SLE: The Challenge Continues..!

Hani Almoallim

MBBS, ABIM, FRCPC(IM&Rheum),DipMedEd(Dundee)Assistant Professor, Umm Alqura University, MakkahConsultant of Internal Medicine and Rheumatology, KFSHRC, Jeddah

Grand Round 29/10/2008

SLE is a challenging disease..!!!

Challenge of clinical presentation.

Challenge of diagnosis.

Challenge of treatment.

Challenge of severe lupus: high mortality!

Outline

Case presentation Discussion

Case presentation Discussion

Case presentation

A 65 y female

A month history of progressive weakness, numbness of lower limbs and unsteady gait.

loss of bowel and bladder control.

On the day of presentation she was suddenly unable to stand from sitting position.

intermittent history of fever but no weight loss, or night sweat, headache, vomiting and no seizure activity.

No history of recent infections.

Case presentation

Examination:

Conscious, alert and oriented.

Temp. 38.0 °C, H.R 123, B.P 155/80 mmHg and R.R18 with 98% O2.

CN: unremarkable.

Motor examination: hypotonia in the lower limbs with power of 0/5, absent reflexes and down going planter responses bilaterally.

There was loss of all sensation up to the nipples at the level of T4.

Upper limbs: unremarkable.

Case presentation

WBC 17.50×103/L, lymphopenia 11.6%, Hb 150 g/L, plat 203×103/L

ESR:59.

CSF: WBC 371x106/L, 75% lymphocyte, glucose 5.5 mmol/L, protein1419 mg/L, negative cultures for all bacteria and viruses including acid fast bacilli with PCR technique.

Urine culture: positive for E.coli.

MRI & MRA:

MRI of the cervical spine sagittal view, T2 weighted scan showing; mild cord compression at the C3-4 level (black arrow), the C6-7 level demonstrates a small disc centrally (white arrow). Hyperintensity is observed within the cord.

Case presentation

Lupus anticoagulant: positive.

IV pulse: methylprednisolone (MP) (1gram) X 5 days and IV ceftriaxone.

Power 0/5 to 3/5 in lower limbs.

The CSF analysis showed normal protein of 363mg/L, glucose of 3.4 mmol/L and WBC of 272x106/L with mainly lymphocytes.

2/52 power 0/5 again!

The repeat MRI:

MRI of the thoracic spine sagittal view T1 weighted post gadolinium image showing some multifocal areas of enhancement within the cord. It predominantly involves the posterior aspect of the cord (black arrows). There are also extensive focal small enhancing lesions (white arrows).

Case presentation

The suspicion of tuberculous myelitis was raised and the patient was started on anti-tuberculous medication following ID consultation.

Case presentation

Rheumatology consultation:

no joints pains, no morning stiffness

O/E: butterfly rash sparing the nasolabial fold. No synovitis. ANA 1:320. Anti-ds DNA positive repeatedly at 32.9IU/ml (normal less than

10 IU/ml). The repeated lupus anticoagulant: positive again.

Transverse Myelitis as a presenting manifestation of SLE with aPL.

Case presentation

Another pulse IV MP (1 gm)X 5 days.

All anti-TB meds were D/C.

No additional therapeutic interventions.

Her weakness improved significantly. Medications: hydroxychloroquine, a tapering regimen of oral

prednisone, alendronate, oral calcium and vitamin D.

8/12: Her power is almost 5/5 in proximal pelvic girdle muscles with normal sensory exam.

The repeat MRI demonstrated some improvement in previously present hyperintensity within the upper thoracic cord.

Discussion

Late-onset SLE

Late onset disease is the type of SLE whose manifestations begin after the age of 50 in majority of studies or after the age of 65.

Rovensky, J. and Tuchynova, A., Systemic lupus erythematosus in the elderly. Autoimmun Rev, 2008. 7(3): p. 235-9.

Karoubi Nordon, E., Hayem, G., Mentres, F., Palazzo, E., Legrain, S., Meyer, O., et al., Letter to the Editor: Late onset systemic lupus erythematosus: A new approach. Lupus, 2007. 16(12): p. 1011-4.

Boddaert, J., Huong, D.L., Amoura, Z., Wechsler, B., Godeau, P., and Piette, J.C., Late-onset systemic lupus erythematosus: a personal series of 47 patients and pooled analysis of 714 cases in the literature . Medicine (Baltimore), 2004. 83(6): p. 348-59.

Pu, S.J., Luo, S.F., Wu, Y.J., Cheng, H.S., and Ho, H.H., The clinical features and prognosis of lupus with disease onset at age 65 and older. Lupus, 2000. 9(2): p. 96-100.

Late-onset SLE

The incidence of late-onset SLE is rare.

As low as 3.7%* and to as high as 20.1%**.

This may be related to the different ethnic backgrounds included in the studies and the variable definitions of late-onset SLE.

* Costallat, L.T. and Coimbra, A.M., Systemic lupus erythematosus: clinical and laboratory aspects related to age at disease onset. Clin Exp Rheumatol, 1994. 12(6): p. 603-7.

** Jacobsen, S., Petersen, J., Ullman, S., Junker, P., Voss, A., Rasmussen, J.M., et al., A multicentre study of 513 Danish patients with systemic lupus erythematosus. I. Disease manifestations and analyses of clinical subsets. Clin Rheumatol, 1998. 17(6): p. 468-77.

Late-onset SLE

The sex ratio declines with age in SLE.

In a pooled analysis of 714 cases of late-onset SLE reported in the literature and 4700 young SLE patients, the female to male ratio observed with age in SLE was 4.4:1 vs. 10.6:1 respectively*.

This probably reflects the relationship between SLE and estrogen status which decline in the elderly.

Boddaert, J., Huong, D.L., Amoura, Z., Wechsler, B., Godeau, P., and Piette, J.C., Late-onset systemic lupus erythematosus: a personal series of 47 patients and pooled analysis of 714 cases in the literature. Medicine (Baltimore), 2004. 83(6): p. 348-59.

Late-onset SLE

In general, late onset SLE is characterized by a lower disease activity.

Skin manifestations, photosensitivity, Raynaud phenomenon, arthritis, nephritis and NP manifestations were less frequent in comparison with young SLE patients.

In late-onset SLE, a higher occurrence of pulmonary involvement, serositis, and Sjögren's syndrome were observed.

Boddaert, J., Huong, D.L., Amoura, Z., Wechsler, B., Godeau, P., and Piette, J.C., Late-onset systemic lupus erythematosus: a personal series of 47 patients and pooled analysis of 714 cases in the literature. Medicine (Baltimore), 2004. 83(6): p. 348-59.

Costallat, L.T. and Coimbra, A.M., Systemic lupus erythematosus: clinical and laboratory aspects related to age at disease onset. Clin Exp Rheumatol, 1994. 12(6): p. 603-7.

Rovensky, J. and Tuchynova, A., Systemic lupus erythematosus in the elderly. Autoimmun Rev, 2008. 7(3): p. 235-9.

Late-onset SLE

Anti Ds DNA did not correlate with organ complications of late-onset disease in one study.

A higher prevalence of rheumatoid factor, anti-Ro

and anti-La antibodies were observed in late-onset SLE.

However, lower prevalence of anti-RNP antibodies and hypocomplementemia were observed as well.

Padovan, M., Govoni, M., Castellino, G., Rizzo, N., Fotinidi, M., and Trotta, F., Late onset systemic lupus erythematosus: no substantial differences using different cut-off ages. Rheumatol Int, 2007. 27(8): p. 735-41.

Maddison, P.J., Systemic lupus erythematosus in the elderly. J Rheumatol Suppl, 1987. 14 Suppl 13: p. 182-7. Belostocki, K.B. and Paget, S.A., Inflammatory rheumatologic disorders in the elderly. Unusual presentations, altered outlooks. Postgrad Med, 2002.

111(4): p. 72-4, 77-8, 81-3.

Transverse Myelitis (TM)

The American College of Rheumatology recognizes 19 SLE neuropsychiatric (NP) syndromes including myelopathy.

The prevalence of TM in SLE patients is 1-2%.

It can occur as the initial manifestation of SLE in up to 39% or within the first five years of a diagnosis of SLE in 42% of the total patient population analyzed in one study.

The predominant presentation of TM in SLE is a sensory level commonly in the thoracic region, spastic paraparesis and sphincter disturbance consistent with the findings in our case.

Nived, O., Sturfelt, G., Liang, M.H., and De Pablo, P., The ACR nomenclature for CNS lupus revisited. Lupus, 2003. 12(12): p. 872-6. D'Cruz, D.P., Mellor-Pita, S., Joven, B., Sanna, G., Allanson, J., Taylor, J., et al., Transverse myelitis as the first manifestation of systemic lupus

erythematosus or lupus-like disease: good functional outcome and relevance of antiphospholipid antibodies. J Rheumatol, 2004. 31(2): p. 280-5. Kovacs, B., Lafferty, T.L., Brent, L.H., and DeHoratius, R.J., Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and

review of the literature. Ann Rheum Dis, 2000. 59(2): p. 120-4.

MRI and Neuropsychiatric SLE MRI is considered the gold standard for the evaluation of central nervous system

(CNS) manifestation of SLE in clinical practice.

MRI finding are diverse, and atrophy and hyperintense white matter lesions often correlated poorly with clinical manifestations.

It is more likely to show abnormalities if there are focal neurological deficits. Appenzeller, S., Pike, G.B., and Clarke, A.E., Magnetic Resonance Imaging in the Evaluation of Central Nervous System Manifestations in Systemic Lupus Erythematosus. Clin Rev Allergy Immunol,

2007.

Only few cases of TM with longitudinal involvement of the spinal cord similar to that in which we described were reported in the literature.

Chen, H.C., Lai, J.H., Juan, C.J., Kuo, S.Y., Chen, C.H., and Chang, D.M., Longitudinal myelitis as an initial manifestation of systemic lupus erythematosus . Am J Med Sci, 2004. 327(2): p. 105-8.

Heinlein, A.C. and Gertner, E., Marked inflammation in catastrophic longitudinal myelitis associated with systemic lupus erythematosus . Lupus, 2007. 16(10): p. 823-6. Kimura, K.Y., Seino, Y., Hirayama, Y., Aramaki, T., Yamaguchi, H., Amano, H., et al., Systemic lupus erythematosus related transverse myelitis presenting longitudinal

involvement of the spinal cord. Intern Med, 2002. 41(2): p. 156-60.

Antiphospholipid antibodies and TM The majority of TM cases reported in the literature

were positive for aPL, 73% in one series and 55-64% in another.

One of the strongest risk factors for the development of significant NP damage was the presence of aPL.

Hanly, J.G. and Harrison, M.J., Management of neuropsychiatric lupus. Best Pract Res Clin Rheumatol, 2005. 19(5): p. 799-821.

This has resulted in the introduction of anticoagulant therapy in the management of TM patients with positive aPL, but it remains controversial.

CSF in TM

CSF: variable, for the majority cell count may be entirely normal (D'Cruz, D.P., et al J Rheumatol, 2004. 31(2)). or it may reveal lymphocytosis (D'Cruz, D.P., et al J Rheumatol, 2004. 31(2)). (Chen, H.C., et al Am J Med Sci, 2004. 327(2)) similar to our case or even neutrophilic predominate mimicking bacterial meningitis (Heinlein, A.C., et al Lupus, 2007. 16(10))

Protein may be high or normal and glucose may be normal or low.

Oligoclonal bands may also present (D'Cruz, D.P., et al J Rheumatol, 2004.

31(2)).

TM: a major therapeutic challenge! The ideal drugs, doses, and the length of treatment

are not yet well defined.

As TM in SLE is a rare manifestation treatment guidelines for this entity have not been developed.

In older studies, most patients were treated with IV corticosteroid alone, whereas more recently some centers prefer a more aggressive approach with IV MP pulse therapy plus IV cyclophosphamide.

TM: a major therapeutic challenge! There were no clear differences between both

drugs in five cases of TM when both were studied against each other after an induction therapy with MP.

Barile-Fabris, L., Ariza-Andraca, R., Olguin-Ortega, L., Jara, L.J., Fraga-Mouret, A., Miranda-Limon, J.M., et al., Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheum Dis, 2005. 64(4): p. 620-5

However, several studies reported good to fair functional outcomes with combined treatment

D'Cruz, D.P., Mellor-Pita, S., Joven, B., Sanna, G., Allanson, J., Taylor, J., et al., Transverse

myelitis as the first manifestation of systemic lupus.

TM: a major therapeutic challenge! Plasmapheresis has been used to complement this treatment

regimen and it is still unclear if it has any additional therapeutic benefit.

There are recent reports on the successful use of anti-CD20 in patients with TM

Chehab, G., Sander, O., Fischer-Betz, R., and Schneider, M., [Anti-CD20 therapy for inducing and maintaining remission in refractory systemic lupus erythematosus] . Z Rheumatol, 2007. 66(4): p. 328, 330-6.

Armstrong, D.J., McCarron, M.T., and Wright, G.D., SLE-associated transverse myelitis successfully treated with Rituximab (anti-CD20 monoclonal antibody) . Rheumatol

Int, 2006. 26(8): p. 771-2. [22, 23].

The patient had significant improvement with the use of steroid.

TM in the elderly might be controlled with the use of large dose of steroid only.

Take home message

Late-onset SLE: >50, low disease activity, 4:1.

TM presents with sensory level commonly in the thoracic region, spastic paraparesis and sphincter disturbance.

TM can be a presenting feature of late-onset SLE.

TM in late-onset SLE might be responsive to steroid therapy alone

A different challenge!

NPSLE may still present a very difficult diagnostic challenge.

Joseph, F.G., Lammie, G.A., and Scolding, N.J., CNS lupus: a study of 41 patients. Neurology, 2007. 69(7): p. 644-54.

NPSLE is NOT the only diagnostic challenge!!

This is another case with a different challenge!

Question

What is the most common diagnostic test used by doctors?

Introduction

The physical examination

will always retain its importance as the most

common diagnostic test used by doctors and an essential tool for modern practice.

(Joshua AM et al, I.M.Journal, 2005; 35)

Question

• How accurate are residents in recognizing auscultatory heart sounds?

• What about pulmonary auscultatory sounds?

• Does the year of training differ?

Physical examination skills

• On average, residents accurately

recognized 20% of the cardiac auscultatory sounds (from 31 programs on the

east coast), a rate not significantly different than that of the medical students.

(Mangione S, et al , JAMA. 1997;278:717-22)

Physical examination skills

• On average, residents accurately recognized 40% of pulmonary auscultatory sounds.

• lack of significant improvement by year of training.

(Mangione S, et al, Am J Res Crit Care Med,1999;159:1119-24

Case presentation

Case presentation• A 23 year old male

• 2 days history of fever and dyspnea.

• Rigors, night sweats and shivering for one week.

• Weight loss of 17 kg over 3/12

• There were no more symptoms reported like joints pain or swellings neither in the ER notes nor in the internal medicine admission note.

Case presentation• P/E on admission note: 38.9 C, BP110/70, HR 88, RR 18 per

minute. O2 92% on RA.

• Diffuse lymphadenopathy.

• No hepatic or splenic enlargement.

• He had ejection systolic murmur.

• The rest of the examination was reported as normal.

• There were no comments on musculoskeletal examination findings.

Case presentation

• WBC 1.9, platelets 81, Hb 8.8 mg/dl.

• Hematology service.

• Antibiotics. Septic work-up: negative.

• BMB: hypocellular bone marrow with marked reduction in erythroid and myeloid series.

• Echo: normal.

• “ drug related side effect”.

Case presentation

• During the hospital stay: No response and significant hair loss was noted.

• ANA: positive, Normal C3 & C4, AntidsDNA:positive. ESR 65

• Rheumatology consultation: morning stiffness about 60 minutes. A scalp rash, no mouth ulcers, malar rash or photosensitivity.

• P/E: scarring alopecia measured 4X2 cm. R and L elbows were warm and swollen and FFC of 15 degrees. Knees, wrists and MCPs were tender and ROM was full but tender.

Case presentation• protienurea of 1.8 gm/24. DPGN (stage IV).

• Pulse therapy with MP.

• The patient was discharged and maintained on prednisone and mycophenolate mofetil 2 gm/day.

• Follow up assessment revealed a normal magnetic resonance imaging of the brain.

• A 24 hour urine collection decreased to 400 mg.

• However, the anti-dsDNA antibodies titer remained elevated.

What happened in this case?

• The patient had active arthritis for 7 days in the hospital without diagnosis!!

• A similar case in UBC-hospital, Vancouver, Canada

Is this normal?Whom to blame?

What is the most common reason(s) for medical visits?

Answer

• First: upper respiratory illnesses

• Second: musculoskeletal symptoms, accounting for approximately 20 per cent of both primary-care and emergency-room visits.

( 5 studies, see discussion in Freedman KB et al, The Journal of

Bone and Joint Surgery, 1998, 80(10)).

More evidence!!

• In a health survey, musculoskeletal disorders were ranked first in prevalence as the cause of chronic health problems, longterm disabilities, and consultations with a health professional.

(Badley EM, J.Rhuem, 1994, 21(3)).

JOINTS are

CRYING

The Crying Studies

1. Doherty M et al. Audit of medical inpatient examination: a cry from the joint. J R Coll Physicians Lond 1990; 24

2. Ahern MJ et al. The musculoskeletal examination: a neglected clinical skill. Aust N Z J Med. 1991;21(3)

3. Lillicrap MS et al, Musculoskeletal assessment of general medical inpatient-joints still crying out for attention. Rheumatology 2003;42

The Crying Studies

• Among 200 general medical inpatients in a teaching hospital the MSK symptoms and signs were recorded in their hospital notes in only 14.5% and 5.5% respectively.

• This compared poorly with recorded examination of other systems and regions (eg cardiovascular 100%; respiratory 99.5%; abdomen 99%; nervous system 77%; skin 13%; female

breasts 13%) (Doherty

M)

The Crying Studies

• In 66 patients, a history of MSK symptoms was recorded in 40.4% and the examination in only 14.5%.

• 80% of symptomatic patients received either no treatment for their rheumatic disorder, or treatment that was regarded as suboptimal or inappropriate.

(Ahern MJ)

The Crying Studies

• In 100 patients, 63% had MSK symptoms and/or

signs. • Relevant MSK history was missed in

49% of the patients, whilst signs were missed in 78%.

• 42% of those with MSK conditions would have benefited

from additional treatment.

(Lillicrap MS)

The Crying Studies: McCarthy E.M.et al,Clin Rheum, Sept 08, online first

• Only 16% of medical admission notes contained a reference to the musculoskeletal system.

• Most doctors (sample size=80) felt competent in hand assessment (68.8%) but only 12.5% could examine the foot.

• More than one third could not confidently diagnose common rheumatic conditions, while 75% felt unable to diagnose a connective tissue disorder.

The Crying Studies: McCarthy E.M.et al,Clin Rheum, Sept 08, online first

• The majority (88.7%) regarded the MSK assessment as difficult/challenging and 61.3% thought that it should not be included as part of a general medical examination.

• 80% of doctors felt that they had not received adequate teaching in MSK assessment and would welcome further training.

Questions

• Are you happy about your MSK examination skills?

• Do you know what you need to master?

• What is the best teaching method that should be provided to improve skills in MSK examination?

Answers from the literature

• Dissatisfaction of internal medicine residents and family physicians about musculoskeletal training is well described in the literature. (Houston

et al, J Gen Intern Med, 2004; 19).

• Competencies identification are lacking.

Answers from the literature

• There is a need for simplifying and standardizing MSK physical examination. (Coady D, medical teacher, McGaghie WC, J Rheum, Walker DJ, Rheumatology )

• Small group instruction with hands-on supervised practice is superior to more passive instructional methods for teaching MSK examination. (Lawry GV et al, Acade

Med; 1999, 74(2))

Take home messages

• Basic competency skills in MSK examination represent an essential tool to face the challenge of SLE.

Take home messages

• Early diagnosis and treatment improves quality of life and longevity,

• while reducing the incidence and prevalence of disease complications, particularly joint damage,

osteoporosis, atherosclerosis and

malignancy.

• Naz SM, Symmons DPM (2007) Mortality in established rheumatoid

arthritis. Best Pract Res Clin Rheumatol 21:871–883

Thank you