Approach to a Patient with Suspected Connective Tissue Disorder

Connective tissue diseases can be difficult to diagnose but early diagnosis is essential to initiate effective treatment and prevent/minimize tissue injury. The key point is to be able to recognize the clinical features which prompt the question “Could this patient have a connective tissue disease?” The spectrum of clinical manifestation is wide with skin and joints affected most frequently. It is of paramount importance to perform a detailed history and physical examination and laboratory testing which includes various highly sensitive serologic tests.

History-taking and physical examination

1. Nonspecific symptoms
   Patients with CTD can present with nonspecific symptoms such as fever, myalgia, arthralgia, malaise, fatigue and weight loss. In patients with systemic lupus erythematosus (SLE), up to 60% will present with fever during the disease course or as a manifestation of their flares; however, with inflammatory arthritis such as RA, fever is less likely.
2. Skin and mucous membranes
   ( a ) Rash
   Rashes can occur in several of the connective tissue diseases. Malar rash which is photosensitive and sparing the nasolabial fold is characteristics of SLE .SLE can also present with bullous or discoid lesion .The heliotrope rash of dermatomyositis (DM) is purplish in color, located in the periorbital area, especially over the upper eyelid. The gottrons papules are erythematous or violaceous lesions located over the bony prominence metacarpophalyngeal joints and proximal interphalyngeal joints. These are pathognomonic features seen in dermatomyositis.

   

(b) Alopecia and oral ulcer

Alopecia or hair loss and oral ulcers are frequently seen in SLE.

(c) Oral dryness

Oral dryness is a feature of Sjogren syndrome.

(d) Skin thickening, telangiectasia

It is a primary feature of systemic sclerosis and skin thickening usually begins in the fingers(sclerodactyly), feet, and face and then may progress proximally especially in those with the diffuse cutaneous subtype. Telangiectasia of varying numbers can be identified on the hands, anterior chest, and face.

(d) Palpable purpura

It is a manifestation of primary vasculitis or secondary to connective tissue disease especially SLE and reflects disease activity.

3.  Raynaud’s phenomenon (RP)
This triphasic change in colour of the fingers from white,blue to red is commonly seen in systemic sclerosis (SSc) and mixed connective tissue disease (MCTD). This secondary type of RP is associated with older age of onset >35 years, asymmetrical attacks, digital ulcers, detection of autoantibodies, abnormal nail fold capillaries when looking with nail fold microscopy. It can progress to irreversible tissue injury with ulceration, scarring, or gangrene

4. Eyes
The commonest symptom is of dry, gritty eyes, occurring in patients with Sjögren’s syndrome.

5. Musculoskeletal symptoms
Involvement of the musculoskeletal system is common. Duration of arthritis, presence and duration of early morning stiffness, number of joints involved and their pattern of important consideration. In inflammatory arthritis, morning stiffness is prolonged (i.e., more than one hour) and activity may improve symptoms while rest way worsen the pain and fatigue is usually significant. Unlike rheumatoid arthritis, arthritis seen in SLE, MCTD and Sjogren syndrome is usually non erosive and non-deforming. Proximal muscle weakness occurs in inflammatory myopathies such as polymyositis and dermatomyositis. The characteristic feature of muscle weakness in inflammatory myopathies is sparing ofextraocular and facial muscle.

6. Cardiorespiratory
Patients with SSc are at increased risk of interstitial lung disease, pulmonary hypertension and pericarditis. Pericardial effusion is occasionally seen in SLE. Therefore, if not volunteered, questions should be asked about all cardiorespiratory symptoms.

7. Gastrointestinal
Swallowing difficulty, often with reflux symptoms, is very common in patients with SSc. These patients may also experience a wide range of GI symptoms including: alteration in bowel habit; diarrhea may reflect bacterial overgrowth; constipation; and colonic dysmotility. Abdominal pain can (rarely) be caused by mesenteric ischaemia, which can occur in patients with mesentericvasculitis especially SLE.

8. Renal
SLE with renal involvement can present with generalized edema and frothy urine.

9. Neuropsychiatric
SLE can be associated with involvement of peripheral, central, and autonomic nervous systems, cognitive impairment and psychiatric disturbance. Mononeuropathy, mononeuritis multiplex and cranial neuropathy can be seen in CTD.

Laboratory investigations

1. CP
   Anaemia is common in CTD. It is usually normochromomic normocyctic anaemia due to chronic inflammation.The use of NSAID may cause hemolytic and iron deficiency anemia. Lymphopenia and thrombocytopenia may present in SLE.
2. Acute phase reactants
   Elevation of ESR and CRP are usually seen in CTD which indicates persistent inflammation. CRP level in SLE are either normal or modestly elevated if associated with serositis.
3. Urine
   All patients with a suspected or proven diagnosis of connective tissue disease should have their urine tested. The presence of active sediments (RBC, WBC, casts) and or proteinuria indicates renal involvement in the form of glomerulonephritis.
4. Renal and liver function tests
   Many patients with connective tissue disease have renal or (less frequently) hepatic involvement which may be asymptomatic.
5. Muscle enzymes
   In suspected case of myositis, ALT, AST, LDH, CK should be ordered. Creatine phosphokinase (CK) is most commonly used in diagnosis and response to treatment.
6. Antinuclear antibodies (ANA)
   ANA is an antibody against a nuclear component of a cell. Although nearly all patients with SLE have positive ANA titers, it is also noteworthy that most patients with a positive titer may not have SLE. The most accurate test for ANA is via indirect immunofluorescence assay.Once a patient has a positive ANA titer, it is rarely helpful to repeat the test; ANA levels fluctuate and do not reflect disease activity. Different autoantibodies manifest as different ANA patterns.

AntiJo-1antibody is seen in patient with inflammatory myopathies and interstitial lung disease .Note- Isolated anti-DFS70 (Dense fine speckled) without concomitant Autoimmune-specific autoantibodies represent a potentially important biomarker that can be clinically used to discriminate autoimmune disease from non-autoimmune related patients in ANA positive individuals.

Further reading

1. Ali,Y. (2018)Rheumatologic Tests: A Primer for Family Physicians, American Family Physician, 3(98), 164-170
2. Gundı´n,S.,Irure-Ventura,J.,Asensio,E.,Ramos,D.,Mahler,M.,Martınez-Taboada,V., Lo´pez ]-Hoyos,M. (2016) Measurement of anti-DFS70 antibodies in patients with ANA-associated autoimmune rheumatic diseases suspicion is cost-effective. Autoimmune Highlights,7,10-16
3. Herrick, A. (2011)General approach to the assessment of patients with a suspected connective tissue disease. In :Gordon, C. Connective Tissue Diseases.1sted.Oxford; Atlas Medical Publishing Ltd,pp-1-16
4. Meehan,R.T.(2015) History and physical examination. In: West,S.J. Rheumatology Secrets. 3rded.USA.Mosby,pp-41-47
5. Patel,L., Gizinski, A,M(2018). A Primer on Rheumatologic Laboratory Tests ,What They Mean and When to Order Them ,Prim Care Clin Office Pract ,45 , 181–191
6. Ventura,J.,Reid,P. and Jan,R. (2018) Approach to Patients with Suspected Rheumatic Disease, Prim Care Clin Office Pract ,45 , 169–180
7. Waklu, A., Sahoo, R.R (2018). Approach to a patient with suspected connective tissue disorder. In: Chaturvedi, V. et al. Manual of Rheumatology. 5th ed.NewDehli; CBS publishers and distributors Pvt Ltd.pp125-129