"Matrix Metalloproteinases 7 and 9 in Rheumatoid Arthritis Patients With Interstitial Lung Disease"

Introduction Rheumatoid arthritis (RA) is a systemic inflammatory disorder most commonly affects the joints, causing progressive, symmetric, erosive destruction of cartilage and bone, usually associated with autoantibody production. Although joint disease is the main presentation, there are several extra-articular manifestations including subcutaneous nodule formation, vasculitis, inflammatory eye disease and lung disease. Of these manifestations, lung disease is a major contributor to morbidity and mortality.

Clinically significant interstitial lung disease (ILD) occurs in approximately 5% to 15% of people with rheumatoid arthritis (RA).

The prognosis after RA-ILD diagnosis is poor, with the observed median survival being between 3 and 8 years. For the poor prognosis and emerging immunomodulatory and antifibrotic treatment options, there is substantial interest in identifying RA-ILD at an early stage.

Clinical and epidemiologic studies have identified older age, male sex, cigarette smoking, higher RA disease activity, RA autoantibodies, and genetic factors as risk factors for RA-ILD.

In addition to autoantibodies and select genetic variants, other categories of candidate biomarkers evaluated in RA-ILD to date have included extracellular matrix proteins, cytokines and chemokines, lung epithelial-related proteins, tumor markers, and growth factors.

Matrix metalloproteinases (MMPs) are a family of enzymes involved in a number of physiologic processes, including extracellular matrix degradation and remodeling, inflammation, and immunity.

Rheumatoid arthritis is a rheumatic autoimmune disease that causes not only joint destruction but also vascular (microvascular and macrovascular) damage, thus increasing morbidity and mortality. Microvascular involvement is present from the early stage of RA and can be seen even in the absence of macrovascular damage. Rheumatoid vasculitis, a serious complication of rheumatoid arthritis, can occur in severe forms of the disease.

Aim of the study

• To assess the matrix metalloproteinase 7 and 9 (MMPs 7,9) as a screening tool for interstitial lung disease in rheumatoid arthritis patients and to assess for correlation with RA-disease activity.
• To investigate whether certain MMPs could be potential biomarkers reflecting the lung fibrotic process in RA patients.
• To assess the capillaroscopy changes in RA and RA-ILD.
• To detect correlation between MMPs and capillaroscopic changes in RA patients. Patients and Methods This case control study will be done at Rheumatology Department, Assiut University Hospital. It will include RA patients fulfilling the American College of Rheumatology and European League against Rheumatism (ACR / EULAR) 2010 classification criteria.

All patients will be followed by treating rheumatologists per routine clinical care.

The patients will be divided into 3 groups:

Group (1): RA patients with ILD. Group (2): RA patients without ILD Group (3): Healthy controls

All patients will be subjected to:

A- Complete medical history:

Detailed medical history will be taken including demographic data (age, sex, disease duration, morning stiffness, joint involvement, smoking, habits of medical importance), articular and extra articular manifestations. Detailed respiratory manifestations as (dyspnea, cough, chest wheeze, others)

B- Clinical examination:

• General and local rheumatological examination.
• Local chest examination (inspection, palpation, percussion, auscultation).
• Assessment of RA disease activity using DAS 28 ESR.

DAS 28 score include 28 joints including shoulders, elbows, wrists, metacarpophalangeal, and proximal interphalangeal of both hands, thumb interphalangeal joints and knees.

DAS 28 score includes tender joint count (0:28), swollen joint count (0:28) ESR level, general health assessment.

Score interpretation <2.6 suggests disease remission. 2.6-3.2 suggests low disease activity 3.2-5.1 suggests moderate disease activity >5.1 suggest high disease activity

C- Laboratory investigations:

Peripheral venous blood samples for CBC, C-reactive protein, erythrocyte sedimentation rate, antibody status.

D- Radiology and PFT:

PFTs and HRCT chest patterns will be done for patients.

E- MMP measurement:

Serum samples will be collected at the time of registry enrollment, MMP 7 and 9 concentrations will be measured using enzyme-linked immunosorbent assays.

F. The capillaroscopy procedure

• Handwashing: Ensure fingers are clean. Patients washed their hands with antibacterial soap and water or wiped them lightly with an alcohol sponge.
• Patient acclimatization: To relax the patients before the test, they sat at room temperature (20-25 °C) for 15-20 min. Depending on the outside temperature, hands were positioned at heart level.
• An immersing oil was applied between the skin and lens to enhance light penetration and improve image quality.
• Capillaroscopy contact: The capillaroscopy made direct contact with the patient's nail fold. To reduce reflections, the contact angle and direction were adjusted. A sharp image of the capillary branches was obtained by manually adjusting the focusing system and using the camera head.
• Image capture: Four consecutive images (1 × 1 mm in size) were taken from the middle of the nail fold at 200× magnification.

Typically, the 2nd, 3rd, 4th, and 5th fingers were examined, excluding thumbs due to poor observation and frequent micro trauma. At least four images were taken per finger to maximize visualization. The most precise evaluations were from the 4th and 5th fingers due to higher skin transparency.

• Image evaluation: After assessing different microvascular abnormalities, stored images were compared and analyzed by an experienced observer.

Inclusion criteria

• 1- Age >18. 2- RA diagnosis according (ACR / EULAR) 2010.

Exclusion criteria

• Age <18 years.
• Other connective tissue diseases (systemic sclerosis, systemic Lupus and Mixed connective tissue disease)
• Malignancy
• Another chest presentation
• Patient refuse
• Patients with recent nail trauma
• Patients with heavy manual activities
• Poor nailfold hygiene
• Congestive heart failure
• Individuals unable to cooperate during the nailfold capillaroscopic examination.