INTRODUCTION
CASE IN DETAIL
For 2 months now, NV has noticed a weight loss of 5 kg, with associated severe lethargy and progressive exertional dyspnoea. On presentation she could not walk more than 10 metres on flat ground. However, she denied any associated orthopnoea or paroxysmal nocturnal dyspnoea. Two weeks ago she developed a cough, which soon became productive with yellow-green sputum. She also had intermittent fevers at irregular intervals, with associated chills and rigors. She denied any chest pain. Five days ago her family doctor prescribed her an antibiotic, which did not cause any improvement in her symptoms despite good compliance. She presented to the hospital 2 days ago, and after multiple investigations a diagnosis of pneumonia was established and she was commenced on an intravenous antibiotic. She has not experienced any fever since commencement of the current medication, and she believes that her cough is improving.
She has had generalised rheumatoid arthritis for the past 10 years. Involved joints include hand and wrist joints, elbows, shoulders, knees, ankles and toes bilaterally together with the left hip joint. Five years ago she had a prosthetic hip replacement in the left side and her left ankle fused. Three years ago she had her right knee replaced too. She also has cervical spinal involvement, but with no neurological deficit.
She experiences joint stiffness in the morning, particularly in the hands, shoulders, neck and feet, which lasts about 2 hours and improves with activity. She is dependent in most activities of daily living but is able to feed herself. She usually cannot walk more than 50 metres due to joint and limb pain, and on such occasions she uses a wheelchair. Her daughter is her main carer.
She has been managed on variable doses of prednisone over the past 10 years, the maximum dose being 50 mg daily and the minimum 5 mg daily. She currently takes 7.5 mg prednisone daily. She has experienced multiple side effects associated with the chronic steroid treatment, including weight gain, acne, easy bruising, osteoporosis and diabetes mellitus.
She has also been treated with multiple other medications over the years, including diclofenac sodium, sulfasalazine and parenteral gold. Diclofenac therapy was stopped due to gastritis and sulfasalazine was stopped due to a rash. Gold therapy was stopped due to proteinuria. Currently she is managed on methotrexate 7.5 mg twice weekly together with celecoxib 200 mg twice daily. Both medications were commenced 8 months ago. She also takes folic acid 5 mg daily. She denies any known side effects associated with this treatment so far.
Her symptoms have never been completely controlled by any of the medications she has been treated with and she has experienced progressive deformity of both hands and feet over the years. The current level of control is the best she has ever achieved.
She denies any eye complaints, oral symptoms, vasculitic symptoms or sicca symptoms associated with her rheumatoid arthritis.
She was diagnosed with gastritis 8 years ago when she presented with epigastric pain. She denies any gastrointestinal bleeding, and the diagnosis of gastritis was established on gastroscopy. Subsequently the diclofenac therapy was stopped, and she was commenced on ranitidine 150 mg twice daily and has been symptom-free ever since. She does not know her Helicobacter pylori status and denies ever having been treated with the triple-therapy combination.
She was incidentally diagnosed with diabetes mellitus 6 years ago. She denied any symptoms of polyuria, polydipsia or weight loss on presentation. She was initially treated with dietary modifications and exercise alone. She was commenced on metformin 2 years ago. Currently she is managed on 500 mg metformin three times daily. She denies any side effects associated with this therapy. Her GP monitors her blood sugar level every 2 weeks and currently it averages around 6–10 mmol/L. She has seen an ophthalmologist on only one occasion, about 2 years ago. She was not diagnosed with any ocular complications. She denies any current ocular symptoms. She denies any known diabetic nephropathy. She has had proteinuria on only one occasion previously, which was attributed to the gold therapy. It resolved on stopping the drug. Her GP checks her urine every 6 months. She has never seen a podiatrist and denies any symptoms in her feet.
She denies ischaemic heart disease, stroke or calf claudication. She denies any neurological symptoms associated with diabetes.
She was diagnosed with osteoporosis 1 year ago when her rheumatologist ordered bone densitometry, but she denies any fractures. Her osteoporosis is treated with monthly pamidronate injections, which she has had for the past 6 months without any side effects. She also takes calcium carbonate 1500 mg daily together with calcitriol 0.5 mg twice daily.
She was diagnosed with chronic airflow limitation 1 year ago when she was investigated for progressive exertional dyspnoea. She is treated with salbutamol and ipratropium bromide via a metered dose inhaler two puffs twice daily. She was hospitalised for 3 days, 7 months ago, with infective exacerbation of chronic airflow limitation, which was treated with intravenous antibiotics.
Her current medications include prednisone, celecoxib, methotrexate, metformin, pamidronate, calcium carbonate, calcitriol, salbutamol and ipratropium bromide.
She gave up smoking 1 year ago, prior to which she had a smoking history of 20 pack-years. She consumes alcohol only very rarely, on social occasions.
She has been a divorcee for the past 15 years. She was married only once and has two adult daughters. She lives with her older daughter, who is 42 years old and is well. The second daughter is 38 years old, is married and lives separately but in the same city. She has two grandchildren. She has regular contact with her second daughter too. She is dependent on her daughter for assistance in all activities of daily living except feeding. She lives on the ground floor of a two-storey house. She has no steps to negotiate. Her house was modified previously under an occupational therapist’s recommendations to accommodate her needs. Her usual pastimes are watching television and listening to radio.
Her dietary history reveals adequate nutrition but no compliance with the diabetic diet.
She denies any sleep problems and she has never been depressed, despite her multiple significant medical problems.
Her family history is significant, in that her mother suffered from severe rheumatoid arthritis. She died at the age of 75 from an unknown cause. Her father died of an acute myocardial infarction at the age of 60. She has no brothers or sisters.
She worked as a clerk typist before retiring 20 years ago. She is on a disability pension, which is just adequate for her living. The daughter who lives with her is employed part-time as a nanny.
Her insight into her multiple medical problems seems satisfactory.
ON EXAMINATION
NV was alert, oriented and cooperative. She appeared cachectic and unwell. Her pulse rate was 72 beats per minute and respiratory rate 24 per minute. Her blood pressure was 110/60 mmHg without postural drop, and she was afebrile. Her estimated body mass index was about 20.
She had an intravenous cannula in the dorsum of her left hand and its insertion site was not inflamed. There were multiple ecchymoses in the dorsal aspect of her hands and forearm bilaterally.
She was using accessory muscles of inspiration and demonstrated pursed-lip breathing. Chest expansion was reduced in the upper and lower zones bilaterally and there was no dullness on percussion. Breath sounds were vesicular in the upper zone but there were crepitations in the mid- and lower zones bilaterally. Vocal resonance was not increased. The sputum mug contained yellow-green sputum.
Rheumatological examination showed bilateral symmetrical arthropathy of the hands and wrists with ulnar deviation at the metacarpophalangeal joints, ‘Z’ deformity of both thumbs, swan-neck deformity of the left index and right ring fingers and boutonnière deformity of the right middle finger. There was subluxation of the wrist joints bilaterally. There was wasting of the intrinsic musculature of the hands. These joints were oedematous but not tender or warm to touch. There was severe restriction of movement in all directions in the metacarpophalangeal joints, proximal interphalangeal joints and wrist joints bilaterally due to swelling, stiffness and deformity. Her hand power was severely restricted and functionality significantly compromised, with inability to unbutton, pick up a pen and write, or hold a cup.
There were non-tender, firm nodules of 2 cm diameter in the dorsal aspect of her elbows bilaterally.
There was tenderness in the anterior aspect of the left shoulder joint together with restriction of abduction to 60°, flexion to 90°, internal rotation and external rotation to 10° in each direction, bilaterally, due to stiffness.
There was tenderness over the C2, C3, C6 and C7 vertebrae, with severe restriction of neck flexion, extension and rotation.
There was tenderness over the temporomandibular joint bilaterally.
There was valgus deformity and medial joint line tenderness, together with crepitus on flexion, in the knee joints bilaterally. There was no Baker’s cyst.
There was hallux valgus deformity bilaterally in the feet with subluxation of all metatarsophalangeal joints. There was no tenderness or warmth to touch. Severe wasting of the intrinsic musculature of the feet was present.
Cardiovascular examination was unremarkable, with dual and normal heart sounds and the presence of all peripheral pulses.
Neurological examination showed a visual acuity of 6/24 with correction bilaterally. Fundoscopy showed multiple hard and soft exudates in the macular region bilaterally. The rest of the cranial nerve examination was unremarkable.
Upper limb examination showed profound weakness bilaterally in the intrinsic musculature of the hand and on shoulder abduction. Power was preserved at the other levels together with tone, reflexes, coordination and sensation.
Lower limb examination showed moderate proximal weakness with 3/5 power, bilaterally, on hip flexion, extension, abduction and adduction. Otherwise the lower limb neurological examination was unremarkable. The plantar response was flexor bilaterally.
She had difficulty with mobilisation due to weakness and a waddling gait.
Gastrointestinal examination was unremarkable. There was no organomegaly.
She had no lymphadenopathy.
Diabetic foot examination did not show any painful callosities, corns or ulcers.
In summary, this is a 65-year-old woman with severe rheumatoid arthritis presenting with a history of progressive dyspnoea and fevers on a background of diabetes mellitus, osteoporosis and chronic airway limitation. Her independence is severely compromised.
I have identified one acute problem and two main long-term problems that need addressing:
• The acute problem is the definitive diagnosis and treatment of her lung pathology. The possible differential diagnoses include pneumonia secondary to infective exacerbation of chronic airway limitation, or pulmonary sepsis secondary to relative immunocompromisation due to multiple causes, which include diabetes mellitus, chronic corticosteroid use and myelosuppression associated with methotrexate therapy. Pulmonary fibrosis secondary to rheumatoid arthritis or methotrexate therapy should also be considered.
• Long-term problems include optimal management of the rheumatoid arthritis so as to achieve maximum disease control, at the same time as minimising therapy-related complications, restoring mobility and planning discharge with maximum supportive services.
To address the issue of pulmonary disease, I would like to see:
1. The latest full blood count, looking for leucocytosis or leucopenia with associated anaemia
3. A recent chest X-ray, looking for consolidation, hyperexpansion or lung fibrosis
4. The results of formal lung function studies, looking for a mixed obstructive and restrictive pattern. In addition I would like to see the blood culture results if she was febrile on presentation, and the sputum microbiological test results.
Questions and answers
Q: How would you interpret this full blood count and what would you do about it?
A: This result shows a normocytic, normochromic anaemia. The possible causes include mixed haematinic deficiency secondary to chronic gastrointestinal bleeding and malnutrition, anaemia of chronic disease and myelosuppression due to methotrexate therapy. I would like to follow these results up with a blood film, iron studies, B12 and red cell and serum folate levels, and a bone marrow biopsy. There is leucopenia with a neutropenia and mild thrombocytopenia. These results collectively suggest myelosuppression, and the bone marrow biopsy will further clarify this.
I would stop the methotrexate therapy immediately but continue with the folic acid replacement. I would commence parenteral folinic acid rescue therapy to facilitate marrow recovery. I would maintain disease control by increasing the prednisolone dose to 10 mg daily. I would also commence antibiotic therapy against community-acquired organisms with intravenous ceftriaxone 1 g daily and oral roxithromycin 150 mg twice daily. I would closely monitor her temperature and the white cell count.
Q: What do you think about this chest X-ray?
A: This frontal-projection, posteroanterior view chest X-ray of NV done on (insert date) shows patchy opacifications diffusely distributed in the mid- to lower zones of the lung fields bilaterally. I cannot see air bronchograms. There is flattening of the diaphragmatic shadow, hyperinflation of the lungs and osteoporosis of the skeletal structures. The lateral projection shows similar diffuse patchy opacifications in the right middle lobe and the lower lobe and in the left lower lobe. I would like to further correlate this chest X-ray with high-resolution CT of the chest, looking for a ground glass appearance in the mid- to lower zones of the lung fields.
Q: What would you look for in the CT scan?
A: The patchy changes may signify consolidation due to pneumonia or areas of interstitial pneumonitis or areas of fibrosis. She has two risk factors that can cause pulmonary fibrosis. First is her severe rheumatoid arthritis. Second is the methotrexate use. A ground glass appearance may suggest active pneumonitis. In that case, stopping methotrexate and increasing the corticosteroid dose may help prevent progression of the pneumonitis and arrest progression to fibrosis.
Q: How active do you think this woman’s arthritis is currently?
A: I believe this woman’s rheumatoid arthritis is currently clinically active. The clinical markers of disease activity are: 1) duration of joint stiffness, and 2) swollen joint count. This woman experiences about 2 hours of joint stiffness in the morning and her swollen joint count exceeds 12—these findings indicate active disease. I would like to confirm my clinical findings by looking at the most recent erythrocyte sedimentation rate and serum C-reactive protein level.
Q: Well, her ESR is 80 mm/h and CRP is 105 mg/L. If you were to stop methotrexate, given the severity and the resistant nature of this woman’s disease, how would you propose to manage her rheumatoid arthritis?
A: My plan of action for the management of her rheumatoid arthritis has two arms. One is the use of disease-modifying drugs to control disease progression and antiinflammatory medications to control inflammation and related symptoms. The second arm is physical therapy to preserve/restore joint mobility and rehabilitation.
On stopping methotrexate I would consider commencing this woman on leflunomide. Until the leflunomide started acting I would maintain this woman on a tapering course of oral corticosteroid therapy. I would plan to maintain her at the lowest prednisolone dose possible and stop completely when the disease-modifying agent started to take effect, after about 2–3 months. For antiinflammatory therapy I would continue the cyclo-oxygenase-2 inhibitor celecoxib at the current dose. Other options that I might consider include infliximab or etanercept.
I would refer her to a physiotherapist for light mobilisation exercises and hydrotherapy.
Q: If leflunomide fails to control her disease, are there any other therapeutic options that you could consider?
A: In the event of disease progressing in spite of maximum-dose leflunomide therapy, I would consider novel therapeutic agents (such as infliximab, which is a monoclonal antibody against TNF-alpha or etanercept, which is a soluble TNF receptor), according to their availability. Another agent I would consider in case of resistant disease is cyclosporin.
Q: How would you administer infliximab or etanercept?
A: Infliximab is given intravenously once every 2 months and etanercept is given subcutaneously twice a week. Therefore I would educate the patient’s daughter in injection techniques or organise the therapy to be administered by her GP or at the infusion centre of the local hospital.
Q: Please interpret these liver function test results. What do you think is the problem?
A: These liver function indices show a moderate hepatitic picture with significant elevation of the AST and ALT levels disproportionate to the ALP elevation. There is also hyperbilirubinaemia and a low serum albumin level. I consider methotrexate-induced liver toxicity as my top differential diagnosis. Other possible differential diagnoses are chronic active hepatitis due to hepatitis B or hepatitis C, autoimmune hepatitis and diabetic fatty liver.
I would image her liver with CT or MRI looking for parenchymal or anatomical changes, and check hepatitis B, hepatitis C and autoimmune serology (antinuclear antibody, anti-liver-kidney microsomal antibody type 1 and antibodies to soluble liver antigen) to further clarify the diagnosis.
I would follow up her liver function tests, looking for improvement on stopping methotrexate.
Q: How would you manage her chronic airways disease?
A: The oral steroids prescribed for her rheumatoid arthritis will help improve airway inflammation too. I would advise the patient to use the short-acting bronchodilator medication only when symptomatic with wheezing or dyspnoea. I would maintain her on regular twice-daily inhaled corticosteroid therapy with fluticasone 500 mg via the Accuhaler device, given its efficacy of drug delivery and convenience of use. After 4 weeks, if there was no significant improvement in disease control, I would add a long-acting inhaled bronchodilator to the therapeutic regimen.
Q: How would you plan her discharge?
A: On resolution of her symptoms I would plan her discharge in association with the physiotherapist, occupational therapist, social worker and her daughter. I would consult the occupational therapist regarding assessing and optimising her functional status. I would obtain their assessment and recommendations on safety and comfort in the patient’s home environment.
I would initiate a program of rehabilitation with the physiotherapist and plan continuation of this on discharge, either at a local facility or at the outpatients physiotherapy department.
In association with the social worker I would assess how her daughter was coping and organise necessary assistance and support.