Long Case - A 44 Year Old Man with Chronic Joint Pains and New Onset Generalized Edema

Long Case Presentation

History

A 44 year old man presented with a 3-day history of bilaterally symmetrical rapidly progressive generalized edema.

Present Illness

An agile stonemason, the patient reported that this symptom first started suddenly 3 days ago, at night, when he noticed he started feeling facial puffiness with pedal edema. The next morning, while brushing his teeth, the patient noticed he had facial puffiness, in the mirror. At the same time, he also noticed that he developed bilaterally symmetric, pitting type pedal edema, extending upto the middle of his legs. He immediately presented to the hospital with these complaints. 

On interviewing the patient further, he denied having breathlessness, palpitations or chest pain. He reported frothing of urine but no haematuria. He also reported gradually decreasing urine output over the past 3 days. He did not have pain during micturition, no pus or any other abnormal discharge (casts) in urine. He did not have any history of vomiting or diarrhea, no history of acute retention of urine, no prior history of fever or rash, no history of antibiotic usage or any drugs in the past 1 week. The patient also denied any history of yellowish discoloration of skin or sclera.

Prior to this, the patient reported that since 2011, he had severe joint pains, which were initially asymmetric and gradually became bilaterally symmetrical and involving the small joints of his hands and wrist. The joint pains were associated with significant local edema, and painful limitation of movements, which made his job (stonemasonry) difficult. 

[Other activities which were painful and difficult for the patient were - 

Holding his cup of tea or glass of water, 

Pain in his finger joints and wrist while brushing, 

Pain while holding mug when taking bath and 

Pain in toes and ankles on both sides when walking)]

He reported that he also had debilitating early morning pains and limitation of movements in his hands, wrists and feet, which usually lasts for about an hour, He reported that the pains and limitation of movements improved with activity, with gradual reduction in edema of joints.

From 2011 to 2019, these joint symptoms gradually progressed in severity, now also involving several large joints (shoulders, elbows, knees and hips) warranting several medical consults, where he was frequently prescribed pain killers. The patient did not have any documentation of the pain killers he took in these 8 years. In December 2020, he presented to our hospital with similar complaints of joint pains, when he was prescribed with Etoricoxib and Febuxostat (he had hyperuricemia). He reported that his symptoms alleviated with these drugs but he intermittently had worsening of same symptoms in the interim. The patient denied any history of skin rash, photosensitivity, nasal or oral ulcers, chest pain or abdominal pain, weakness in his limbs (such as difficulty in taking stairs or lifting heavy stones and nor any weakness in his distal aspects of limbs such as mixing food, buttoning his shirt or holding a glass or slipping of footwear), isolated single joint pain or edema, or a past history of kidney stones. He also does not have any history of difficulty in swallowing, altered bowel habits, pain in the pulp of his digits, or painful tearing, photophobia or visual loss. He also denied any history of gritty sensation in eyes or dryness of mouth.

Apart from these, the patient reported that, for the past 3 days, he has burning sensation in his eyes with increased tearing but no visual deficits. He also reported for the past 1 year, he developed subcutaneous swellings in the proximal joints of his fingers. He denies any history of early satiety or post prandial fullness or pain. He reported that his clothes have slightly loosened over the past 1 year with involuntary weight loss and loss of appetite. He denies having a history of wrist or foot drop, chest pain, palpitations or breathlessness. No history of loss of consciousness, falls or tingling or numbness in his feet or hands.

Past History

No significant past history.

Medical/Surgical History

Chronic intermittent use of analgesics (type and dose unknown). Has been using Etoricoxib 60 mg and Febuxostat 80 mg intermittently for the past 8 months. No relevant surgical history. No history of allergy or atopy.

Personal History

The patient had been working as a stonemason for the past 20 years. He is a devout Catholic Christian and a strict teetotal (has never smoked or consumed alcohol in his life). He stays with his wife and 2 children (elder son and younger daughter) in Miriyalguda. He is from a close-knit family and regularly socialises with his family (parents and his 2 elder brothers). Apart from his troubling joint pains, he used to a have a fairly balanced and good quality of life, with good sleep every night, good appetite and adequate access to nutritious food and clean drinking water. He also had a balanced social well-being with a tightly-knit community at home and his church.

However, since the last 1 year, his appetite started to decrease and he also involuntarily lost weight. His bowel and bladder habits have always been normal but these joints pains have forced him into early voluntary retirement from his job in 2019. His and his family's finances have been supported by his brothers and from generous donations from his church. He feels his mental health has remained intact, thanks to his supportive family and fellow churchgoers.

Family History

No significant family history reported.

Social & Educational History

Married for 18 years with 2 children. Primary education upto Class 7 in Telugu medium.

Immunization History

None taken since birth.

Problem Representation / History Analysis

A 44 year old stonemason from Miriyalguda, presented with a 3 day history of anasarca, frothy urine and gradually decreasing urine output, on a background of a 10 year history of chronic bilaterally symmetric polyarthritis (evidenced by severe pain, edema and limitation of joint movements).

Localisation of Acute Problem

Anasarca and frothy urine with decreasing urine output suggest a renal pathology. Proteinuria causing anasarca likely due to glomerular pathology. Other systemic causes like heart failure and liver dysfunction can be ruled out due to absence of dyspnea, palpitations, bendopnea or syncope. Liver dysfunction can be ruled out by lack of jaundice, melaena or hematemesis (from bleeding varices), and abdominal distention not occurring prior to pedal edema.

Within the kidney, pre-renal and post-renal causes can be effectively ruled out from the absence of volume loss (vomiting, diarrhea, diuretic abuse or burns) and no history of acute retention of urine or lower urinary tract symptoms (LUTS) like frequency, urgency, hesitancy or precipitancy. The presence of frothy urine and edema strongly supports a glomerular pathology due to significant loss of protein and also decreased urine output. Isolated defects in tubular/interstitium are unlikely as such patients have a deficit in maintaining urinary concentration, which causes polyuria. Such a high range of proteinuria causing anasarca is also not seen with tubular/interstitial pathologies alone.

Provisional Diagnosis - Acute Glomerulopathy (Glomerulonephritis / Nephrotic syndrome)

Features to look for - 

1. Hypertension (secondary hypertension in Glomerulonephritis)
2. Haematuria on Urine Microscopy (particularly dysmorphic RBCs in urine)
3. Quantification of Proteinuria
4. Serum Albumin / Total Proteins
5. Urine specific gravity / calculated urine osmolality to check for isosthenuria (to look for secondary tubular/interstitial damage) 
6.  Renal biopsy, if diagnosis remains uncertain

Localisation of Chronic Problem

This 44 year old man has a 10 year history of bilaterally symmetrical progressive inflammatory polyarthritis. Features favouring an inflammatory pathology are -

1. Features of inflammation such as severe pain associated with edema of the joints and limitation of range of active movements
2.  Early morning stiffness, lasting for more than 30 mins (for 1 hour in this patient)
3. Pain and edema of joints improving with activity and worsening with rest
4. Features of uncontrolled systemic inflammation such as fever, involuntary loss of weight associated with loss of appetite.
5. Swellings at joints and deformation of normal joint posture 

Provisional Diagnosis - Bilaterally Symmetric Chronic Progressive Inflammatory Peripheral Polyarthritis

Clinical Examination

Initial examination revealed, the patient was conscious, coherent and co-operative, lying in bed in supine position. He was in some visibly apparent distress with flexion at his elbows and wrists, bilaterally, which were mildly painful when resting on the bed and his abdomen, respectively. The patient was dressed in a round neck t-shirt and when asked to sit up and take his t-shirt off, he had significant pain and limitation of movements at multiple joints but no weakness.

Vitals were taken in supine and sitting position - 

Supine Position

Pulse - 92 bpm, regular, normal volume, condition of vessel wall - normal, no radio-radial or radio-femoral delay. All peripheral pulses were normal.

Blood Pressure - 140/90 mmHg

Temperature - 99.3F

Respiratory Rate - 24 cycles per minute. Mildly acidotic + (with prolonged duration of expiration)

Sitting Position

Pulse - 96 bpm, regular, normal volume, condition of vessel wall - normal, no radio-radial or radio-femoral delay.

Blood Pressure - 150/90 mmHg

Head to Toe General Examination

General Condition - Fair built and appears well nourished.

Hair - Thin and slightly greyed. Not easily pluckable or no areas of scarring or non-scarring hair loss. No lesions noted on the scalp.

Eyes - No conjunctival chemosis or injection, No redness or corneal lesions. Bilateral, purplish reticular markings noted on the sclera of both eyes. Palpebral conjunctival pallor +. No icterus. No cyanosis. Bilateral Periorbital puffiness +

Periorbital Edema +. Pallor was also +

General Head, Neck & ENT - No abnormalities. No lymph node enlargement.

Axial - No apparent spinal deformities

Fingers and Nails - Leukonychia +. No clubbing or cyanosis. Capillary refill time - 2 seconds.

Bilateral pitting type pedal edema +, extending upto middle of legs.

Systemic Examination

Musculo-Skeletal System

Axial Skeleton

Inspection - No visibly apparent spinal deformities; 

Palpation - Inspectory findings confirmed. No spine tenderness. 

Movements - Atlanto-occipital - Flexion, extension and lateral flexion normal

                      Atlanto-axial - Rotation of head normal

                      Spinal Flexion, Spinal Extension, Lateral Flexion and Rotation are normal

Appendicular Skeleton - Upper Limbs (Positive Findings)

Shoulders (both sides) - 

       - Inspection - Attitude - Slightly flexed and internally rotated; Contour normal; No edema or erythema

       - Palpation - Mild increase in temperature on both sides

       - Range of Movements - Mild Active and Passive limitation of all range of movements (flexion, extension, adduction, abduction, internal rotation and external rotation)

Elbows (both sides) -

        - Inspection - Attitude - mid-flexion;  alignment of elbow and forearm - normal; Edema + ; No scars or sinuses; no muscle wasting

        - Palpation - All Inspectory findings are confirmed; Raised temperature +; Edema +; Wincing on touch + ; Fluctuation test + ; 3 point bony relationship intact

        - Range of Movements - Severe pain on active movements of flexion, extension; Mild pain with supination and pronation;  

Wrists (both sides) - 

        - Inspection - Attitude - Mild extension; Radial deviation of wrists +; Diffuse edema +; Redness +;

        - Palpation - All Inspectory findings confirmed; Temperature raise +;  Wincing on touch +; 

        - Range of Movements - Severely limited and extremely painful active movements of flexion, extension, radial deviation and ulnar deviation.

Hands (both sides) - 

        - Inspection - Attitude - Palmar subluxation and Ulnar deviation of the MCP joints; Swollen and Erythematous PIP joints; No swelling or redness of DIP joints; No apparent muscle wasting; Mild hyper-extension of PIP of thumbs; Pulp of fingers normal

        - Palpation - All Inspectory findings are confirmed; Temperature raise +; Wincing on gentle palpation of MCP joints and PIP joints; Palpation of DIP joints is normal; Swellings also + on 3rd and 4th PIP joints on both sides. Z-deformity +.

        - Range of Movements - Severe pain and severe limitation of active movements of flexion, extension and ulnar and radial deviation of MCP joints; severe pain and limitation of active and passive movements of flexion and extension at PIP joints. DIP joints normal.

Appendicular Skeleton - Lower Limbs (Positive Findings only)

Hip Joints (both sides)

        - Limitation of passive movements of flexion and extension (towards the end of range of motion);

Knee Joints (both sides)

        - Inspection - Swelling and erythema + ; Attitude - flexion; 

        - Palpation - All Inspectory findings are confirmed; Raised temperature + ;

        - Range of movements - Severe pain and limitation of active and passive movements of flexion and extension and lateral and medial rotation; (Patient was unable to stand on Day 1 and was able to stand on Day 2 with analgesic use).

Ankles (both sides)

         - Mild pain and limitation of active and passive movements of plantar flexion and dorsiflexion; Mild pain and limitation of movements of inversion and eversion.

        - Palpation of Achilles tendon is normal.

Foot examination (both sides)

        - Mild pain and limitation of passive movements of flexion and extension of MTP joints; great toe flexion and extension normal;

Other Systems Examination

Cardiovascular System - No abnormalities detected

Respiratory System - No abnormalities detected

Abdominal Exam - No abnormalities detected

Nervous System - No deficits detected

Investigations

X-ray AP view of the hands and wrists - Osteopenia and erosions of the MCP and PIP joints are noted. Scallop sign +. Significant soft tissue swelling is also noted.

Chest X-ray PA view - Full inspiratory, underexposed film with no malrotation or angulation. Bones - Clavicle, Head of Humerus, Coracoid process and acromion of scapula appear normal. The ribs are normal. No mediastinal lymph nodes or enlargement. The right heart border shows mildly dilated right atrium. The left heart border shows a prominent aortic knuckle, the pulmonary bay area is normal, the left atrial appendage appears normal and the left ventricular free wall also appears normal. The bronchovascular markings are also prominent, likely due to underexposure.

Standard 12 lead ECG with normal voltage and speed @ 25mm/s; P waves, QRS complexes and T waves have normal morphology and duration; P-P and R-R intervals are normal. PR and QTc intervals are normal.

Current Admission - Blood tests

Blood work from previous presentations to hospital. RA factor was negative

Urine Microscopy - Freshly voided urine sample was centrifuged at high speed (> 2700 RPM) and sediment collected and fixed on glass slide and examined under microscope at 400 (10x * 40x) showed DYSMORPHIC RBCs (black circles) and occasional pus cells (red circles). Dysmorphic RBCs were those that had altered shape, microcytic or with membrane defects.

Diagnostic Approach

With a provisional diagnosis of Acute Glomerulopathy on the background of bilaterally symmetric chronic progressive erosive peripheral polyarthritis, features supporting the diagnosis of glomerulonephritis were - 

- Secondary Hypertension

- Oliguria (360 ml urine in the last 24 hours)

- Hypoalbuminemia (Serum Albumin 2.5g/dl) and Anasarca

- Dysmorphic RBCs in Urine

  (A review of literature was done to evaluate the sensitivity and specificity of dysmorphic RBCs for glomerular disease pathologies - One study conducted in Bangladesh showed that urinary dysmorphic RBCs were 92.7% sensitive and 100% specific for a biopsy confirmed diagnosis of glomerulonephritis. [1]

Similar values of sensitivity and specificity was also confirmed in another study jointly conducted in Australia and China, where glomerulonephritis was confirmed with renal biopsy. [2] )

Thus, with glomerular disease being most likely, an anatomical diagnosis is made. The etiological cause for glomerular injury needs to be ascertained.

A careful construction of the problem representation for this patient and insight into the sequence of his life events can provide clues that the current acute problem could be a sequelae of his long term, poorly treated chronic problem.

Thus, a good clinical diagnosis of his musculo-skeletal problems is required to get a better picture of his current illness.

The patient has Bilaterally Symmetrical Chronic Progressive Erosive Peripheral Polyarthritis. Differential diagnosis for such conditions include - 

1. Rheumatoid Arthritis (most likely)
2. Rheumatoid Arthritis with coexistent Gout
3. Psoriatic Arthritis
4. Enteropathic Arthritis
5. Reactive Arthritis
6. SLE
7. Polymyositis / MCTD (Mixed Connective Tissue Disorder) (least likely)

With Rheumatoid Arthritis being most likely, ACR/EULAR classification criteria can be applied for diagnosis - 

This patient has >10 joints involved with multiple small joints involvement - 5 points; Symptom duration 10 years - 1 point; RA Factor - NEGATIVE; CRP elevated & ESR - 120 mm/hr - 1 point; Total Score - 7/10 [3]

Thus, a diagnosis of Rheumatoid Arthritis is likely. The clinical utility of RA factor came into question. A review of literature showed that sensitivity of RA factor for Rheumatoid Arthritis was 28% and specificity was 87%. For non RA rheumatological disorders, the sensitivity was 29% and the specificity was 88% [4]. Thus, the authors concluded that (due to high specificity and NPV), the test is best ordered when the suspicion for a rheumatological is low but just high enough, that a negative result would increase the post-test probability of a rheumatological disorder being unlikely.

This patient had a chronic history of symmetric small joint and then large joint inflammatory peripheral polyarthritis, With minor erosions notable in the PIP and MCP joints of both hands, classification criteria are diagnostic for Rheumatoid Arthritis.

No history of skin rash (psoriatic arthritis) or chronically altered bowl habits (enteropathic arthritis); No history of dysuria or burning pain during micturition or a history of severe burning pain in eyes with photophobia and excessive tearing or discharge (reactive arthritis) makes the other diagnoses unlikely.

Epidemiologically, SLE occurs more commonly in females at a ratio of 9:1, coupled with this, the absence of other features of SLE, such as alopecia, photosensitivity rash, nasal or oral ulcers, serositis, hemolytic anemia etc. makes this diagnosis very unlikely.

The absence of muscle weakness, muscle pain and the presence of destructive arthritis makes Polymyositis / MCTD extremely unlikely (Polymyositis usually causes nonerosive arthritis).

Thus the current acute glomerulonephritis can be framed in the background of Chronic Poorly Treated Rheumatoid Arthritis.

4 scenarios are possible - 

1. Poorly treated RA causing Secondary Amyloidosis (most likely)

        Secondary amyloidosis is most commonly seen in chronic poorly treated systemic inflammatory syndromes. This study shows that secondary amyloidosis is the most common cause of rapidly progressive glomerulonephritis in patients who were untreated for more than 10 years. [4] Coupled with features of amyloidosis of the heart, this is the most likely cause of his renal dysfunction.

2. Vasculitic Glomerulonephritis (IgA Mediated)

        The incidence of IgA nephropathy in patients with RA is similar to that in the general population. [5]

3. Primary Glomerulonephritis (Idiopathic)

        These include Mesangial / Mesangio-proliferative glomerulonephritis; Membranous Nephropathy; FSGS [6]

4. Renal Dysfunction secondary to drug use (less likely)

        Most commonly implicated drugs causing nephritic/nephrotic syndrome are Gold and Pencillamine, neither of which the patient used. The patient had chronic intermittent use of Etoricoxib but NSAIDS usually cause Tubulo-interstitial nephritis and not nephrotic syndrome.

5. Crystal Nephropathy (less likely)

        Gout crystals precipitate at a pH of 7.0 and often precipitated in the collecting ducts in the medulla, causing Acute Tubular Necrosis with little interstitial or glomerular involvement.

Final Diagnosis - A 44 year old, who presented with a 3 day history of anasarca and decreased urine output is diagnosed with -

• Acute Glomerulonephritis, likely due to Secondary Amyloidosis due to Chronic Poorly Treated Seronegative Erosive Rheumatoid Arthritis.
• Dilutional Hyponatremia secondary to Anasarca due to Glomerulonephritis
• Hyperuricemia likely due to decreased Uric Acid Excretion Precipitating Gouty Arthritis
• Anemia of Chronic Disease secondary to Poorly Treated Rheumatoid Arthritis.

Further Plan

Abdominal Fat Pad Biopsy for Amyloidosis

Needle Aspiration of Synovial Fluid for Crystal Induced Arthritis (Gout)

Treatment

1. Free water restriction for Hyponatremia
2. Tab. PREDNISOLONE P/O 20 mg OD
3. Tab FEBUXOSTAT P/O 80 mg OD
4. Haemodialysis for worsening renal dysfunction

Pedagogic Questions

1. Abdominal fat pad biopsy vs Renal biopsy ?

The clinical data and biopsy results of 194 SA patients who were treated in Peking Union Medical College Hospital from January 2009 to June 2015 were retrospectively analyzed. Results The highest sensitivity was achieved by biopsy of affected organs,with renal biopsy 97.4%,heart biopsy 95.0% and liver biopsy 87.5%. Among non-invasive biopsy methods,tongue biopsy was found to be 75% sensitive,followed by gingiva biopsy at 57%,abdominal fat pad aspiration at 57%,rectum biopsy at 16%,and bone marrow examination at 8%. Combination of tongue and abdominal fat pad biopsy yielded a detection rate of 93.1%. Conclusions Biopsy of the involved organ has the highest sensitivity. However,combination of multiple non-invasive biopsy methods may has sensitivity comparable to organ biopsy and is safer and more convenient. [7]

    2. Single DMARD vs Combination therapy ?

A Cochrane review, published in The BMJ [8] looked at the clinical efficacy of Methotrexate monotherapy vs Combination therapy (MTX + Non-biological or MTX + Biologicals). Data of Methotrexate -naïve patients was gleaned from this meta-analysis - 

Outcomes - The major outcomes of the review were American College of Rheumatology (ACR) 50 response, a composite measure of improvement in disease activity (dichotomous outcome); radiographic progression, measured by Larsen, Sharp, or modified Larsen/Sharp scores (continuous outcome); and withdrawals due to adverse events, including death (dichotomous outcome).

    3. When to initiate dialysis ? How long can we wait ?

Ex tempore interpretation of the AKIKI-2 trial. [9]

 

    4. Can Rheumatoid Arthritis and Gout co-exist together ?

The study population included 813 patients, 537 (66%) were rheumatoid factor positive; 33% had rheumatoid nodules, and 53% had erosive joint disease. During 9771 total person-years of follow-up (mean 12.0 years per RA patient), 22 patients developed gout by clinical criteria. The great toe was the most common site of gout (12 of 22 patients).  The 25 year cumulative incidence of gout diagnosed by clinical criteria was 5.3%. Typical intracellular monosodium urate crystals were present in 9 of 22 patients with acute gout; all had developed gout after the RA incidence date. The 25 year cumulative incidence of gout diagnosed by clinical criteria including presence of urate crystals is 1.3%. The prevalence of gout in RA on Jan 1, 2008 was 1.9% (11 of 582 patients) as opposed to expected prevalence of 5.2% (or 30 patients) based on National Health and Nutrition Examination Survey (NHANES) data using age and sex specific prevalence rates. [10]

    5.  Efficacy of Febuxostat vs Allopurinol for Gout ?

[11] 

 

References

1. Sultana T, Sultana T, Rahman MQ, Rahman F, Islam MS, Ahmed AN. Value of dysmorphic red cells and G1 cells by phase contrast microscopy in the diagnosis of glomerular diseases. Mymensingh Med J. 2011 Jan;20(1):71-7. PMID: 21240166.
2. Pollock C, Liu PL, Györy AZ, Grigg R, Gallery ED, Caterson R, Ibels L, Mahony J, Waugh D. Dysmorphism of urinary red blood cells--value in diagnosis. Kidney Int. 1989 Dec;36(6):1045-9. doi: 10.1038/ki.1989.299. PMID: 2689749.
3. https://www.eular.org/myUploadData/files/RA%20Class%20Slides%20ACR_Web.pdf.
4. Helin H, Korpela M, Mustonen J, et al. Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arthritis Rheum 1995;38(2):242–7.
5. Korpela M, Mustonen J, Helin H, et al. Immunological comparison of patients with rheumatoid arthritis with and without nephropathy. Ann Rheum Dis 1990;49(4): 214–8.
6. Horak P, Smrzova A, Krejci K, et al. Renal manifestations of rheumatic diseases. A review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2013;157(2):98–104.
7. Zhang CL, Feng J, Cao XX, Zhang CL, Shen KN, Huang XF, Zhang L, Zhou DB, Li J. Selection of Biopsy Site for Patients with Systematic Amyloidosis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2016 Dec 20;38(6):706-709. doi: 10.3881/j.issn.1000-503X.2016.06.013. PMID: 28065238.
8. Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe DJ, Bombardier C. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti‐rheumatic drugs for rheumatoid arthritis: A network meta‐analysis. Cochrane Database of Systematic Reviews. 2016(8).
9. Gaudry S, Hajage D, Martin-Lefevre L, Louis G, Moschietto S, Titeca-Beauport D, La Combe B, Pons B, De Prost N, Besset S, Combes A. The Artificial Kidney Initiation in Kidney Injury 2 (AKIKI2): study protocol for a randomized controlled trial. Trials. 2019 Dec;20(1):1-0.
10. Jebakumar A, Crowson C, Udayakumar D, Matteson E. Co-Existence of Gout in Rheumatoid Arthritis: It Does Happen! A Population Based Study.: 134. Arthritis & Rheumatism. 2012 Oct;64.
11. Huang X, Du H, Gu J, Zhao D, Jiang L, Li X, Zuo X, Liu Y, Li Z, Li X, Zhu P. An allopurinol‐controlled, multicenter, randomized, double‐blind, parallel between‐group, comparative study of febuxostat in C hinese patients with gout and hyperuricemia. International journal of rheumatic diseases. 2014 Jul;17(6):679-86.