within normal limits:
alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, -glutamyl transferase, serum proteins.
The C3 fraction of complements was slightly reduced (88 mg/dl), while C4 was markedly reduced (3 mg/dl). The X-rays
of hands, wrists and knees excluded both bone erosions and calcifications. Virological tests for HBV, HIV, adenoviruses,
and Parvovirus B19 were negative, while serum anti-HCV antibodies were present. Ultrasonography showed mild

distension of the ankle, without power Doppler signal. The MCP joints were normal.
3. What do you think about these data (three correct)?
a. The absence of anti-CCP virtually exclude the diagnosis of rheumatoid arthritis.
False. approximately 15-20% of patients with RA are anti-CCP negative
b. Further investigations should be performed to exclude a Sjgrens syndrome
True. Yes, a Sjgrens syndrome can appear with non-erosive oligo-arthritis. The rheumatoid factor and the
reduction of C4 fraction of the complement can be observed in Sjgrens syndrome. Further clinical analysis to
investigate about the presence of sicca syndrome should be performed.
c. Although X-rays are normal and anti-CCP is absent it is possible a diagnosis of early rheumatoid arthritis
False. The diagnosis of early rheumatoid arthritis is improbable, while ultrasonography shows no involvement of MCP
joints and the absence of power doppler signal in involved joints.
d. ANA negativity doesn't exclude an autoimmune disease
True. ANA can be negative in a low percentage of connective tissue diseases, and in a lot of vasculitides
e. Anti-HCV Ab positivity is not very important because liver function is normal
False. A high percentage (more than 30%) of HCV-infected patients exhibits no liver enzyme elevations, while joint
involvement is.
f. Isolated very low C4 and serum RF strongly positive suggest the search for cryoglobulins
True. these data strongly suggest the diagnosis of cryoglobulinemia
The presence of isolated very low C4, HCV antibodies and high levels of RF in the serum suggests the search for mixed
cryoglobulins.
4. Which three of the following statements about the preliminary methodological approaches in detecting and
analysing serum cryoglobulins is true?
a. The isolation of serum for cryoglobulin detection should be performed in the same place where the blood is sampled
True. This would be the best method to use.
b. Blood sampling, clotting, and serum separation by centrifugation should be always carried out at 37C
True. Storage at 37 is the best option when it is not possible to perform the cryoglobulin detection in the same place
where the blood is sampled
c. Clotting, and serum separation by centrifugation should be always carried out at +8C
False. Its important to perform pre-analytical cryoglobulin detection at 37C to avoid losing cryoglobulins
d. The presence of cryoglobulins should be evaluated in the serum sample stored at +4C, after 7 days
True.
The search for cryoglobulins is positive: cryocrit 3%
5. Do you need more details? What is important to know about this aspect (one correct)?
a. It is sufficient to know that cryoglobulins are present
False. The cryoglobulin composition is useful to confirm the diagnosis of mixed cryoglobulinaemia and to exclude some
haematologic disorders
b. Ig composition of cryoglobulins
True. Type II and III are the more frequently associated to cryoglobulinaemic syndrome. Type I is frequently related to
multiple myeloma, Waldenstrm disease or other lymphoproliferative disorder.

The cryocrit was 3% with type II cryoglobulins (monoclonal IgM k + polyclonal IgG). After 3 months the patient showed
purpura at the lower limbs bilaterally. Pain and swelling of proximal interphalangeal joint of the third finger of the right
hand was reported, mild swelling of wrists, knee and left ankle was referred, too.
6. Which of the following symptoms you could expect in this patient (three correct)?
a. Bone erosions to X-rays
False. In HCV related arthritis and mixed cryoglobulinaemia arthritis is usually not erosive
b. Paresthesias at the first 3 fingers of the hands
False. This symptom suggests a carpal tunnel syndrome
c. Paresthesias on the legs, with stocking-socks distribution
True. Sensitive neuropathy has commonly a stocking-socks distribution in mixed cryoglobulinaemic syndrome
d. Presence of purpura below the knee
True. Purpura is usually present at the legs, more frequently below the knee
e. Presence of purpura on the shoulders
False. No, purpura is usually orthostatic, whit prevalent distribution to lower limbs
f. Sensation of sand, foreign body, burning or pain in the eyes
True. Yes, sicca syndrome is frequently associated to HCV-related mixed cryoglobulinaemia
g. Fever
False. No. Fever is not typical for mixed cryoglobulinaemia
h. Cough and dyspnoea
False. No, cough and dyspnoea are usually referred in patients with interstitial lung disease. A subclinical alveolitis has
been described in cryoglobulinaemic syndrome, but cough and dyspnoea are rare.
In the next months the patient developed a typical mixed cryoglobulinaemic syndrome, with weakness, paresthesias with
glove and sock distribution. He referred appearance of multiple, reddish-brown, 1-3 mm macules extending from the
knee down to ankles, with restitutio ad integrum within some weeks.
7. What of the follows investigations will be in the follow-up schedule (three correct)?
a. Clinical and routine laboratory tests (blood chemistry, liver and kidney function) examination every 3-6 months
True.
b. Abdominal ultrasonography every year
True. to evaluate liver parenchyma, spleen and abdominal lymph nodes
c. Heart ultrasonography every year
False. Heart involvement described in cryoglobulinaemic syndrome, but it is very uncommon.
d. Bone marrow biopsy every 2 years
False. A bone marrow biopsy is requested only when a lymphoproliferative disorder is suspected
e. Complement C3/C4 every 3-6 months
True. A reduction of C4 may be associated with active disease, while abnormally increased levels of complement may
be an early manifestation of complicating lymphoma
f. Cryocrit every 3-6 months
False. Cryocrit is poorly related to clinical manifestations. On the contrary, cryoglobulins typing could be useful to

early identify a lymphoproliferative disorder

g. Electro-neurophysiological study on arms and legs every 6-12 months
False. A Electro neurophysiological study has to be performed only when a sensory/motor neuropathy is suspected
Clinical case 2
A man of 40 years old was hospitalized for purpura, lower limbs oedema, asthenia and arthralgia. Before this
hospitalization, he was followed for psychotic disorders controlled by chlorpromazine.
At the examination, blood pressure was of 150/94 mmHg, and heart rate of 95/mn. He presented purpura of the lower
limbs and oedema; Knees and ankles joints were painful without signs of synovitis. Neurological examination was
normal.
Laboratory investigations revealed the following abnormalities: anemia (haemoglobin 10,5g/dl), thrombocytopenia
(105000/mm3), CRP 120 mg/l, alanine aminotransferase 54IU/L, alkaline phosphatase 105UI/L, bilirubin 13 mol/l,
creatininemia 240mol/l. Prothrombin time 99%.
Immunological analysis showed: cryoglobulinemia 0,48 g/l (IgM Kappa), rheumatoid factor activity and decreased C4
serum level. Antinuclear antibodies, ANCA, and anti DNA antibodies were negative.
Hepatitis C virus (HCV) serology was positive but those of HIV and hepatitis B virus were negative. HCV genotype was
of type 3 and HCV RNA PCR of 5,4 log. The Fibrotest shows a METAVIR score of A1-F1.
Urinary analysis showed haematuria and 2g/24h of proteinuria.
Histological findings of renal biopsy showed membranoproliferative glomerulonephritis.

1. What is your therapeutic option for this patient with HCV-MC vasculitis?
a. Rituximab and antiviral therapy
True.
b. Rituximab alone
False. we have also to eradicate HVC with antiviral treatment
c. Antiviral therapy alone
False. this is a severe MC vasculitis requiring Rituximab therapy
d. Peg interferon, ribavirin and steroids
False. steroids alone are not as efficient as rituximab

2. Why did you choose this treatment ?

a. Rituximab is indicated because there are criteria of vasculitis severity (kidney involvement)
True. renal involvement, severe neuropathy are criteria of severity of vasculitis and warrant treatment with rituximab
b. Rituximab is indicated because it is always recommended for HVC-related mixed cryoglobulinemia
False. rituximab is recommended only in case of criteria of severity
c. Antiviral therapy because rituximab is not indicated for this patient
False.
d. Both treatments are indicated because they are synergic and this association is more efficient on renal involvement
and decreases the delay of clinical response
True.

3. In which two cases are antiviral treatments strictly forbidden?

a. Uncontrolled depression
True.
b. Cirrhosis
False.
c. Mild thrombopenia
False.
d. Pregnancy
True.
e. Hypertension
False.

4. Which parameters do you have to monitor during follow up?

a. Troponin
False.
b. HCV PCR
True.
c. TSH
True. to follow treatment tolerance
d. Cryoglobulin and C3, C4 and CH50
True. to follow immunological response
e. Lipid analysis
False.
f. AAN
False.

5. What are the main side effects of antiviral therapy?

a. Dyslipidaemia
False.
b. Cytopenia (anaemia, thrombopenia, neutropenia)
True.
c. Granulomatosis with Interferon
True.
d. Renal insufficiency
False.

Twelve weeks after the beginning of treatment, purpura, asthenia and arthralgia disappeared, PCR HCV was negative
and renal function became normal. Cryoglobulin disappeared. However, 12 months after treatment the patient relapsed
with skin ulcers and renal involvement.
6. Regarding relapses, what two propositions are true?
a. Relapses occur mainly after reconstitution of B cells (6 to12 months after rituximab)
True. relapse usually occur at the time of B cell reconstitution in up to 35% of cases
b. Relapses of vasculitis are often associated with a virologic relapse
True.
c. Relapses never occur despite eradication of HCV
False. it can occur, notably in case of refractory B cell clone s producing cryoglobulin and sometimes associated with an
overt B cell lymphoma
d. In non responder patients to antiviral therapy with vasculitis relapse, rituximab is not more efficient than other
immunosuppressants
False. Rituximab is more efficient
Relapse occurred despite persistent negative HCV RNA and skin ulcers persisted despite rituximab therapy.
7. What two propositions are true?
a. The presence of a malignant B cell lymphoma may be associated with relapse of cryoglobulinaemia vasculitis without
HCV virological relapse
True.
b. High dose steroids is the only therapeutic option in this case
False.
c. Rituximab is always efficient in skin lesions of MC vasculitis
False.
d. Plasmapheresis may be useful to control the vasculitis
True.