Rheumatology Potpourri

Dr. Philip A. Baer

Seacourses Asia CME December 2017

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Learning Objectives

Diagnose and treat polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) while minimizing the adverse effects of steroid therapy.

Distinguish CPPD arthritis from other forms of crystal-induced arthritis, and manage CPPD arthritis appropriately.

Recognize different muscle problems associated with statin use, particularly necrotizing autoimmune myopathy (NAM).

Case 1 History

76 y.o. woman

Controlled hypertension and angina

Usually active

2 months history of aching pain in shoulders, upper arms, thighs

Morning stiffness 1 hour

Limited in daily activities

Appetite down; weight loss 8 pounds

Case 1 Exam & Labs

Exam:

Vital signs normal

OA hands

Tender proximal muscles

No weakness

Labs:

Hgb 106, MCV 88, ESR 65

CK normal, slightly low albumin

Musculoskeletal Pain in Older Patients

Think polymyalgia rheumatica when

• Age >60

• Proximal muscle myalgias and stiffness without specific muscle

weakness

• High ESR

• Anemia

Polymyalgia Rheumatica (PMR)

A clinical syndrome characterized by aching and stiffness of the shoulder

and hip girdle muscles affecting older patients, associated with an

elevated ESR, lasting over 1 month and responsive to low dose steroids

First description in 1888 (Bruce)

Barber suggested the present name in 1957

PMR: Epidemiology

Incidence in Canada: Approximately 50/100,000 patients over age 50/year

Predominant age: 60 or older. Incidence increases with age (rare under 50

years old)

Predominant gender: Female > Male (2:1)

PMR: Core Inclusion Criteria

PMR: Core Exclusion Criteria

Active infection

Active cancer

Active giant cell arteritis (GCA)

PMR: Features Suggesting GCA

Abrupt-onset headache (usually temporal) and temporal tenderness

Visual disturbance, including diplopia

Jaw or tongue claudication

Prominence, beading or diminished pulse on examination of the temporal artery

Upper cranial nerve palsies

Limb claudication or other evidence of large-vessel involvement

PMR: Other Diseases to Exclude

Other inflammatory rheumatic diseases

Drug-induced myalgia

Chronic pain syndromes

Endocrine disease

Neurological conditions, e.g. Parkinson’s disease

PMR: General Principles

PMR: Lab Evaluation

PMR: Initial Steroid Dose

PMR: Initial Therapy and Follow-up

A patient-reported global improvement of ≥70% within a week of commencing steroids is consistent with PMR, with normalization of inflammatory markers in 4 weeks

A lesser response should prompt the search for an alternative condition

The diagnosis of PMR should be confirmed on further follow-up. Follow-up visits should include vigilance for mimicking conditions

Consider low-dose ASA, CV risk assessment, and osteoporosis prophylaxis during follow-up

PMR: High Dose Steroids?

PMR: NSAIDs?

PMR: Steroid Tapering

PMR: Steroid Tapering

www.rheuminfo.com

PMR: Immunosuppressants?

PMR: Biologics?

PMR: Duration of Therapy

Usually 1–3 years of treatment, although some will require small doses of steroids beyond this.

Steroids may be stopped when the patient is asymptomatic from their inflammatory symptoms.

Isolated raised ESR or CRP is not an indication for continuing steroid therapy but may require investigation and referral.

Persistent pain may arise from co-existing OA and rotator cuff tears.

PMR: Therapy of Relapses

Relapse is the recurrence of symptoms of PMR or onset of GCA, and not just unexplained raised ESR or CRP

Treatment of relapse:

Clinical features of GCA: treat as GCA (usually oral prednisone 40–60mg daily)

Clinical features of PMR: increase prednisone to previous higher dose

Single i.m. injection of methylprednisolone 120mg can also be used

Further relapses: consider introducing DMARD therapy after two relapses

Resources

www.rheuminfo.com

www.rheuminfo.com

www.rheumatology.org

ACR/EULAR PMR Algorithm

Relationship between PMR & GCA

10-15% of patients with PMR have GCA

40-60% of patients with GCA have PMR

PMR

GCA

GCA PMR

Case 2: History

A 68-year-old man presents with complaints of diffuse

muscle pain, weakness, and total body fatigue. He

reports:

• Gradual onset over past 6 months

• Morning stiffness lasting 2 to 3 hours

• Difficulty with getting out of a chair and combing his hair

• Recent onset of right-sided headache

• Recent onset of jaw pain when eating

Case 2: Exam and Labs

Proximal muscle

tenderness without

objective weakness

Tender right temporal

scalp region

Normal visual acuity

Hgb 98 g/L

ESR 85

CK 32

Case 2: Question

Based on the clinical findings, what is the most

important next step?

A. Treat now with prednisone 5 mg bid, and observe

B. Schedule a temporal artery biopsy for tomorrow morning

and use the results to determine whether prednisone will

be used

C. Start an NSAID at maximal dose

D. Treat now with prednisone at 40 to 60 mg per day and

schedule temporal artery biopsy in the next few days

Case 2: Answer

D. Treat now with prednisone at 40 to 60 mg per day and

schedule temporal artery biopsy for next week

• Sudden visual loss may occur in GCA

• Visual loss occurs in 1/3 of untreated patients

• The visual loss is usually not reversible

Nordberg E, et al. Rheum Dis Clin North Am. 1995;21:1013–1026.

For probable temporal arteritis:

TREAT NOW! BIOPSY LATER!

Biopsy as soon as possible

Hunder GC. Primer on Rheum Dis. 11th edition. 1997:294–300.

Don’t Hesitate

Elastic stain of temporal artery in GCA:

Disruption of elastic lamina and narrowing of the lumen

GCA - granulomatous inflammation and

multinucleated giant cells

DIAGNOSIS OF GCAHalo sign

GCA: Dilated Temporal Artery

GCA: Optic Atrophy

Giant Cell Aortitis

Risk of Thoracic Aortic Aneurysm in GCA: 15%

GCA: Steroid Therapy

GCA without visual symptoms:

Prednisone 20-40 mg daily for 8 weeks

Reduce by 5 mg q3-4 weeks to 10 mg daily

Then treat as PMR

GCA with possible or definite visual symptoms:

Prednisone 40-80 mg daily for 8 weeks

Reduce over 4 weeks to 20 mg daily

Then treat as uncomplicated GCA

GCA: Other Therapies

Methotrexate, azathioprine, and other immunosuppressive drugs have been used to limit dosage and duration of corticosteroid therapy.

No clear-cut data suggest that any of these drugs is superior to corticosteroid therapy.

Anti-TNF therapy with infliximab failed in GCA studies.

Anti-IL6 therapy with tocilizumab is now approved for GCA (USA)

Resources

www.rheuminfo.com

www.rheumatology.org

Case 3: History

80 y.o. woman, independent, lives alone

Occasional aches in knees, wrists

Acute swelling of right knee with pain, local warmth and redness

Prior episode in L wrist and hand

No trauma

Low grade fever, no recent infection

X-ray: Chondrocalcinosis

Aspiration: Bloody fluid

Case 3: Labs

CBC: WBC 14,000 with left shift

eGFR 55, uric acid 200

Calcium/PO4/Alkaline Phosphatase normal

Synovial fluid:

WBC 15,000

Thin, bloody fluid

Gram stain/culture negative

CPPD Disease: Crystals

Calcium

pyrophosphate

crystals

Ordinary, polarized,

and compensated

polarized light

microscopy

CPPD Disease: Classification

Chondrocalcinosis

Acute Pseudogout

Pyrophosphate Arthropathy

Chondrocalcinosis

Chondrocalcinosis: Epidemiology

Elderly – Radiographic evidence:

65-74yr 15%

75-84yr 36%

>84yr 50%

Male = Female

No geographic or racial predisposition

CPPD Disease: Clinical Features

Acute synovitis

Monoarthritis

Polyarticular: rare

Any joint: commonest in knee

: wrist, shoulder, ankle

Rapid onset of pain, stiffness and swelling (6-24 hrs)

Low-grade fever common

CPPD: Pathophysiology

CPPD Disease: Triggers

CPPD Disease: Diagnosis

Observation of calcium pyrophosphate dihydrate crystals

in synovial fluid leukocytes in a patient with acute

synovitis

CPPD crystals are

Rhomboid

Positively birefringent

Synovial Fluid Crystals

CPPD Disease: Treatment Principles

No definitive therapy for prevention

Goals in managing acute attacks

reduce symptoms

identify and treat any associated or triggering illnesses

encourage mobility as inflammation subsides

Acute CPPD Disease:

Treatment Options

Joint aspiration

NSAIDs

Colchicine (not as effective as for gout)

Steroids (not as effective as for gout)

oral

intra-articular

Analgesics

Acute CPP Crystal Arthritis:

Treatment Options

Chronic Pyrophosphate Arthropathy:

Clinical Features

Findings mimic any type of arthritis

Terminology -Pseudo RA

-Pseudo OA

-Pseudo neuropathic joint disease

Distinguishing points-Pattern of involvement

-Inflammation

-Superimposed pseudogout

Chronic Pyrophosphate Arthropathy:

Epidemiology and Distribution

Elderly

Female

Large/medium joints

Knees

Wrists, shoulders, elbows

Hips, midtarsal, MCPs (2+3)

Knee radiograph showing hypertrophic OA features. Note prominent patello-femoral involvement, typical of pyrophosphate arthropathy.

Chronic CPPD Arthropathy:

Treatment Options

Steroid injection

Colchicine

NSAID + PPI

Oral low dose steroids

Hydroxychloroquine

Methotrexate

Surgery to preserve function

Resources

www.rheuminfo.com

www.rheumatology.org

www.nejm.org June 30, 2016

Muscle Fibre: Normal Anatomy

Statin-induced Myopathy

▪ 1.5-3% of statin users in RCTs and 10-13% of participants enrolled in prospective clinical studies develop myalgias; rates of myositis lower (~0.1-0.5%) & dose-dependent

▪ Mean duration of statin therapy before onset of symptoms: 6 months

▪ Mean duration of myalgias after stopping statin therapy: 2 months

Statin-induced Myopathy: Questions

▪ What if a patient develops a myopathy after several years of taking a statin?

▪ Not likely to be statin-induced. 2/3 develop symptoms within 6 months of starting therapy, however it is still possible to develop muscle symptoms at ANY time during treatment.

▪ Are some statins more likely to cause muscle damage? Which ones?

▪ Lipophilic statins (for example, simvastatin, atorvastatin, lovastatin) are more likely to produce muscular effects than are relatively hydrophilic agents (such as pravastatin, rosuvastatin, and fluvastatin). Lipophilic compounds are more likely to penetrate into muscle tissue, enhancing the potential for myotoxic effects.

Statin-Induced Myopathy: Management

▪ Significant muscle symptoms: discontinue statin

▪ Asymptomatic but with CK>10x ULN: discontinue statin

▪ Rhabdomyolysis: no statins at any time due to risk of recurrence

▪ If patient requires a statin but muscle toxicity other than rhabdomyolysis: discontinue statin

▪ Once symptoms have resolved and the CK has returned to baseline, can try pravastatin or fluvastatin with careful monitoring

Statin-induced Myopathy: Questions

▪ When are EMG or muscle biopsy necessary in suspected statin myopathy?

▪ EMG and muscle biopsy are often done in atypical cases of statin induced myopathy. These would include those patients with persistent muscle pain after D/C of statin or with persistent, worsening weakness after D/C of statin, or persistently elevated CK long after D/C of statin (several months).

▪ Electromyography findings are commonly reported to show myopathic changes, usually in the proximal muscles, in agreement with clinical findings.

▪ Muscle pathology in statin induced myopathy is nonspecific, with necrosis, degeneration, and regeneration of fibres and phagocytic infiltration.

▪ Is Coenzyme Q10 helpful?

▪ Unclear. In one small RCT, 41 patients taking statins who had muscle pain received either coenzyme Q10 or vitamin E. After one month of treatment, 18 of 21 patients taking coenzyme Q10 reported improvement in muscle pain, compared with three of 20 taking vitamin E (P<0.001).

Statin-associated necrotizing myopathy

▪ Myopathy which persists or progresses after stopping statin

▪ Linked to autoantibodies against HMG-CoA reductase

▪ Distinct muscle biopsy findings:

▪ Macrophagocytic infiltrate engulfing necrotic muscle fibers

▪ Responds to immunosuppressant therapy

Necrotizing Autoimmune Myositis

Statin-associated necrotizing myopathy (NAM)

Necrotic muscle fibre undergoing myophagia WITHOUT inflammatory infiltrate (no lymphocytes or

neutrophils) & excessive variability of muscle fibre size. The absence of inflammation distinguishes this

entity from the idiopathic inflammatory myopathies.

Statin-associated necrotizing myopathy (NAM)

EMG findings (All Inflammatory Myopathies)

▪ Fibrillation, PSWs, CRDs at rest

▪ Increased insertional activity

Myositis: Non-medical therapies

▪ Physiotherapy and Occupational Therapy

▪ Aerobic exercise programs after the acute phase

▪ Prevent contractures

▪ May help with steroid side effects (weight gain, osteoporosis, type 2 fibre atrophy)

▪ Speech therapy

▪ Especially if concomitant dysphagia

Pharmacologic Treatment of Myositis

Myositis: Resources

Myositis: Resources

Myositis: Resources

Myositis: Resources

Statin-Associated Autoimmune Myopathy: Approach

Statin-Associated Autoimmune Myopathy: Approach

PEARLs: Rheumatology Potpourri

Think of PMR if over age 65 with proximal joint/muscle pain

Start high dose steroids immediately if GCA suspected to prevent visual loss

Think CPPD in older women with acute monoarthritis and aspirate joint if

possible for crystal analysis

Consider autoimmune statin-induced myopathy (NAM) in patients where

myopathy persists after stopping statins

Barriers to Change: Rheum. Potpourri

PMR/GCA: Difficulty distinguishing flares from OA and other comorbidities,

leading to higher than required use of steroids

CPPD: Confusion with gout and with cellulitis

Statin-induced NAM: Difficulty recognizing this syndrome given so many

patients on statins present with myalgias and high CKs

Questions ?