CIS School 2007Santa Fe

FATIGUE AND PAIN COMPLAINTS IN AN ADOLESCENT GIRL

J.F. Swart, MD

Fellow Pediatric Rheumatology

Amsterdam/Utrecht, the Netherlands

• 17 yr old Asian ♀

• Medical history:

- frequent febrile convulsion from 1-8 years with

transient use of anticonvulsant drugs

- infectious mononucleosis at 13 years

Spontaneously expressed complaints

• 12 wks of pain in her legs, groins, wrists and back

• Headaches and hyperesthesia of scalp

• Fatigue

• No experienced muscle weakness

• Ibuprofen up to 6 times 400 mg without pain good relief

• 1 week before referral: vomiting and throat pain

1 day fever 102.9° F (=39.4°

C)

Specific anamnesis

• no abdominal pain, abnormal stools

• no weight loss

• no difficulty in swallowing or breathing

• no exercise intolerance

• more irritability

• family history unknown (adoptive parents)

Specific anamnesis part 2

• no irregular periods or macroscopic hematuria

• frequently oral ulcers

• no alopecia, dry eyes or mouth

• no photosensitivity

• a few months before: triphasic purple, white,

red discolorations fingers on cold

Swart ©

Diagnosis RP

1. Are your fingers unusually sensitive to cold?

2. Do your fingers change color when they are exposed to cold temperatures?

3. Do they turn white, blue, or both?

• -RP if all three positive

• -No RP if 2. or 3. negativeBrennan P, Silman A etal.

Br J Rheumatol 1993; 32:357.

Differential diagnosis our patient

• Primary Raynaud Phenomenon (RP) with pain syndrome and fatigue

• Secondary RP with myalgia or myositis (e.g. as seen in SLE, MCTD, dermatomyositis)

Physical examination

• adiposity (weight for length > 2.5 SD)

• RR 102/59 mm Hg

• one ulcer at her lower lip

• no abnormalities in her eyes, skin, nails or joints

• normal auscultation and palpation of her chest,

abdomen, muscles and arteries

• lymph nodes not palpable

Raynaud Phenomenon (RP)

An exaggerated vascular response to cold or stress

Sharply demarcated color changes of digital skin

White and/or blue attack for 15-20 min if rewarmed

On recovery most of the time erythema by reperfusion

Starts in single finger with symmetrical bilateral spread

Digitus II,III and IV most commonly involved

Wigley, F. M. Clinical manifestations and diagnosis of the RP.

UpToDate. 25-8-2006; World Wide Web

• Uncomplicated RP is completely reversible on rewarming

• Mild RP: sensations of needles, numbness, aching or clumsy

• Severe RP: pain or ulceration of the skin

• Prevalence in M 3-13%; in F 5-20%

• Presenting symptom in >90% systemic scleroderma patients

functional

vasodilation vasoconstriction

intrinsic factors extrinsic factors intrinsic factors extrinsic factors

α2c-adrenergic

receptors ↑

Protein Tyrosine

Kinase ↑

Calcitonin Gene

Related Protein ↓

Substance P ↓

NO ↓

Endothelin-1 ↑

Thromboxane ↑

Serotonin ↑Sympathetic NS

(norepinephrine)

Prostaglandins ↓

α1-adrenergic

receptors ↓

Pathogenesis Raynaud phenomenon

In secondary RP there is also structural vessel damage

(e.g. intimal proliferation)

Intrinsic factors for RP1) Thermoregulatory α2c-receptors mostly in digital arteries

2) In cold→Rho-kinases signal to Golgi→ release α2cR

3) Vessel wall reactivity coincides with higher PTK-activity

4) Contractile proteins of smooth muscle ↑ sensitive to Ca2+

Therapeutic use:

Inhibition of α2-receptors: prazosin → moderate effect

Inhibition of α2c-receptors: OPC 28326 → improvement

Inhibition of Rho-kinases: fasudil → improvement

Inhibition of PTK: experiment by Genistein → less reactivity

Inhibition of Ca2+: nifidipine → vasodilation and spasmolytic

C. Sunderkötter etal. Hautarzt 2006

Extrinsic factors• Lower vasodilatatory activity• Calcitonin Gene Related Protein in digital nervefibres ↓• Endothelin↑ → ETA- or ETB-receptors → vasoconstriction• NO and prostacyclin → cAMP and cGMP → vasodilation• Phosphodiesterases break down cAMP and cGMP • Serotonine gives vasoconstriction

Therapeutic use successfull with:• Antagonist of endothelin-receptors• Prostacyclin-derivates• Phosphodiesterase inhibitors• SSRI

C. Sunderkötter etal. Hautarzt 2006

Keep it warm

Primary RP• 76-90% of all RP• Symmetric episodic attacks • No evidence of peripheral vascular

disease • No tissue gangrene, digital pitting, or

tissue injury • Negative nailfold capillary examination • Negative antinuclear antibody test and

normal erythrocyte sedimentation rate

Wigley, F. M. Clinical manifestations and diagnosis of the RP.

UpToDate. 25-8-2006; World Wide Web

Secondary RP• Autoimmune diseases: scleroderma, systemic lupus erythematosus,

MCTD, overlap syndromes, polymyositis, dermatomyositis, rheumatoid arthritis,

Sjögren's syndrome, undifferentiated connective tissue disease, and vasculitis

• Occlusive vascular disease:

arteriosclerosis, atheroemboli, and thromboangiitis obliterans

• Drug-induced: amphetamines, beta blockers,

bleomycin, cisplatin, clonidine, cocaine, cyclosporine, ergotamine, interferon-alpha,

methysergide, nicotine, vinyl chloride, and vinblastine

• Hemorrheologic: Cold agglutinin disease, cryofibrinogenemia,

cryoglobulinemia, paraproteinemia, and polycythemia

• Frostbite

Wigley, F. M. Clinical manifestations and diagnosis of the RP.

UpToDate. 25-8-2006; World Wide Web

Presence of ≥ 1 feature increases likelihood for secondary RP

• Later age of onset (>40 years)• Male gender• Painful severe events with ulceration• Asymmetric attack• RP associated with signs/symptoms of another

disease• Abnormal lab results• Ischemic signs proximal to the fingers• Nailfold capillaroscopy with enlarged or distorted

capillary loops

Wigley, F. M. Clinical manifestations and diagnosis of the RP.

UpToDate. 25-8-2006; World Wide Web

Evaluation• Always thorough history, physical examination

including nailfold capillaroscopy• If a moderate suspicion of secondary RP:

Complete blood count

General blood chemical analysis

Rheumatoid factor

Complement (C3 and C4)

ANA (if positive also ENA)Wigley, F. M.

Clinical manifestations and diagnosis of the RP. UpToDate. 25-8-2006; World Wide Web

Figure 4. "Late" scleroderma pattern: severe capillary architecture disorganization with loss of capillaries, presence of ramified and enlarged capillaries, absence of giant capillaries, few hemorrhages     

Figure 3. "Active" scleroderma pattern: frequent giant capillaries and hemorrhages, moderate loss of capillaries and disorganization of capillary architecture, absent or mild ramified capillaries (magnification 200x)

Figure 1. Normal nailfold videocapillaroscopy pattern (magnification 200x)

Figure 2. "Early" scleroderma pattern: well preserved capillary architecture and density, presence of enlarged capillaries, giant capillaries and hemorrhages (magnification 200x)

Cutolo M, Sulli A,

Pizzorni C.

Division of Rheumatology

University Genova, Italy

From Pictorial essays,

EULAR 2001

S. Pavlov-Dolijanovic.

Pediatric Dermatology 2006

laboratory tests in our case• Haemoglobin 10.6 g/dl (6.6 mmol/l ), thrombocytes

345* 109/l, Leucocytes 3.8* 109/l: lymphocytes 0.80*

109/l, neutrophils 2.5* 109/l, ESR 116 mm/ hr

• CRP 21 mg/l, Creatinin 64 µmol/l, electrolytes and

liver-enzymes normal, CPK 672 U/l, LDH 600 U/l,

Aldolase 9.0 U/l (normal -7.6)

• Direct Coombs negative, clotting normal, anti-

phospholipids negative and VWF antigen 457%

(normal -130%)

• TSH 1.1 IE/l, fT4 18 pmol/l

• Urine: normal sediment, no protein

immunology tests

• IgM 0.97 g/l, IgA 2.64 g/l, IgG 21.3 g/l

(normal -16.0), rheumafactor not performed

• ANA was positive (titre 1:1000)

• ENA: positive anti-SmB, anti-RNP-70K, anti-

RNP-A and anti-RNP-C

• anti-ds-DNA 1 U/ml

Imaging & function tests• An X–ray of the chest normal

• MRI of the brains normal

• Lung-function including CO-diffusion normal

• ECG and ultrasound of the heart normal

• Childhood Myositis Assessment Scale 90% of normal

manual dynamometry overall -1.5 SD flexors

of the hip << -2 SD exercise

tolerance << 10th percentile

Criteria according to Kasukawa Disease category Symptom

polyarthritis lymphadenopathy malar rash/ facial erythema pericarditis or pleuritis

SLE

thrombocytes < 100 109/l or leukocytes < 4,0 109/l sclerodactyly longfibrosis or restrictive lungdisease (VC <80%) or CO-diffusion <70%

progressive systemic sclerosis

oesophageal hypomotility or dilatation muscle weakness elevated serumlevels of myogenic enzymes polymyositis myogenic pattern on EMG

MCTD criteria are met in case of Raynaud phenomenon or presence of swollen hands or fingers or positivity for anti-U1 snRNP- antibodies and at least 1 symptom in 2 of 3 disease categories Kasukawa, R.

Excerpta Medica. 1987

Criteria for MCTD according to Kasukawa

Diagnosis and treatment

• mixed connective tissue disease (MCTD)

• treated with prednisone for a few weeks in a dosage of 1 mg/kg/d

• her myositis and anaemia resolved quickly

• she is more fit and has no more pain

• steroids are being tapered.

Conclusion

• Fatigue and pain might be presenting symptoms of an auto-immune disorder

• In case of Raynaud Phenomenon be alert for underlying diseases